This document discusses metabolic activation of natural products at the Dalian Institute of Chemical Physics, Chinese Academy of Sciences. It provides examples of their research on the metabolic activation of rutaecarpine, evodiamine, pyrrolizidine alkaloids, and strychnine. For each compound, it identifies the cytochrome P450 enzymes involved in bioactivation and describes efforts to characterize reactive metabolites through trapping and protein adduct formation. The research aims to better understand metabolism-mediated toxicity of natural products.
Tio2 photocatalysis uses titanium dioxide to generate reactive oxygen species like hydroxyl radicals when exposed to light that can directly and indirectly destroy bacteria, viruses, and other microorganisms by disrupting their cell membranes and intracellular components, providing highly effective and long-lasting sterilization. It has advantages over traditional antiseptics in not requiring heat, producing fewer toxic byproducts, and continuing to decompose pathogens even after initial killing.
The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and a primary or secondary amine. This results in an aminoalkylation and formation of a β-aminocarbonyl compound known as a Mannich base. Modifications using preformed Mannich bases and reactive substrates extend the scope and selectivity of the reaction. The Mannich reaction has wide applications in organic synthesis and for producing natural and medicinal compounds.
This document discusses alkaloids, which are nitrogenous plant compounds that have physiological effects. It describes their characteristics, sources, uses, and importance in pharmacy. Key points include: alkaloids are bitter and derived from amino acids; sources include various plant families; uses include analgesic, narcotic, and mydriatic effects; important alkaloids include morphine, codeine, nicotine, and atropine. Tests are outlined to identify the presence of alkaloids. The document also classifies and describes important alkaloid groups such as tropane and solanaceous alkaloids.
Alkaloids are nitrogen-containing organic compounds found in plants that are typically basic and have physiological effects. While traditionally defined as being derived from plants, some alkaloids come from other organisms. Alkaloids have a variety of structures but generally contain heterocyclic rings with nitrogen atoms. They can exist in different forms including as free bases, salts, and glycosides. Many plants produce alkaloids as a protective mechanism against herbivores.
This document discusses several types of alkaloids, including their sources, chemistry, and pharmacological activities. It describes true alkaloids that originate from amino acids, such as atropine, morphine, and reserpine. Pseudoalkaloids are also mentioned, which do not originate from amino acids and include compounds like caffeine. The mechanisms of action, indications, and important properties are summarized for several major alkaloids - atropine, quinine, morphine, papaverine, and ephedrine. Their isolation sources and chemical structures are also outlined.
Metabolic Pathways in Higher Plants and their DeterminationDr. Siddhi Upadhyay
a) Brief study of basic metabolic pathways and formation of different secondary metabolites through these pathways- Shikimic acid pathway, Acetate pathways and Amino acid pathway.
b) Study of utilization of radioactive isotopes in the investigation of Biogenetic studies.
This document defines alkaloids as basic, heterocyclic nitrogenous compounds derived from amino acids that are physiologically active. However, it notes some deviations from this definition, including that some alkaloids are not basic, do not contain heterocyclic nitrogen, or are derived from sources other than plants. It then provides qualitative chemical tests to identify alkaloids and discusses their physical and chemical properties, distribution in plants, extraction methods, classification, and biosynthesis.
Tio2 photocatalysis uses titanium dioxide to generate reactive oxygen species like hydroxyl radicals when exposed to light that can directly and indirectly destroy bacteria, viruses, and other microorganisms by disrupting their cell membranes and intracellular components, providing highly effective and long-lasting sterilization. It has advantages over traditional antiseptics in not requiring heat, producing fewer toxic byproducts, and continuing to decompose pathogens even after initial killing.
The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and a primary or secondary amine. This results in an aminoalkylation and formation of a β-aminocarbonyl compound known as a Mannich base. Modifications using preformed Mannich bases and reactive substrates extend the scope and selectivity of the reaction. The Mannich reaction has wide applications in organic synthesis and for producing natural and medicinal compounds.
This document discusses alkaloids, which are nitrogenous plant compounds that have physiological effects. It describes their characteristics, sources, uses, and importance in pharmacy. Key points include: alkaloids are bitter and derived from amino acids; sources include various plant families; uses include analgesic, narcotic, and mydriatic effects; important alkaloids include morphine, codeine, nicotine, and atropine. Tests are outlined to identify the presence of alkaloids. The document also classifies and describes important alkaloid groups such as tropane and solanaceous alkaloids.
Alkaloids are nitrogen-containing organic compounds found in plants that are typically basic and have physiological effects. While traditionally defined as being derived from plants, some alkaloids come from other organisms. Alkaloids have a variety of structures but generally contain heterocyclic rings with nitrogen atoms. They can exist in different forms including as free bases, salts, and glycosides. Many plants produce alkaloids as a protective mechanism against herbivores.
This document discusses several types of alkaloids, including their sources, chemistry, and pharmacological activities. It describes true alkaloids that originate from amino acids, such as atropine, morphine, and reserpine. Pseudoalkaloids are also mentioned, which do not originate from amino acids and include compounds like caffeine. The mechanisms of action, indications, and important properties are summarized for several major alkaloids - atropine, quinine, morphine, papaverine, and ephedrine. Their isolation sources and chemical structures are also outlined.
Metabolic Pathways in Higher Plants and their DeterminationDr. Siddhi Upadhyay
a) Brief study of basic metabolic pathways and formation of different secondary metabolites through these pathways- Shikimic acid pathway, Acetate pathways and Amino acid pathway.
b) Study of utilization of radioactive isotopes in the investigation of Biogenetic studies.
This document defines alkaloids as basic, heterocyclic nitrogenous compounds derived from amino acids that are physiologically active. However, it notes some deviations from this definition, including that some alkaloids are not basic, do not contain heterocyclic nitrogen, or are derived from sources other than plants. It then provides qualitative chemical tests to identify alkaloids and discusses their physical and chemical properties, distribution in plants, extraction methods, classification, and biosynthesis.
This document provides an overview of alkaloids. It defines alkaloids as basic, nitrogen-containing compounds found in plants. Alkaloids are classified in several ways, including by their chemical structure, biosynthetic pathway, pharmacological effects, and the taxonomic plant family they are found in. Methods for isolating and purifying individual alkaloids from crude mixtures are also described. The molecular modification of opioid alkaloids like morphine to enhance their medical usefulness is discussed. Finally, the document outlines some of the biological activities that alkaloids can have in plants and humans, ranging from protective effects to therapeutic applications to toxicity.
1) Alkaloids are nitrogen-containing plant compounds that are mainly extracted from families like Solanaceae, Rubiaceae, and Liliaceae.
2) They have important pharmacological actions and many modern drugs are derived from plant alkaloids, such as morphine, quinine, and reserpine.
3) Alkaloids are usually colorless solids but some are liquids, and they are basic compounds that form salts with acids which aids in their extraction from plants.
Alkaloids are nitrogen-containing organic compounds found in plants that have strong physiological effects. True alkaloids are derived from amino acids and have nitrogen in a heterocyclic ring, while other classes of alkaloids like pseudoalkaloids and protoalkaloids vary in their origin and structure. Alkaloids serve functions like protecting plants from herbivores and can have pharmacological actions like analgesic, stimulant, or respiratory effects when consumed. They are classified based on their chemical structure and pharmacological properties.
Natural chemistry Structure elucidation of EmetineAnam Ilyas
The document discusses the structure elucidation of the alkaloid emetine, which is derived from the dried roots of Ipecacuanha plant. It summarizes that emetine has the molecular formula C29H40N2O4 and contains two 6,7-dimethoxyisoquinoline units joined to a C5H8 fragment. The structure of emetine was proved through its total synthesis. Spectroscopic techniques such as 1H NMR, 13C NMR, and mass spectrometry were used to further characterize the structure of emetine.
Structure Elucidation of Reserpine (M. Pharm)MohdShafeeque4
1. Reserpine is an indole alkaloid isolated from the roots of Rauvolfia serpentina that has been used medicinally as a treatment for hypertension and anxiety.
2. The structure of reserpine was elucidated through chemical degradation studies that identified its core skeleton and functional groups.
3. Key evidence for reserpine's structure included identification of its molecular formula, hydrolysis products, and synthesis from simpler precursors. Together, these studies showed reserpine has the structure of a C-glycoside consisting of a reserpic acid moiety linked as a diester to a 3,4,5-trimethoxybenzoic acid group.
The document discusses alkaloids, which are naturally occurring chemical compounds that mostly contain basic nitrogen atoms. It covers their classification (including by biosynthesis, chemistry, pharmacology, and taxonomy), isolation, purification, biological activity, and structural determination. Methods for structural elucidation include functional group determination, degradation reactions like Hoffman exhaustive methylation, oxidation, and physical methods like spectroscopy. Specific alkaloids discussed include morphine, emetine, and reserpine.
This document summarizes key information about alkaloids. It discusses that alkaloids are nitrogen-containing organic compounds found in plants that have physiological effects. Common alkaloids like morphine, codeine, caffeine, and cocaine are mentioned. The characteristics, occurrence in plants, classification based on chemical structure, and examples of alkaloids used in modern medicine are described. The biosynthesis pathways of morphine and codeine from opium poppy are also summarized.
2) study of utilization of radioactive isotopes in the investigation of bioge...SONALI GADGE
1. Radioactive isotopes (radioisotopes) emit radiation and are unstable, while stable isotopes do not emit radiation. Radioisotopes like 3H, 14C, and 35S are used as tracers in biological investigations.
2. Tracer techniques involve growing plants in radioactive compounds like 14CO2 and then analyzing plant parts over time to determine the sequential formation of metabolites. Double and multiple labelling can provide evidence of biochemical incorporation pathways.
3. Applications of tracer techniques include studying terpenoid biosynthesis, the pathways of alkaloids and coumarins, and determining how plants uptake nutrients like calcium and phosphorus from soil.
Alkaloids are a group of naturally occurring chemical compounds that mostly contain basic nitrogen atoms.
The term alkaloid was coined by Meissner, a German pharmacist, in 1819.
Alkaloids are cyclic organic compounds containing nitrogen in a negative state of oxidation with limited distribution among living organisms.
Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions.
Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).
Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric.
Many alkaloids dissolve poorly in water but readily dissolve in organic solvents.
Most alkaloids have a bitter taste or are poisonous when ingested.
This document provides an overview of alkaloids, including their classification, isolation, purification, and structural determination. Alkaloids are basic, nitrogen-containing plant compounds that act as chemical defenses. They are classified into different groups based on their chemical structure. Methods for isolating alkaloids from plants and purifying them are described. The document also discusses molecular modification of alkaloids to develop drugs and techniques used to determine alkaloid structures, such as degradation, spectroscopy, and X-ray analysis. Ephedrine is given as an example alkaloid whose structure was determined.
The document discusses the tracer technique, which involves incorporating radioactive isotopes into plant metabolites to trace biosynthetic pathways. It defines the technique and explains that radioactive isotopes like carbon-14 and hydrogen-3 are commonly used. The summary describes some key applications of the technique, like tracing the pathway from phenylalanine to the cyanogenic glycoside prunasin, and determining the location and quantity of compounds containing a radioactive tracer like glucose. It also lists some requirements for the technique, such as using a sufficient starting concentration of the tracer and ensuring it is involved in the relevant synthesis reactions.
This document provides information about natural products and terpenoids. It begins by defining natural products and describing their sources from plants, microbes, and animals. It then discusses the history of isolating and identifying pure natural compounds in the 18th-19th centuries. The rest of the document focuses on terpenoids, including their classification, isolation, properties, and structure elucidation. Specific terpenoids like myrcene, geraniol, and citral are discussed as examples.
Alkaloids: Introduction, Property and classification OP VERMA
Alkaloids are major secondary metabolites reported in higher plants. In this PPT I have covered Introduction, Property, Clarification and identification tests.
Synthesis of schiff base complexes and their biological studies presentationShafqat Ali
The document discusses the synthesis of Schiff base ligands and their metal complexes, and characterization of the compounds. It then examines the biological activities of some complexes, including their ability to interact with DNA through intercalation, and inhibition of fungal growth through antifungal testing. The goal was to enhance knowledge of Schiff base metal complexes and investigate their potential biological applications.
Definition, Classification, chemical test, properties , uses, Distribution and occurrence, Extraction isolation, chromatography methods of purification,Function of alkaloids.
This document discusses alkaloids found in plants. It begins by defining alkaloids and their properties, including that they are basic compounds derived from plants and contain nitrogen. It then covers the history of alkaloid isolation, distribution in different plant families, and classification based on chemical structure. The document focuses on the variety of alkaloids and systems used for their classification. It provides examples of different alkaloid skeletal structures and the plant families that contain them.
These are the organic products of natural or synthetic origin which are basic in
nature & contain one or more than one nitrogen atoms, normally of heterocyclic nature &
possess specific physiological actions on human or animal body, when used in small quantites.
The term is derived from the word ‘alkali-like’ & hence they resemble some of characters
of naturally occuring amines.
The term is derived from the word ‘alkali-like’ & hence they resemble some of
characters of naturally occuring amines.
- Alkaloids are basic nitrogenous plant compounds with physiological effects. They contain heterocyclic nitrogen structures derived from amino acids.
- Atropine is an alkaloid obtained from plants like belladonna. It acts as an anticholinergic and is used to treat conditions like nausea, vomiting, Parkinson's disease, and as a pre-anesthetic.
- Reserpine is obtained from Rauwolfia serpentina and works by depleting catecholamines. It is used to treat psychosis, anxiety, hypertension, and aggression.
- Ephedrine is a sympathomimetic alkaloid obtained from Ephedra that stimulates alpha and beta receptors. It is
The document discusses alkaloids, which are basic nitrogenous plant compounds that are physiologically active. It defines alkaloids and describes their distribution in plants, forms, nomenclature, extraction and classification. Key points include that alkaloids are found mainly in dicots and families like Apocynaceae, with properties like being crystalline solids, bitter taste, and soluble in organic solvents but not water. Common tests for alkaloids are Mayer's, Dragendorff's, Wagner's and Hager's tests. Alkaloids are classified based on their biogenetic pathway, plant source, basic chemical skeleton or type of amine group.
The Mitsunobu reaction allows the conversion of alcohols to various functional groups using trialkyl/triaryl phosphine and dialkyl azodicarboxylate reagents. It proceeds via an oxidation-reduction mechanism. Common applications include esterification, etherification, and N-alkylation reactions. Recent advances have focused on replacing conventional reagents to improve selectivity and yields. The Mitsunobu reaction has been widely used in the synthesis of natural products and pharmaceuticals.
This document summarizes phase 1 reactions in drug metabolism. Phase 1 reactions include oxidative, reductive, and hydrolytic reactions. Oxidative reactions involve the oxidation of aromatic carbons, olefinic carbons, benzylic carbons, allylic carbons, carbon atoms to carbonyl/imine groups, aliphatic carbons, alicyclic carbons, and carbon-heteroatom systems. Reductive reactions include the reduction of aldehydes, ketones, nitro compounds, and azo compounds. Hydrolytic reactions involve ester and amide hydrolysis. The objectives of phase 1 reactions are to increase hydrophilicity, reduce stability, and facilitate conjugation in phase 2 reactions
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
This document provides an overview of alkaloids. It defines alkaloids as basic, nitrogen-containing compounds found in plants. Alkaloids are classified in several ways, including by their chemical structure, biosynthetic pathway, pharmacological effects, and the taxonomic plant family they are found in. Methods for isolating and purifying individual alkaloids from crude mixtures are also described. The molecular modification of opioid alkaloids like morphine to enhance their medical usefulness is discussed. Finally, the document outlines some of the biological activities that alkaloids can have in plants and humans, ranging from protective effects to therapeutic applications to toxicity.
1) Alkaloids are nitrogen-containing plant compounds that are mainly extracted from families like Solanaceae, Rubiaceae, and Liliaceae.
2) They have important pharmacological actions and many modern drugs are derived from plant alkaloids, such as morphine, quinine, and reserpine.
3) Alkaloids are usually colorless solids but some are liquids, and they are basic compounds that form salts with acids which aids in their extraction from plants.
Alkaloids are nitrogen-containing organic compounds found in plants that have strong physiological effects. True alkaloids are derived from amino acids and have nitrogen in a heterocyclic ring, while other classes of alkaloids like pseudoalkaloids and protoalkaloids vary in their origin and structure. Alkaloids serve functions like protecting plants from herbivores and can have pharmacological actions like analgesic, stimulant, or respiratory effects when consumed. They are classified based on their chemical structure and pharmacological properties.
Natural chemistry Structure elucidation of EmetineAnam Ilyas
The document discusses the structure elucidation of the alkaloid emetine, which is derived from the dried roots of Ipecacuanha plant. It summarizes that emetine has the molecular formula C29H40N2O4 and contains two 6,7-dimethoxyisoquinoline units joined to a C5H8 fragment. The structure of emetine was proved through its total synthesis. Spectroscopic techniques such as 1H NMR, 13C NMR, and mass spectrometry were used to further characterize the structure of emetine.
Structure Elucidation of Reserpine (M. Pharm)MohdShafeeque4
1. Reserpine is an indole alkaloid isolated from the roots of Rauvolfia serpentina that has been used medicinally as a treatment for hypertension and anxiety.
2. The structure of reserpine was elucidated through chemical degradation studies that identified its core skeleton and functional groups.
3. Key evidence for reserpine's structure included identification of its molecular formula, hydrolysis products, and synthesis from simpler precursors. Together, these studies showed reserpine has the structure of a C-glycoside consisting of a reserpic acid moiety linked as a diester to a 3,4,5-trimethoxybenzoic acid group.
The document discusses alkaloids, which are naturally occurring chemical compounds that mostly contain basic nitrogen atoms. It covers their classification (including by biosynthesis, chemistry, pharmacology, and taxonomy), isolation, purification, biological activity, and structural determination. Methods for structural elucidation include functional group determination, degradation reactions like Hoffman exhaustive methylation, oxidation, and physical methods like spectroscopy. Specific alkaloids discussed include morphine, emetine, and reserpine.
This document summarizes key information about alkaloids. It discusses that alkaloids are nitrogen-containing organic compounds found in plants that have physiological effects. Common alkaloids like morphine, codeine, caffeine, and cocaine are mentioned. The characteristics, occurrence in plants, classification based on chemical structure, and examples of alkaloids used in modern medicine are described. The biosynthesis pathways of morphine and codeine from opium poppy are also summarized.
2) study of utilization of radioactive isotopes in the investigation of bioge...SONALI GADGE
1. Radioactive isotopes (radioisotopes) emit radiation and are unstable, while stable isotopes do not emit radiation. Radioisotopes like 3H, 14C, and 35S are used as tracers in biological investigations.
2. Tracer techniques involve growing plants in radioactive compounds like 14CO2 and then analyzing plant parts over time to determine the sequential formation of metabolites. Double and multiple labelling can provide evidence of biochemical incorporation pathways.
3. Applications of tracer techniques include studying terpenoid biosynthesis, the pathways of alkaloids and coumarins, and determining how plants uptake nutrients like calcium and phosphorus from soil.
Alkaloids are a group of naturally occurring chemical compounds that mostly contain basic nitrogen atoms.
The term alkaloid was coined by Meissner, a German pharmacist, in 1819.
Alkaloids are cyclic organic compounds containing nitrogen in a negative state of oxidation with limited distribution among living organisms.
Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions.
Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).
Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric.
Many alkaloids dissolve poorly in water but readily dissolve in organic solvents.
Most alkaloids have a bitter taste or are poisonous when ingested.
This document provides an overview of alkaloids, including their classification, isolation, purification, and structural determination. Alkaloids are basic, nitrogen-containing plant compounds that act as chemical defenses. They are classified into different groups based on their chemical structure. Methods for isolating alkaloids from plants and purifying them are described. The document also discusses molecular modification of alkaloids to develop drugs and techniques used to determine alkaloid structures, such as degradation, spectroscopy, and X-ray analysis. Ephedrine is given as an example alkaloid whose structure was determined.
The document discusses the tracer technique, which involves incorporating radioactive isotopes into plant metabolites to trace biosynthetic pathways. It defines the technique and explains that radioactive isotopes like carbon-14 and hydrogen-3 are commonly used. The summary describes some key applications of the technique, like tracing the pathway from phenylalanine to the cyanogenic glycoside prunasin, and determining the location and quantity of compounds containing a radioactive tracer like glucose. It also lists some requirements for the technique, such as using a sufficient starting concentration of the tracer and ensuring it is involved in the relevant synthesis reactions.
This document provides information about natural products and terpenoids. It begins by defining natural products and describing their sources from plants, microbes, and animals. It then discusses the history of isolating and identifying pure natural compounds in the 18th-19th centuries. The rest of the document focuses on terpenoids, including their classification, isolation, properties, and structure elucidation. Specific terpenoids like myrcene, geraniol, and citral are discussed as examples.
Alkaloids: Introduction, Property and classification OP VERMA
Alkaloids are major secondary metabolites reported in higher plants. In this PPT I have covered Introduction, Property, Clarification and identification tests.
Synthesis of schiff base complexes and their biological studies presentationShafqat Ali
The document discusses the synthesis of Schiff base ligands and their metal complexes, and characterization of the compounds. It then examines the biological activities of some complexes, including their ability to interact with DNA through intercalation, and inhibition of fungal growth through antifungal testing. The goal was to enhance knowledge of Schiff base metal complexes and investigate their potential biological applications.
Definition, Classification, chemical test, properties , uses, Distribution and occurrence, Extraction isolation, chromatography methods of purification,Function of alkaloids.
This document discusses alkaloids found in plants. It begins by defining alkaloids and their properties, including that they are basic compounds derived from plants and contain nitrogen. It then covers the history of alkaloid isolation, distribution in different plant families, and classification based on chemical structure. The document focuses on the variety of alkaloids and systems used for their classification. It provides examples of different alkaloid skeletal structures and the plant families that contain them.
These are the organic products of natural or synthetic origin which are basic in
nature & contain one or more than one nitrogen atoms, normally of heterocyclic nature &
possess specific physiological actions on human or animal body, when used in small quantites.
The term is derived from the word ‘alkali-like’ & hence they resemble some of characters
of naturally occuring amines.
The term is derived from the word ‘alkali-like’ & hence they resemble some of
characters of naturally occuring amines.
- Alkaloids are basic nitrogenous plant compounds with physiological effects. They contain heterocyclic nitrogen structures derived from amino acids.
- Atropine is an alkaloid obtained from plants like belladonna. It acts as an anticholinergic and is used to treat conditions like nausea, vomiting, Parkinson's disease, and as a pre-anesthetic.
- Reserpine is obtained from Rauwolfia serpentina and works by depleting catecholamines. It is used to treat psychosis, anxiety, hypertension, and aggression.
- Ephedrine is a sympathomimetic alkaloid obtained from Ephedra that stimulates alpha and beta receptors. It is
The document discusses alkaloids, which are basic nitrogenous plant compounds that are physiologically active. It defines alkaloids and describes their distribution in plants, forms, nomenclature, extraction and classification. Key points include that alkaloids are found mainly in dicots and families like Apocynaceae, with properties like being crystalline solids, bitter taste, and soluble in organic solvents but not water. Common tests for alkaloids are Mayer's, Dragendorff's, Wagner's and Hager's tests. Alkaloids are classified based on their biogenetic pathway, plant source, basic chemical skeleton or type of amine group.
The Mitsunobu reaction allows the conversion of alcohols to various functional groups using trialkyl/triaryl phosphine and dialkyl azodicarboxylate reagents. It proceeds via an oxidation-reduction mechanism. Common applications include esterification, etherification, and N-alkylation reactions. Recent advances have focused on replacing conventional reagents to improve selectivity and yields. The Mitsunobu reaction has been widely used in the synthesis of natural products and pharmaceuticals.
This document summarizes phase 1 reactions in drug metabolism. Phase 1 reactions include oxidative, reductive, and hydrolytic reactions. Oxidative reactions involve the oxidation of aromatic carbons, olefinic carbons, benzylic carbons, allylic carbons, carbon atoms to carbonyl/imine groups, aliphatic carbons, alicyclic carbons, and carbon-heteroatom systems. Reductive reactions include the reduction of aldehydes, ketones, nitro compounds, and azo compounds. Hydrolytic reactions involve ester and amide hydrolysis. The objectives of phase 1 reactions are to increase hydrophilicity, reduce stability, and facilitate conjugation in phase 2 reactions
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
3-Introduction to pharmaceutical Chemistry-and physicochemical properties (3)...HelmyFauz
Pharmachemistry is the science at the intersection of chemistry and pharmacology involved with designing, synthesizing, and developing pharmaceutical drugs. It deals with discovering new therapeutic chemicals and developing them into medicines. Pharmachemists study how to make new compounds, determine their biological effects, optimize their structure for efficacy and safety, and examine how drugs are absorbed, distributed, metabolized, and excreted. Drug activity can be structurally specific, depending on interactions with cellular receptors, or non-specific, relating to physical properties like solubility.
Homogeneous catalysis involves metal complexes in the same phase as reactants, usually liquid. It has advantages like high selectivity and mild reaction conditions. Key aspects include the metal's oxidation state and ligands used. Ligands affect catalysis electronically by donating or accepting electrons from the metal. They also impact catalysis sterically based on their size. The catalytic cycle involves the metal complex having vacant sites for substrates to coordinate through steps like oxidative addition and reductive elimination.
A reagent is a substance added to cause or test for a chemical reaction. Reactants are consumed in reactions while catalysts are not. In biochemistry, substrates are reactants in enzyme-catalyzed reactions. In organic chemistry, reagents cause desired transformations of organic substances like Collins, Fenton's, and Grignard reagents. Analytical reagents detect or measure other substances through color changes. Reagents used commercially or in labs must meet purity standards to ensure precision. Biology reagents in the 1980s enabled identifying and manipulating cells, including antibodies, oligomers, and cloning tools. Reagents include electrophiles that attract electrons and nucleophiles that donate electrons in organic reactions.
This document discusses alkaloids, including their classification, isolation, purification, biological activity, and structural elucidation. It describes four main ways alkaloids can be classified: by their biosynthetic pathway, chemical structure, pharmacological effects, and the taxon they are found in. Methods for isolating alkaloids from plants include Soxhlet extraction and the Stas-Otto process. Key steps in determining alkaloid structure are identifying functional groups, characterizing unsaturated bonds and rings, and performing degradation reactions. The structures of specific alkaloids like morphine, reserpine and emetine are discussed in detail.
Medicinal chemistry involves the discovery and design of new therapeutic chemicals and their development into medicines and drugs. It is an interdisciplinary field combining chemistry and biology. Medicinal chemists work to design new drug compounds, determine their biological effects, optimize their structures for desired effects and minimal side effects, and study how the body processes drugs. The physicochemical properties of drugs, like solubility, acidity, and reactivity influence their biological actions and interactions with targets in the body. Understanding these properties helps predict drugs' behaviors and design new candidates. A drug's solubility is key to its formulation and absorption in the body. Both lipophilic and hydrophilic structural features impact a molecule's solubility profile. Acidity and
Antidotes are substances that counteract toxins and poisons. They can work physically by binding or coating toxins, chemically by neutralizing or changing toxins into non-toxic compounds, or physiologically/pharmacologically by competing with or blocking toxins from receptors or restoring normal bodily functions. Antidotes are classified by their mode of action as physical, chemical, or physiological/pharmacological, and by their site of action within the body. Activated charcoal is a common physical antidote that works by adsorbing toxins in the gastrointestinal tract to prevent absorption. Chemical antidotes include chelating agents that bind to heavy metals and antibodies that bind to toxins. Physiological ant
DEFINITION:
The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties
Physical property of drug is responsible for its action 2)Chemical Properties
The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.
Various Physico-Chemical Properties are,
Solubility Partition Coefficient
Dissociation constant Hydrogen Bonding Ionization of Drug Redox Potential Complexation Surface activity Protein binding Isosterism
1. Solubility:
• The solubility of a substance at a given temperature is defined as the concentration of the dissolved solute, which is in equillibrium with the solid solute.
• Solubility depends on the nature of solute and solvent as well as temperature , pH & pressure.
• The solubility of drug may be expressed in terms of its affinity/philicity or repulsion/phobicity for either an aqueous or organic solvent.
The atoms and molecules of all organic substances are held together by various types of bonds (e.g. hydrogen bond, dipole –dipole, ionic bond etc.)
These forces are involved in solubility because it is the solvent-solvent, solute-solute, solvent-solute interactions that governs solubility.
Methods to improve solubility of drugs
1) Structural modification (alter the structure of molecules) 2) Use of Cosolvents (Ethanol, sorbitol,PPG,PEG)
3) Employing surfactants 4) Complexation
Importance of solubility
1. Solubility concept is important to pharmacist because it govern the preparation of liquid dosage form and the drug must be in solution before it is absorbed by the body to produce the biological activity.
2. Drug must be in solution form to interact with receptors.
This document discusses electrophilic aromatic substitution on benzene derivatives. It explains that substituents can either activate or deactivate the benzene ring towards electrophilic attack by induction or resonance effects. Donor groups activate by directing electrophiles to the ortho- and para-positions, while acceptor groups deactivate by directing to the meta-position. Oxidation can convert an activator into a deactivator or vice versa. Strategies like protection/deprotection, reversible blocking, and multi-step synthesis are used to overcome reactivity issues. Electrophilic substitution in polycyclic aromatic compounds is also discussed.
Oxygen is highly reactive atom that is capable of becoming part
of potentially damaging molecule commonly called “free radical.”
Free radicals are capable of attacking cells of the body, causing
them to lose their structure and function.
Free radicals have been implicated in the pathogenesis of at
least 50 diseases.
Free radial formation is controlled naturally by various compounds
known as antioxidants.
It is when the ability of antioxidant is limited that this damage can
become cumulative and debilitating.
Following criteria should be considered while selecting an antioxidant.
It should be able to produce desire redox reaction.
It should be physiologically and chemically compatible.
It should be physiologically inert.
It should be non-toxic both in the reduced and oxidized forms.
It should be effective in low concentration.
It should provide prolonged stability to the formulation.
This document provides an overview of alkaloids presented by O.P. Verma. It defines alkaloids and discusses their properties, distribution in plants, classification based on chemical structure and biosynthesis, methods of extraction, and chemical tests used to identify alkaloids. Key points include that alkaloids are basic nitrogen-containing plant metabolites that can have pharmacological effects. They are classified based on their heterocyclic ring structures and precursor amino acids. Common chemical tests for alkaloids involve the formation of precipitates with reagents such as Dragendorff's solution and Mayer's reagent.
This document provides information on the chemistry of various classes of pesticides, including their structure, synthesis, mode of action, and uses. It discusses organochlorines like DDT and lindane, organophosphates such as malathion and parathion, carbamates including carbaryl and carbofuran, and quinone pesticides. For each class, examples are given of their preparation and the biological effects of inhibiting important enzymes in insects, such as cholinesterase for organophosphates and carbamates. A variety of natural and synthetic pesticides are also mentioned.
Oxidative stress occurs when there is an imbalance between free radicals and antioxidants in the body. Free radicals are reactive molecules that can damage cells, and are produced through normal metabolic processes or external factors like pollution. They react with lipids, DNA, and proteins which can lead to cell injury. Lipid peroxidation caused by free radicals can disrupt cell membranes and form toxic compounds. Oxidative stress is measured indirectly through biomarkers of damage like lipid peroxides and DNA oxidation products, or directly through assays of reactive oxygen species and antioxidants. Maintaining the balance between free radicals and antioxidants is important for health.
The document discusses drug stability and degradation kinetics. It defines drug stability as the ability of a pharmaceutical dosage form to maintain its physical, chemical, therapeutic and microbial properties during storage and usage. The main criteria for acceptable stability are that each active ingredient retains its chemical integrity and potency. Degradation kinetics aims to predict a drug's intrinsic stability by determining the order of degradation reactions and their rate constants. Common degradation pathways include hydrolysis, oxidation, photolysis and racemization. The Q10 method can be used to estimate shelf life based on a drug's activation energy.
The document discusses the synthesis of various oxacyclic derivatives such as furan, pyran, coumarins, and dioxanes using ionic liquids as reaction media. Ionic liquids offer advantages over traditional organic solvents as they are non-volatile, thermally stable, and recyclable. The synthesis of oxacyclic derivatives in ionic liquid media results in improved yields and reduced reaction times. Ionic liquids provide a more environmentally friendly approach for synthesizing important compounds like pharmaceuticals, agrochemicals, and fragrances.
Hydrocarbons are major constituents of crude oil and petroleum. They can be biodegraded by naturally-occurring microorganisms in freshwater and marine environments under a variety of aerobic and anaerobic conditions. Oxygen, nitrate, or sulfates are sometimes added as electron acceptors to enhance biodegradation rates.
This document discusses research on intestinal microflora being conducted in Korea. It describes several research groups and projects investigating the roles of intestinal microflora in drug metabolism, food digestion, and human health. The goals are to better understand how microflora influence toxicity and to characterize differences in Korean microflora related to factors like diet. There is also a focus on developing diagnostic tools and establishing a Korean intestinal microflora database. The research aims to improve safety evaluation of drug metabolites and enable personalized medicine based on individual microfloral profiles.
1) Human intestinal bacteria can convert naturally-occurring plant compounds called phytoestrogens into estrogenic compounds. 2) Studies found lower rates of breast and prostate cancer in Japan and Finland where diets include soybeans and rye bread containing phytoestrogens. 3) These phytoestrogens structurally resemble the human hormone estradiol and can have estrogenic or anti-estrogenic effects depending on blood concentrations.
This document discusses ginseng saponins and their intestinal bacterial metabolites. It shows that ginsenosides extracted from ginseng have various biological activities including anti-tumor effects. When ginsenosides are administered orally, intestinal bacteria metabolize them into compounds like M1 and M4. These metabolites, rather than the original ginsenosides, are responsible for the anti-metastatic effects, as demonstrated by inhibiting lung metastasis in mice. The anti-metastatic effects are mediated by the bacterial metabolites in the serum, not the original ginsenosides.
NCTR is a research center within the FDA that conducts toxicology research to support risk assessment and regulatory decision making. It has unique facilities including primate and BSL-3 laboratories. NCTR research focuses on emerging issues like nanotechnology, nutrition, and critical path initiatives. Bioimaging technologies like microPET and MRI are used to study effects of substances like ketamine anesthesia on brain development in primates. Studies found ketamine increased neuronal cell death markers in the frontal cortex of developing monkeys.
1. The document discusses metagenomics research on the human gut microbiome using a gene-centric approach.
2. It involves sequencing microbial DNA from gut samples to identify genes and characterize functional profiles of the microbiome.
3. Analysis of Japanese gut microbiome samples identified over 600,000 genes, including many novel to the gut microbiome, providing insight into microbiome composition and functions.
This document discusses the evaluation of drug toxicity through metabolomic profiling. It describes how metabolomics can be used to detect liver and kidney toxicity induced by various compounds. The study designs involve administering hepatotoxic or nephrotoxic drugs to animals and collecting blood, urine, and tissue samples for analysis. Nuclear magnetic resonance spectroscopy is used to analyze metabolic profiles in biofluids and multivariate statistical analysis is applied to identify biomarkers of toxicity. The document outlines several studies conducted by the National Institute of Food and Drug Safety Evaluation investigating drug toxicity using metabolomics approaches.
[1] Molecular inflammation is proposed as the underlying mechanism of the aging process. [2] It is driven by the accumulation of oxidative damage and redox imbalance over time, which activates NF-kB and leads to a pro-inflammatory state. [3] Calorie restriction is able to modulate this process and blunt the age-related increase in inflammatory markers.
This document describes a comparative analysis of the human gut microbiota of Koreans using barcoded pyrosequencing. It finds that the Korean gut microbiome has high diversity at the species and strain levels, with over 800 species-level phylotypes identified on average per individual. The analysis identifies 14 core genera that are consistently present across Korean guts, including Bacteroides, Prevotella, Clostridium, and Ruminococcus. The phylum-level diversity of the Korean gut microbiome is similar to other human populations.
This document summarizes research on ginsenosides and their metabolites. It notes that ginsenosides have poor oral absorption but are transformed by gut bacteria into active metabolites that show better absorption. One metabolite, M1, has been found to inhibit tumor cell proliferation, invasion, and adhesion in vitro. Studies in humans and rats have demonstrated M1's inhibitory effects on tumor metastasis after oral administration. The document also discusses the metabolism and pharmacokinetics of M1.
This document summarizes an investigation into how gut microflora affects endogenous metabolic pathways using mass spectrometry-based metabolomics. Pseudo germ-free rats were used as a model by administering antibiotics to suppress gut microflora. Urine metabolites were then analyzed and compared between control and pseudo germ-free rats using UPLC-QTOF-MS. Validation steps included repeatability testing of QC samples and a test mixture to ensure method reliability. Multivariate analysis of metabolic profiles identified differences between control and pseudo germ-free groups, suggesting gut microflora influences certain metabolic pathways.
Strategies for Effective Upskilling is a presentation by Chinwendu Peace in a Your Skill Boost Masterclass organisation by the Excellence Foundation for South Sudan on 08th and 09th June 2024 from 1 PM to 3 PM on each day.
The simplified electron and muon model, Oscillating Spacetime: The Foundation...RitikBhardwaj56
Discover the Simplified Electron and Muon Model: A New Wave-Based Approach to Understanding Particles delves into a groundbreaking theory that presents electrons and muons as rotating soliton waves within oscillating spacetime. Geared towards students, researchers, and science buffs, this book breaks down complex ideas into simple explanations. It covers topics such as electron waves, temporal dynamics, and the implications of this model on particle physics. With clear illustrations and easy-to-follow explanations, readers will gain a new outlook on the universe's fundamental nature.
This presentation includes basic of PCOS their pathology and treatment and also Ayurveda correlation of PCOS and Ayurvedic line of treatment mentioned in classics.
How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
Walmart Business+ and Spark Good for Nonprofits.pdfTechSoup
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it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
1. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic Activation of Natural
Products
Ling Yang
Lab of Pharmaceutical Resource Discovery
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences
www.pharm.dicp.ac.cn
Sep 23rd, 2011
2. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Natural Products
Totally Natural !!!
But
Natural products are generally either
Safe?
of prebiotic origin or originate from
microbes, plants, or animal sources
3. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Mechanisms of Toxicity
Chemicals
Metabolism
About 80% Interaction with Metabolites Detoxicification
Dose-reaction Receptors
relationship
About 20%
On Target Off Target Reactive Structure-
Type A1 Toxicity Type A2 Toxicity Products reaction
relationship
Protein Adducts GSH… Adducts DNA Adducts
Deplete Mutation/Block
Oxidative Defences Polymerases
Haptenized
Trigger High Dose Overwhelm:
get oxidative damage Type D Toxicity
Type B Toxicity Immune Response
Type C Toxicity
Apoptosis/ Period of Dosing: Exemplified
Prime Sites Hypersensitivity
Liver, Blood cells, Skin Necrosis Carcinogenicity and Teratology
Liebler & Guengerich (2005) Nat Rev Drug Discov 4(5):410-420.
4. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Drugs Withdrawn Associated With Idiosyncratic Toxicity or
Drug Interactions
Idiosyncratic Toxicity Drug-Drug interactions
Aclcofenac (antiinflammatory) Astemizole
Alpidem (anxiolytic) Mibefradil
Amineptine (antidepressant) Propulsid
Amodiaquine (antimalarial) Posicor
Benoxaprofen (antiinflammatory) Seldane
Bromfenac (antiinflammatory) Hismanal
Carbutamide (antidiabetic) Palladone
Ibufenac (antiinflammatory)
Iproniazid (antidepressant)
Metiamide (antiulcer)
Nomifensine (antidepressant)
Practolol (antiarrhythmic)
Remoxipride (antipsychotic)
Sudoxicam (antiinflammatory)
Tienilic Acid (diuretic)
Tolrestat (antidiabetic)
Troglitazone (antidiabetic)
Zomepirac (antiinflammatory)
Crit. Rev. Toxicol. 35 (2005) 325-361.
5. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Classification of Reactive Metabolites
Electrophiles (Most):
Hard: a localized positive charge
Soft (Most): a delocalized charge
Free radicals:
Free radicals are characterized by containing an unpaired electron
and they usually abstract a hydrogen atom from molecules,
resulting in a new free radical and thus initiating a chain reaction.
6. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
List of Some Groups liable to Metabolic Activation
Structural Alerts Herbal Components
Anilines: R1 R2
Quinone-imine
R2 + R1
N N
R1 R2 CYP1A2, 3A4
N
OH O
OH O
NH2 HN N
Rutaecarpine (Rut)
Nitroso metabolite
R1, R2=H, alkyl, phenyl acyl, O O
HO
acyloxy, sulfonyl
Benzo-dioxolanes: N
N N
O O HO O
.
H H H
. H H H
O OCH3 OCH3
OH OCH3
O O O
H
carbene CYP2C9 O
O
O
CYP3A4 O
OH O
OCH3 O
OCH3
H3CO H 3CO OCH3
H3CO
catechol
OH
Quinone
O
Noscapine ortho-quinone
Furans: OH
O
O O O CYPs
O
O O O O
βа , -unsaturated dicarbonyl
N
Pyrrolizidine alkaloids (PAs)
Nitrobenzenes:
R1
R1 R1
N
NO2 NH OH
O
R1=phenyl,acyl or heterocyclic
Fang et al. Expert Opin Drug Metab Toxicol. 2011;7(8):989-1007.
...... Zhou et al. Life Sciences (2004) 74: 935–968.
7. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Techniques available to assess RM formation
Trapping and characterizing reactive metabolites
Nucleophilic trapping agents:
Thiols: GSH; NAC Soft nucleophile
Amine: semicarbazide; methoxylamine Hard nucleophile
Mechanism-based inhibition (Time dependant inhibition)
Trapping and characterizing Protein / DNA adducts
Immunoassays
Proteomics
Electrophoresis
8. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
9. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
10. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic Activation of Rutaecarpine (Rut)
Evodia fruit is considered by herbalists to be potential toxic.
A wide range of pharmacological activities: vasorelaxation,
uterotonic action, anoxia and control of body temperature.
Wuzhuyu CYP1A2, 3A4
GSH
Rutaecarpine (Rut)
Screening CYP isoforms involved in
Structural elucidation bioactivation
-273 -129
O NH2
-273
H
N O
O N
H
OH S O HO
HO
N O
N
-129 H
N
-249
In publication
11. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic Activation of Evodiamine (Ed)
Five metabolites were detected after evodiamine was incubated with HLMs and PB-induced RLMs
Metabolic pathways Metabolic pathways
Structural elucidation of GSH conjugate of evodiamine
CYP1A2 or 2C9 GSH
Evodiamine
In publication
12. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
13. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic Activation of Pyrrolizidine alkaloids (PAs)
R O
O OH OH
O O
P450
N N
DHP DHR
High activity and instability
1988 WHO issue the information about toxicity of PA Acute liver toxicity: liver cell necrosis, liver hemorrhage
Chronic liver toxicity: the nucleus increases, giant cell disease of
2002 MHRA proposed to prohibit the drug containing PA
liver; the liver venous congestion of the lungs
2004 WTO, Qianbai Rhinitis Tablet containing toxic plant Senecio, Genotoxicity: genetic combination, DNA cross-linking, DNA-
liver toxicity
protein cross-linking; carcinogenic, teratogenic
2005 China , Qianbai Rhinitis Tablet managed as prescription drug
OH OH
N-oxide O O
Competitive Metabolic
Hydrolysis O
activation O O
O
metabolic pathway O O
11
Deacetylation
22 N
N
Phase II ?
14. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic pathway of PAs
Esterase, FMO, and UGT may play a detoxicification role via competitive
consumption of PAs, resulting in a reduction of available PAs for P450 activation.
N-glucuronidation is a common metabolic pathway of most of PAs.
He et al. (2010) Drug Metabolism and Disposition 38 (4): 626-634.
15. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Toxicity of Senecionine in Primary Human Hepatocytes
Senecionine does not show toxicity in human hepatocytes . However, when the
UGT1A4 activity was inhibited by inhibitor (hecogenin), potent cytotoxicity exhibited ,
indicating that glucuronidation may be an important mechanism against PAs toxicity.
He et al. (2010) Chemical Research in Toxicology 23 (3): 591-599.
16. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Species Differences of Senecionine glucuronidation
Glucuronidation is critically important for rabbits, sheep and other species to defend
toxicity of Senecionine. As rats, mice, and dogs are lack of UGT1A4 expression, but also
the lack of other competition with metabolic activation of metabolic pathways, has
therefore become sensitive to toxic species.
17. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Possible Metabolism-mediated Toxicity Mechanism of PAs
Bioactivation Toxic adducts
Interaction with
Macromolecule
PAs CYPs
Idiosyncratic
toxicity
Toxic
Exposure
Liver Effective
PAs No Effect
Time
UGTs
Increased local
exposure
Glucuronized PAs
Glucuronyl hydrolase
He et al. DMD 2010, 38 (4): 626-34. Enterohepatic PAs
He et al. Chem Res Toxicol 2010, 23 (3): 591-9. circulation
18. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
19. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Introduction of Strychnos nux-vomica L.
Major components:alkaloids, glucosides, organic acids , alcohols…
Pharmacological Effects:
Treatment of rheumatism and rheumatoid arthritis, analgesic effect,
anti-inflammatory
Leathal dose: 7g(crude herb)
Strychnos nux-vomica L.
(Loganiaceae) Toxic target:
nervous system, immune system, digestive system, cardiovascular
system, urinary system
Compatibility :
Licorice, red spoon, Datura metel, white peony root, Rehmannia
To precipitate strychnine Anti-seizure
20. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Introduction of strychnine and brucine
H N H N
H H
OCH3
H H
N O N OCH3
O
O O
strychnine brucine
Clinical Effects: analgesic, anti-inflammatory, anti-tumor, anti-arthritis
Toxicity:seizure, CNS toxicity, nephrotoxicity…
LD50 in mice:strychnine: 3.27mg/kg
brucine: 233mg/kg
Oral toxic doses of brucine are 71 times as strychnine
Injection toxic doses of brucine are 45 times as strychnine
21. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
The Same Enzymes Catalyzes oxidation and Glucuronidation
of both Brucine and Strychnine in HLMs
O
CYP3A4
[ ]
UDP
UGT1A4
Brucine [ ]
H N
H
O
H
H N CYP3A4 H
H
[ O N
O
]
O N H N
H
UDP
O UGT1A4
H
strychnine
[ O N
O
]
22. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
The Species Difference of Brucine and Strychnine
Glucuronidation in Liver Microsomes
LD50 values for strychnine
Species LD50 (mg/kg)
Animal
Cat 0.3-0.5
Dog 0.3-0.8
Rabbit 0.4-0.6
Mouse 0.4-2
Rat 2-16
Human
child 15
adult 30-120
23. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Bioactivation of Strychnine
Hyperthermia
Strychnine Toxicity Rhabdomyolysis
Renal failure
+EPI (658.40) Charge (+0) CE (50) CES (25) FT (20): Exp 2, 2.867 to 2.984 min from Sample 1 (STRY-RLM) of STRY@27Apr10.wiff (Turbo Spray) Max. 2.0e5 cps.
658.4
2.0e5
1.9e5
m/z=385 HOOC
1.8e5
1.7e5
1.6e5
1.5e5 351.4
-307 H
H N HN
1.4e5
1.3e5
1.2e5
S O m/z=529
Intensity, cps
1.1e5
1.0e5
H
9.0e4
8.0e4
-129 O N OH
7.0e4 529.4
O NH
6.0e4
5.0e4
184.2
212.3
333.4 -273 O
4.0e4 385.4
3.0e4
2.0e4
182.0 220.2
1.0e4 194.2 291.4 305.3 640.4
239.2 367.3
0.0
100 150 200 250 300 350 400 450 500 550 600 650
m/z, Da
HOOC NH 2
HOOC
H N H N
H H H N HN
H
CYP3A4 S O
H H O H
O N O N O N OH
O NH
O O O
Proposed pathway of strychnine bioactivation NH2
HOOC In publication
24. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
25. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Noscapine-warfarin Interactions
O
N
O Antitussive (Clinic)
H
H
OCH3
O
Antitumor (phase I,II)
O
OCH3
H3CO
Opium Noscapine
12 clinical cases of the interaction between noscapine and warfarin
International Normalized Ratio (凝血指数 3.0-7.2 (6 days later)
凝血指数):
凝血指数
11 increased INR+1 bleeding
An 82-year-old male Warfarin+Noscapine (50 mg tid)
O O
Warfarin metabolism by CYPs CYP3A4
OH H OH H
CYP2C9
O O O O
S-warfarin CYP1A2 R-warfarin
Aneja et al. (2007) Cancer Chemoth Pharm 60: 831-39.
Rosenborg et al. (2008) Br J of Clin Pharmacol 65: 277-78.
26. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Effects of Noscapine on Human CYPs,
% Control Activity Positive % Control Activity
CYP Isoforms Probe reactions
Remaining IC50 (µM) Control remaining (Positive Control)
CYP1A2 Phenacetin O-deethylation 58.9±0.1 >100 Furafylline 15.6±0.8
CYP2A6 Coumarin 7-hydroxylation 69.2±2.0 >100 8-methoxypsoralen 11.5±0.5
CYP2C8 Paclitaxel 6α-hydroxylation 51.2±0.8 >100 Montelukast 11.2±0.1
CYP2C9 Diclofenac 4'-hydroxylation 16.3±0.1 13.3±1.2 Sulfaphenazole 6.0±0.1
CYP2D6 Dextromethorphan O-demethylation 75.1±1.8 >100 Quinidine 8.6±0.4
CYP2E1 Chlorzoxazone 6-hydroxylation 99.8±3.9 >100 Clomethiazole 18.9±0.4
CYP3A4 Testosterone 6β-hydroxylation 12.3±0.7 10.8±2.5 Ketoconazole 5.0±0.3
For CYP3A4: Competitive, Ki=5.2µM For CYP2C9: Noncompetitive, Ki= 8.8µM
27. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Time- and NADPH-dependant Inhibition
For CYP2C9: IC50 shift 10-fold For CYP3A4: IC50 shift 10-fold
10*decrease
10*decrease
KI= 8.9µM KI=9.3µM
kinact= 0.014 min-1 kinact=0.06 min-1
28. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Metabolic-activation of Noscapine
A GSH conjugate was detected in HLMs Structural elucidation
Conjugate
HLMs
-GSH
-NADPH
Bioactivation process
Fang et al. (2010) British Journal of Clinical Pharmacology 69(2): 193-199.
29. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Prediction of noscapine and Warfarin Drug Interactions
(S)-warfarin: CYP2C9
(R)-warfarin: CYP3A4, CYP1A2
Reversible inhibition: Time-dependent inhibition:
Using Cmax: Using Cmax:
AUC of (S)-warfarin: 1.5% AUC of (S)-warfarin: 110.9%
AUC of (R)-warfarin: 1.1% AUC of (R)-warfarin: 48.9%
Using Cmax,u: Using Cmax,u:
AUC of (S)-warfarin: 0.5% AUC of (S)-warfarin: 41.8%
AUC of (R)-warfarin: 0.4% AUC of (R)-warfarin: 32.7%
Warfarin Concentration
Toxic
in Plasma
Effective
Time
Noscapine-Warfarin Interactions
Fang et al. (2010) Br J of Clin Pharmacol 69(2):193-199.
Rosenborg et al. (2010) Clin Pharmacol Ther 88(3):343-346.
30. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Our Progress
• Metabolic Activation-mediated Toxicity
– Rutaecarpine (Rut) and Evodiamine(Ed)
– Pyrrolizidine alkaloids (PAs)
– Strychnine (Str)
• Metabolic Activation-mediated Drug Interactions
– noscapine
• Ginseng-drug interaction via the inhibition by intestinal
metabolites
31. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Ginsenosides Biotransformation by Intestinal Bacteria
20(S)-protopanaxadiol type 20(S)-protopanaxatriol type
Glc Glc
Glc-Xyl Glc6-1X
Rb3 Rb1,Rb2,Rc Re HO
Rg1
Glc2-1Glc Glc2-1Glc HO
Glc2-1Rha Glc-O Naturally
abundant
Glc OH
Glc
Glc2-1Glc Rd Rg2
HO F1
Glc2-1Rha HO
HO
OH OH
F2 Rh1
Glc
Glc-Xyl HO
Glc
Mx Glc
HO
HO C-K Ppd
OH
HO Ppt
OH
Gastro-
HO
HO intestine .942–542 ,12 .lluB .mrahP .loiB .)8991( .la te oakA
.5841–1841 ,32 .lluB .mrahP .loiB .)0002( .la te eaB
.668–168 ,52 .lluB .mrahP .loiB .)2002( .la te awagesaH
044–634:36 deM atnalP )7991( .la te awagesaH
Blood
Effect .751–351 ,59 .icS .locamrahP .J .)4002( awagesaH
.1701–5601 ,13 .sopsiD .bateM gurD .la te bawaT
50 46
Positive 79%
45
40 Negative 21%
N o. of specimens
Glc-Glc6-O Glc-O
35 OH OH
30
25
20
15 12 Glc-Glc6-O HO
10
5 Rb1 C-K
0
individual differences of hydrolysis
1
in ability of Rb1 Hasegawa et al. (1997) Planta Med 63:436–440.
32. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Natural Occurring Ingredients of Natural Products
How about
Metabolites by
Intestinal Bacteria?
Example: Ginsenosides
33. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Possible Ginseng-drug Interactions via CYPs inhibition by
Ginsenoside Intestinal metabolites
Intestinal Naturally rare Naturally abundant
Bacterial
Metabolites S-
Ppt Ppd CK Rg2 Rg3 Rg3 Rh1 Rh2 F1 Rb1 Rb2 Rc Rd Re Rg1
CYP1A2
CYP2A6
CYP2C9
CYP2D6
CYP2E1
CYP3A4
IC50 ( μ
μ
μ
μ
μ
μ
μ
μ
M) 100 50 10 1 μ
μ
μ
μ
μ
μ
μ
μ
μ
μ
μ
μ
M
Prediction of potential for DDI from In Vitro Data
CB,max CL,max CYP2C9 CYP3A4
Ginsenosides
(µM ) (µM ) Cmax/Ki Prediction Cmax/Ki Prediction
>0.59~0.83
Ppt 1.9 < 0.1 Remote Possible
(0.47, rat)
Ppd >0.12 >1.3 < 0.1 Remote >0.1 Possible
C-K >0.75 >7.8 > 0.1 Possible - -
Liu et al. Toxicological Sciences 92: 356-364.
Liu et al., Planta Medica 72:126-131
Liu et al. Biological & Pharmaceutical Bulletin 27:1555-1560
34. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Role of Cytochrome P450 in Drug Metabolism
Elimination pathways of top 200 drugs
Cytochrome P450 involved in ------70 %
CYP3A4 involved in ------ 45 %
CYP2C9 involved in ------ 16 %
Bjornsson TD, et al. J Clin Pharmacol 2003; 43 (5): 443-69
Wienkers LC, Heath TG. Nat Rev Drug Discov. 2005 Oct;4(10):825-33.
35. Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Acknowledgement
The National Basic Research Program (also called 973 Program) of
China
National High-tech R&D Program (863 Program) of China
National Natural Science Foundation of China
National Key Technology R&D Program in the 11th Five year Plan of
China
Outstanding Overseas Chinese Scientists (One Hundred Talent
Program) from the Chinese Academy of Sciences
Innovation Fund of Chinese Academy of Sciences