Logan Abbott proposes modifying the C17 position of the kappa opioid receptor agonist salvinorin A to synthesize novel analogs. Salvinorin A is a potent and selective KOR agonist but has poor solubility. Previous work showed modifying C17 maintains activity. Abbott will synthesize 5 analogs by converting salvinorin A's acetol to an azide then to an amide through traceless ligation. The goal is identifying a potent KOR agonist to treat drug abuse by targeting receptors other than mu opioid receptors targeted by current therapies. Abbott has experience in the lab synthesizing earlier C17 analogs and will assess compounds' pharmacological activity.
1) Radical retrosynthesis uses one-electron disconnections to simplify synthesis, avoiding protecting groups, functional group interconversions, and redox steps. This enables more direct and minimal syntheses.
2) Radical cross-coupling reactions allow forming C-C and C-X bonds through hydrogen atom transfer or coupling of radicals with redox-active esters, sulfones, or other species. This provides unique chemoselectivity advantages over polar pathways.
3) Case studies demonstrate strategic benefits of radical cross-coupling for synthesis ideality, efficiency, selectivity, and modularity by opening new retrosynthetic opportunities not accessible through two-electron analysis.
The document discusses methodology in organic synthesis, including examples of natural products. It describes convergent and divergent synthesis strategies. Convergent synthesis involves coupling molecular fragments through independent synthesis to improve reaction yields compared to linear synthesis. Divergent synthesis starts from a central core and generates a library of compounds through successive additions. Functional group interconversion and addition techniques are discussed to allow for disconnection of target molecules during retrosynthetic analysis.
The document discusses the key features of auxins including an aromatic ring, an aliphatic side chain with a carboxylic acid group, and a specific spatial configuration between the ring and chain. It also lists some common synthetic auxins like IBA and 4-Cl-IAA and describes how the widely used herbicide 2,4-D mimics auxin action to selectively kill broadleaf weeds over monocot grasses. However, the exact molecular mechanism for this selective activity between dicots and monocots is still not fully understood.
Synthon or Disconnection or Retrosynthesis Approach in Organic Synthesis. This document discusses the key concepts and approaches of retrosynthesis including: 1) Disconnecting a target molecule into logical fragments through breaking bonds to obtain starting materials, 2) It is the reverse of chemical synthesis, 3) Terminologies such as disconnection, synthon, and reagents, 4) Basic rules for preferred disconnections.
The document discusses various aspects of catalysis. It defines catalysis as the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. It describes the three main types of catalysis as homogeneous, heterogeneous, and enzymatic catalysis. It also discusses catalyst parameters, examples of enzyme catalysis reactions and their mechanisms, and applications of catalysis in areas like environment, green chemistry, catalytic converters, ozone depletion, chemical industry, food processing, and fine chemicals.
The document discusses the structure-activity relationship (SAR) of opioids. It begins by defining SAR as the relationship between a molecule's chemical structure and its biological activity. Modifications to a drug's structure, including altering functional groups, can change its potency and effects. The structures of morphine, codeine, and heroin are examined as examples. While the methyl group on codeine decreases potency versus morphine, the acetyl groups on heroin allow it to cross the blood-brain barrier more easily and produce a stronger euphoric effect. Understanding SAR enables the design of new opioid drugs with tailored pharmacological properties.
more chemistry contents are available
1. pdf file on Termmate: https://www.termmate.com/rabia.aziz
2. YouTube: https://www.youtube.com/channel/UCKxWnNdskGHnZFS0h1QRTEA
3. Facebook: https://web.facebook.com/Chemist.Rabia.Aziz/
4. Blogger: https://chemistry-academy.blogspot.com/
Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
Fuctional group determination of drugs in biological activity.vishnu chinnamsetti
The document discusses the role of functional groups in determining biological activity. It defines functional groups as atoms within drug molecules that confer specific chemical and physical properties. The key points are:
1) Functional groups determine properties like ionization, solubility, reactivity, stability, and metabolism. They impact drug shelf life, action duration, and susceptibility to metabolism.
2) There are several types of functional groups including acidic, basic, hydrophilic, intermediate polarity, and lipophilic groups. These groups impact properties like water solubility, lipid solubility, and ability to cross cell membranes.
3) The presence of particular functional groups is important for a drug's intended biological activity and receptor interactions. Understanding functional
1) Radical retrosynthesis uses one-electron disconnections to simplify synthesis, avoiding protecting groups, functional group interconversions, and redox steps. This enables more direct and minimal syntheses.
2) Radical cross-coupling reactions allow forming C-C and C-X bonds through hydrogen atom transfer or coupling of radicals with redox-active esters, sulfones, or other species. This provides unique chemoselectivity advantages over polar pathways.
3) Case studies demonstrate strategic benefits of radical cross-coupling for synthesis ideality, efficiency, selectivity, and modularity by opening new retrosynthetic opportunities not accessible through two-electron analysis.
The document discusses methodology in organic synthesis, including examples of natural products. It describes convergent and divergent synthesis strategies. Convergent synthesis involves coupling molecular fragments through independent synthesis to improve reaction yields compared to linear synthesis. Divergent synthesis starts from a central core and generates a library of compounds through successive additions. Functional group interconversion and addition techniques are discussed to allow for disconnection of target molecules during retrosynthetic analysis.
The document discusses the key features of auxins including an aromatic ring, an aliphatic side chain with a carboxylic acid group, and a specific spatial configuration between the ring and chain. It also lists some common synthetic auxins like IBA and 4-Cl-IAA and describes how the widely used herbicide 2,4-D mimics auxin action to selectively kill broadleaf weeds over monocot grasses. However, the exact molecular mechanism for this selective activity between dicots and monocots is still not fully understood.
Synthon or Disconnection or Retrosynthesis Approach in Organic Synthesis. This document discusses the key concepts and approaches of retrosynthesis including: 1) Disconnecting a target molecule into logical fragments through breaking bonds to obtain starting materials, 2) It is the reverse of chemical synthesis, 3) Terminologies such as disconnection, synthon, and reagents, 4) Basic rules for preferred disconnections.
The document discusses various aspects of catalysis. It defines catalysis as the increase in the rate of a chemical reaction due to the participation of an additional substance called a catalyst. It describes the three main types of catalysis as homogeneous, heterogeneous, and enzymatic catalysis. It also discusses catalyst parameters, examples of enzyme catalysis reactions and their mechanisms, and applications of catalysis in areas like environment, green chemistry, catalytic converters, ozone depletion, chemical industry, food processing, and fine chemicals.
The document discusses the structure-activity relationship (SAR) of opioids. It begins by defining SAR as the relationship between a molecule's chemical structure and its biological activity. Modifications to a drug's structure, including altering functional groups, can change its potency and effects. The structures of morphine, codeine, and heroin are examined as examples. While the methyl group on codeine decreases potency versus morphine, the acetyl groups on heroin allow it to cross the blood-brain barrier more easily and produce a stronger euphoric effect. Understanding SAR enables the design of new opioid drugs with tailored pharmacological properties.
more chemistry contents are available
1. pdf file on Termmate: https://www.termmate.com/rabia.aziz
2. YouTube: https://www.youtube.com/channel/UCKxWnNdskGHnZFS0h1QRTEA
3. Facebook: https://web.facebook.com/Chemist.Rabia.Aziz/
4. Blogger: https://chemistry-academy.blogspot.com/
Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
Fuctional group determination of drugs in biological activity.vishnu chinnamsetti
The document discusses the role of functional groups in determining biological activity. It defines functional groups as atoms within drug molecules that confer specific chemical and physical properties. The key points are:
1) Functional groups determine properties like ionization, solubility, reactivity, stability, and metabolism. They impact drug shelf life, action duration, and susceptibility to metabolism.
2) There are several types of functional groups including acidic, basic, hydrophilic, intermediate polarity, and lipophilic groups. These groups impact properties like water solubility, lipid solubility, and ability to cross cell membranes.
3) The presence of particular functional groups is important for a drug's intended biological activity and receptor interactions. Understanding functional
Directed ortho lithiation of biphenyl - quinton siriannitru-ugc
This document summarizes a study that compared the directing abilities of diisopropyl and diethyl amide directing groups in a biphenyl compound (compound 7) through a directed ortho lithiation reaction. Compound 7 was synthesized using two strategies, with the second strategy yielding it in 16.1% overall. NMR analysis confirmed the structure of compound 7. Future work will involve performing the planned directed lithiation competition reaction on compound 7 and conducting concentration-dependent NMR studies on it.
Medicinal chemistry involves designing and synthesizing pharmaceutical agents to benefit humanity. Key aspects include synthesis, structure-activity relationships, receptor interactions, and absorption/metabolism/excretion properties. Natural products have historically provided many drug leads, with plants estimated to provide over 80% of medications in traditional medicine. Medicinal chemists work to optimize drug candidates through systematic modification and evaluation to improve potency, selectivity, and safety profiles.
The document discusses complexation and protein binding. It defines complexation as the process of combining individual atom groups, ions or molecules to create large ions or molecules. There are various types of complexes that are formed through different interactions. Applications of complexation include improving solubility, stability, and bioavailability of drugs. Methods for determining the stoichiometry of complexes include Job's method, mole ratio method, and slope ratio method which involve measuring a property of complexes formed at different concentration ratios. Protein binding is also discussed in relation to complexation and drug action.
Basic Concepts Of Retrosynthesis (Part1)munirnizami
1. The document discusses the basic concepts of retrosynthetic analysis in organic synthesis. Retrosynthesis is the process of working backward from a target molecule to design synthetic routes using disconnections and functional group interconversions.
2. Key concepts include synthons, which are idealized fragments formed by imagined bond cleavages, and synthetic equivalents, which are actual reagents that can function as those synthons.
3. Effective retrosynthesis requires understanding reaction mechanisms and reliable reactions, as well as considering availability of starting materials and stereochemistry.
This document discusses structure-activity relationships (SAR) through examples of different drug molecules. It provides details on the chemical structures of camptothecin (CPT), taxol, and the flavonoid quercetin and how specific structural features relate to their biological activities. For CPT, rings A-D and the stereochemistry at C-20 are essential for anti-tumor activity, while modifications to rings C and D eliminate activity. The ester linkage and phenylisoserine chain of taxol are required for its anticancer effects. For flavonoids like quercetin, features important for radical scavenging include a catechol structure in ring B and hydroxyl groups that enable hydrogen bonding and electron de
This document discusses molecular variation in homologous series and isosteric replacements for drug discovery. It defines homologous series as molecules that differ by a methylene group, such as monoalkylated derivatives and cyclopolymethylenic compounds. Biological activity often follows a bell-shaped curve with increasing carbon chain length, peaking at an optimal partition coefficient for membrane crossing. Isosteric replacements involve substituting atoms or groups with others of similar size and electronic properties, allowing modification while maintaining biological activity, as seen with clozapine analogs. The concepts of homologous series and isosteric replacements are important tools in medicinal chemistry for analog design and drug discovery.
This document describes Chapter 13 from an organic chemistry textbook. Chapter 13 covers elimination reactions, which involve the loss of two atoms or groups of atoms from adjacent carbons to form a double bond. The chapter discusses the two types of elimination mechanisms - E1 and E2. E1 is a two-step mechanism that proceeds through a carbocation intermediate. E2 is a concerted mechanism where the leaving group and proton leave simultaneously. The chapter also covers the stereochemistry, direction, and factors that determine whether elimination or substitution will occur for a given reaction.
Retrosynthetic analysis, definition, importance, disconnection approach, one group two group disconnection logical and illogical disconnection approach compounds containing two nitrogen atom retrosynthetic analysis of camphor, cartisone, reserpine
The document discusses strategies for drug design such as varying substituents on lead compounds to optimize binding interactions and selectivity. Key strategies include varying alkyl and aryl substituents, extending functional groups, and modifying ring systems through expansions, contractions, or isosteric replacements. Other approaches involve simplifying molecule structures while retaining essential pharmacophores or rigidifying flexible structures to limit undesirable conformations. The goal is to systematically modify lead compounds to improve desired target interactions and properties like potency, selectivity, and toxicity profile.
This document provides an overview of molecular variation in homologous series and isosteric replacements for medicinal chemistry. It discusses different types of molecular variations such as variations based on homologous series with different biological response curves. It also discusses isosteric replacements, including the history and development of isosterism concepts. Current isosteric and bioisosteric modifications are presented. The document also discusses molecular variations based on ring transformations, homodimer and heterodimer ligands using the twin drug approach, and molecular variations in medicinal chemistry applications.
more chemistry contents are available
1. pdf file on Termmate: https://www.termmate.com/rabia.aziz
2. YouTube: https://www.youtube.com/channel/UCKxWnNdskGHnZFS0h1QRTEA
3. Facebook: https://web.facebook.com/Chemist.Rabia.Aziz/
4. Blogger: https://chemistry-academy.blogspot.com/
Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open acc...Austin Publishing Group
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open access journal publishes manuscripts in the following areas but not limited to structures, synthesis, kinetics, organic synthesis, physical organic chemistry, supramolecular chemistry and chemical biology.
Austin Journal of Bioorganic & Organic Chemistry accepts original research articles, review articles, commentaries, Letters, perspectives, and rapid communication on all the aspects of Bioorganic & Organic Chemistry.
ER Publication,
IJETR, IJMCTR,
Journals,
International Journals,
High Impact Journals,
Monthly Journal,
Good quality Journals,
Research,
Research Papers,
Research Article,
Free Journals, Open access Journals,
erpublication.org,
Engineering Journal,
Science Journals,
This document describes research into developing new inhibitors that can selectively target specific calpain isoforms for therapeutic applications. The researcher synthesized a potential calpain inhibitor incorporating a symmetrical (1-2-dithiolan-4-yl) carboxylic acid into a dipeptide motif. Coupling reactions using propylphosphonic anhydride generally worked well but coupling 2-bromo-acrylic acid was complicated. Future work involves further characterizing products, synthesizing the dithiolane acid, and evaluating inhibitors against calpain enzymes.
1) The document discusses how a methyl group attached to an aromatic ring can impact drug safety due to metabolism-dependent effects. While generally producing innocuous metabolites, in some cases it can produce reactive metabolites that cause toxicity.
2) Several examples of drugs are presented where the methyl group is oxidized, potentially producing reactive carbocations, alcohols, or quinone methide intermediates that can cause liver or other organ toxicity.
3) While a methyl group can enhance pharmacological activity, it also introduces a liability if it produces reactive metabolites. Finding excessive glutathione adducts or protein binding in early studies may warrant terminating a drug's development to avoid toxicity issues. Thorough understanding of chemical reactivity is
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
This document provides definitions and classifications of complex compounds. It defines complexes as molecules where most bonding structures can be described by classical theories but one or more bonds are anomalous. Complexes result from donor-acceptor reactions between Lewis acids and bases. They are divided into metal ion complexes, organic molecular complexes, and inclusion complexes. Metal complexes involve coordination between metal ions and ligands. Chelates form cyclic structures with multidentate ligands. Organic complexes involve weaker interactions like hydrogen bonding. Inclusion complexes entrap guest molecules in host structures like channels, layers, or cavities. Common examples of complexes and their properties are discussed.
This document discusses the biological source, isolation, and chemical structure of morphine. It was first isolated from the opium poppy Papaver somniferum in 1804. Morphine has a pentacyclic ring structure and is insoluble in water and some organic solvents. It exerts its effects by interacting with opioid receptors in the central nervous system. The document also discusses morphine metabolism and the importance of various functional groups like hydroxyl groups for receptor binding and activity. Finally, it describes approaches to modify the morphine structure by adding or removing rings to synthesize compounds with analgesic activity.
Este documento resume la resolución de la máquina Breach. El atacante descubre credenciales ocultas en una imagen y accede a una base de datos para obtener contraseñas. Luego sube una webshell para ejecutar comandos y escalar privilegios mediante un script en el directorio init.d, lo que le permite convertirse en usuario root y encontrar la bandera.
Diego Armando Nava es un recién egresado de pedagogía que está trabajando en su tesis sobre el diseño, producción, aplicación y evaluación de material didáctico utilizando las TIC. Él cree que las tecnologías de la información y la comunicación abren nuevos espacios para la enseñanza y el aprendizaje más allá del salón de clases. Su objetivo es crear un curso para maestros de primaria y secundaria sobre cómo hacer radio escolar y producir materiales didácticos utilizando este medio para compart
Directed ortho lithiation of biphenyl - quinton siriannitru-ugc
This document summarizes a study that compared the directing abilities of diisopropyl and diethyl amide directing groups in a biphenyl compound (compound 7) through a directed ortho lithiation reaction. Compound 7 was synthesized using two strategies, with the second strategy yielding it in 16.1% overall. NMR analysis confirmed the structure of compound 7. Future work will involve performing the planned directed lithiation competition reaction on compound 7 and conducting concentration-dependent NMR studies on it.
Medicinal chemistry involves designing and synthesizing pharmaceutical agents to benefit humanity. Key aspects include synthesis, structure-activity relationships, receptor interactions, and absorption/metabolism/excretion properties. Natural products have historically provided many drug leads, with plants estimated to provide over 80% of medications in traditional medicine. Medicinal chemists work to optimize drug candidates through systematic modification and evaluation to improve potency, selectivity, and safety profiles.
The document discusses complexation and protein binding. It defines complexation as the process of combining individual atom groups, ions or molecules to create large ions or molecules. There are various types of complexes that are formed through different interactions. Applications of complexation include improving solubility, stability, and bioavailability of drugs. Methods for determining the stoichiometry of complexes include Job's method, mole ratio method, and slope ratio method which involve measuring a property of complexes formed at different concentration ratios. Protein binding is also discussed in relation to complexation and drug action.
Basic Concepts Of Retrosynthesis (Part1)munirnizami
1. The document discusses the basic concepts of retrosynthetic analysis in organic synthesis. Retrosynthesis is the process of working backward from a target molecule to design synthetic routes using disconnections and functional group interconversions.
2. Key concepts include synthons, which are idealized fragments formed by imagined bond cleavages, and synthetic equivalents, which are actual reagents that can function as those synthons.
3. Effective retrosynthesis requires understanding reaction mechanisms and reliable reactions, as well as considering availability of starting materials and stereochemistry.
This document discusses structure-activity relationships (SAR) through examples of different drug molecules. It provides details on the chemical structures of camptothecin (CPT), taxol, and the flavonoid quercetin and how specific structural features relate to their biological activities. For CPT, rings A-D and the stereochemistry at C-20 are essential for anti-tumor activity, while modifications to rings C and D eliminate activity. The ester linkage and phenylisoserine chain of taxol are required for its anticancer effects. For flavonoids like quercetin, features important for radical scavenging include a catechol structure in ring B and hydroxyl groups that enable hydrogen bonding and electron de
This document discusses molecular variation in homologous series and isosteric replacements for drug discovery. It defines homologous series as molecules that differ by a methylene group, such as monoalkylated derivatives and cyclopolymethylenic compounds. Biological activity often follows a bell-shaped curve with increasing carbon chain length, peaking at an optimal partition coefficient for membrane crossing. Isosteric replacements involve substituting atoms or groups with others of similar size and electronic properties, allowing modification while maintaining biological activity, as seen with clozapine analogs. The concepts of homologous series and isosteric replacements are important tools in medicinal chemistry for analog design and drug discovery.
This document describes Chapter 13 from an organic chemistry textbook. Chapter 13 covers elimination reactions, which involve the loss of two atoms or groups of atoms from adjacent carbons to form a double bond. The chapter discusses the two types of elimination mechanisms - E1 and E2. E1 is a two-step mechanism that proceeds through a carbocation intermediate. E2 is a concerted mechanism where the leaving group and proton leave simultaneously. The chapter also covers the stereochemistry, direction, and factors that determine whether elimination or substitution will occur for a given reaction.
Retrosynthetic analysis, definition, importance, disconnection approach, one group two group disconnection logical and illogical disconnection approach compounds containing two nitrogen atom retrosynthetic analysis of camphor, cartisone, reserpine
The document discusses strategies for drug design such as varying substituents on lead compounds to optimize binding interactions and selectivity. Key strategies include varying alkyl and aryl substituents, extending functional groups, and modifying ring systems through expansions, contractions, or isosteric replacements. Other approaches involve simplifying molecule structures while retaining essential pharmacophores or rigidifying flexible structures to limit undesirable conformations. The goal is to systematically modify lead compounds to improve desired target interactions and properties like potency, selectivity, and toxicity profile.
This document provides an overview of molecular variation in homologous series and isosteric replacements for medicinal chemistry. It discusses different types of molecular variations such as variations based on homologous series with different biological response curves. It also discusses isosteric replacements, including the history and development of isosterism concepts. Current isosteric and bioisosteric modifications are presented. The document also discusses molecular variations based on ring transformations, homodimer and heterodimer ligands using the twin drug approach, and molecular variations in medicinal chemistry applications.
more chemistry contents are available
1. pdf file on Termmate: https://www.termmate.com/rabia.aziz
2. YouTube: https://www.youtube.com/channel/UCKxWnNdskGHnZFS0h1QRTEA
3. Facebook: https://web.facebook.com/Chemist.Rabia.Aziz/
4. Blogger: https://chemistry-academy.blogspot.com/
Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open acc...Austin Publishing Group
Austin Journal of Bioorganic & Organic Chemistry is a peer reviewed, open access journal publishes manuscripts in the following areas but not limited to structures, synthesis, kinetics, organic synthesis, physical organic chemistry, supramolecular chemistry and chemical biology.
Austin Journal of Bioorganic & Organic Chemistry accepts original research articles, review articles, commentaries, Letters, perspectives, and rapid communication on all the aspects of Bioorganic & Organic Chemistry.
ER Publication,
IJETR, IJMCTR,
Journals,
International Journals,
High Impact Journals,
Monthly Journal,
Good quality Journals,
Research,
Research Papers,
Research Article,
Free Journals, Open access Journals,
erpublication.org,
Engineering Journal,
Science Journals,
This document describes research into developing new inhibitors that can selectively target specific calpain isoforms for therapeutic applications. The researcher synthesized a potential calpain inhibitor incorporating a symmetrical (1-2-dithiolan-4-yl) carboxylic acid into a dipeptide motif. Coupling reactions using propylphosphonic anhydride generally worked well but coupling 2-bromo-acrylic acid was complicated. Future work involves further characterizing products, synthesizing the dithiolane acid, and evaluating inhibitors against calpain enzymes.
1) The document discusses how a methyl group attached to an aromatic ring can impact drug safety due to metabolism-dependent effects. While generally producing innocuous metabolites, in some cases it can produce reactive metabolites that cause toxicity.
2) Several examples of drugs are presented where the methyl group is oxidized, potentially producing reactive carbocations, alcohols, or quinone methide intermediates that can cause liver or other organ toxicity.
3) While a methyl group can enhance pharmacological activity, it also introduces a liability if it produces reactive metabolites. Finding excessive glutathione adducts or protein binding in early studies may warrant terminating a drug's development to avoid toxicity issues. Thorough understanding of chemical reactivity is
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
This document provides definitions and classifications of complex compounds. It defines complexes as molecules where most bonding structures can be described by classical theories but one or more bonds are anomalous. Complexes result from donor-acceptor reactions between Lewis acids and bases. They are divided into metal ion complexes, organic molecular complexes, and inclusion complexes. Metal complexes involve coordination between metal ions and ligands. Chelates form cyclic structures with multidentate ligands. Organic complexes involve weaker interactions like hydrogen bonding. Inclusion complexes entrap guest molecules in host structures like channels, layers, or cavities. Common examples of complexes and their properties are discussed.
This document discusses the biological source, isolation, and chemical structure of morphine. It was first isolated from the opium poppy Papaver somniferum in 1804. Morphine has a pentacyclic ring structure and is insoluble in water and some organic solvents. It exerts its effects by interacting with opioid receptors in the central nervous system. The document also discusses morphine metabolism and the importance of various functional groups like hydroxyl groups for receptor binding and activity. Finally, it describes approaches to modify the morphine structure by adding or removing rings to synthesize compounds with analgesic activity.
Este documento resume la resolución de la máquina Breach. El atacante descubre credenciales ocultas en una imagen y accede a una base de datos para obtener contraseñas. Luego sube una webshell para ejecutar comandos y escalar privilegios mediante un script en el directorio init.d, lo que le permite convertirse en usuario root y encontrar la bandera.
Diego Armando Nava es un recién egresado de pedagogía que está trabajando en su tesis sobre el diseño, producción, aplicación y evaluación de material didáctico utilizando las TIC. Él cree que las tecnologías de la información y la comunicación abren nuevos espacios para la enseñanza y el aprendizaje más allá del salón de clases. Su objetivo es crear un curso para maestros de primaria y secundaria sobre cómo hacer radio escolar y producir materiales didácticos utilizando este medio para compart
Daniel Alvarez has extensive experience in retail sales and customer service. He has held positions as a courtesy clerk, alcohol and beverage clerk, and currently works as a financial services representative. He has strong communication, problem solving, and customer service skills developed through building relationships and addressing customer needs.
Besar atau kecil tergantung dari bandingannya. kalau membandingkan dengan yang kecil, tentu kamu lebih besar. kalau membandingkan dengan yang besar, tentu kamu lebih kecil. biasakan untuk bandingkan dengan Sang Pencipta #marikitabelajar
Significance of a Robust AML Risk Assessment Process for FIs and RIAsAML Audit
Regular risk assessments are important for registered investment advisors (RIAs) to evaluate their anti-money laundering (AML) compliance programs. A successful risk assessment provides a detailed analysis of risks and controls to mitigate those risks. The risk assessment should consider various factors like products, transactions, customers, affiliates, regulatory history, and geography. Upon completion, the risk assessment results should be documented and shared with senior management to obtain feedback and identify any necessary business changes. Conducting periodic risk assessments addresses critical elements of an effective AML compliance program and better prepares RIAs for regulatory examinations.
Quick Reference Guide to BSA/AML Risk AssessmentMayank Johri
This document provides an overview of conducting an enterprise risk assessment for anti-money laundering (AML) compliance. It discusses key challenges such as sourcing and validating data from different business lines. The document recommends that financial institutions allocate a dedicated analytics team with AML expertise to automate the risk assessment process. Automating data extraction and leveraging statistical analysis can help set risk thresholds, calculate inherent risks and control effectiveness more robustly and efficiently. This allows the AML team to focus on qualitative work rather than manual data tasks. The end goal is to build a repeatable, defensible risk assessment model that identifies the institution's residual money laundering risks.
Sugyeom Kim completed their bachelor's degree in biochemistry at Northeastern University. They worked in Professor George O'Doherty's lab developing methods for synthesizing natural and unnatural carbohydrate structures to discover new anticancer analogs. Kim's project involved synthesizing new analogs of the natural product SL0101, which selectively inhibits cancer-promoting kinases but has instability issues. Kim synthesized protected and unprotected aglycone groups of SL0101 with various C-ring substitutions, to explore how this affects anticancer activity, kinase inhibition, and metabolic stability.
Rational drug design begins by identifying a biological target implicated in disease. Drugs are then designed to modulate this target's activity in order to treat the disease. For a target to be suitable, there must be evidence it is disease-relevant and capable of binding small molecules. Once identified, the target is cloned, expressed, and purified. This allows high-throughput screening of chemical libraries to identify candidates that modify the target. Successful candidates should have properties predicting oral availability and low toxicity. Prodrugs and combinatorial chemistry are approaches that can improve drug properties and efficiency of discovery.
This document describes a study that prepared and evaluated carvedilol-loaded solid lipid nanoparticles (SLNs) for oral drug delivery. Compritol 888 ATO (COMP) was selected as the lipid material based on its solubility parameter relative to carvedilol. Design of experiments was used to optimize the concentrations of COMP and Poloxamer 188 surfactant in blank SLNs and carvedilol-loaded SLNs. The optimized formulation containing 7.5% COMP, 5.0% Poloxamer 188, and 1.11% carvedilol had a particle size of 161 nm and 94.8% drug entrapment efficiency. In vitro studies showed the SLNs protected carvedilol from acidic environments and
Importance of partition coefficient, solubility and dissociation on pre-formu...SHANE_LOBO145
This document discusses the importance of preformulation studies, specifically focusing on partition coefficient, dissociation constant, and solubility. It defines these key terms and explains their significance in determining drug absorption and developing drug formulations. The partition coefficient indicates a drug's lipophilicity and ability to cross cell membranes. The dissociation constant and Henderson-Hasselbalch equation are used to predict drug ionization and site of absorption in the gastrointestinal tract. Solubility is critical for bioavailability and influences formulation strategies to increase or decrease a drug's aqueous solubility. Understanding these physicochemical properties is essential for designing an optimal drug delivery system.
This document discusses various techniques for enhancing the bioavailability of drug formulations, including cocrystallization, copolymerization, and PEGylation. Cocrystallization involves forming a crystalline complex between an active pharmaceutical ingredient and a co-crystal former, which can improve solubility and bioavailability. Copolymerization uses block copolymer micelles to encapsulate hydrophobic drugs and improve their solubility. PEGylation attaches polyethylene glycol chains to proteins and peptides to increase their circulating half-life and protect them from degradation. The document examines each technique in more detail and concludes that proper selection of a bioavailability enhancement method is key to developing an effective drug formulation.
Lipinski's Rule of Five is a rule of thumb used to evaluate how easily a pharmaceutical drug can be absorbed by the body. It states that, in general, an orally active drug has no more than one violation of the following criteria: a molecular weight under 500 Daltons, no more than 5 hydrogen bond donors, no more than 10 hydrogen bond acceptors, and an octanol-water partition coefficient (clog P) of less than 5. The rule aims to assess whether a compound poses suitable pharmacokinetic properties to be an orally active drug in humans. Over time, extensions to the rule have been proposed to better evaluate druglikeness.
FUNCTIONAL GROUP MODIFICATION : Medicinal ChemistryPRUTHVIRAJ K
Once a lead compound or a pharmacophore structure with the desired pharmacological effect has been identified, organic chemists can introduce modifications in the chemical structure of the lead compound with the goal of improving the pharmacokinetics or pharmacodynamics of a drug candidate. These evolved structures are known as analogs.
3
Crystal Engineering Applied to the Development of Novel Pharmaceutical Solid Forms with Improved Bioavailability: the Co Crystals Case by Javier Ellena in Advancements in Bioequivalence & Bioavailability
Pharmaceutical co crystal technology has emerged as a promising strategy to enhance bioavailability of poorly water soluble drugs. This mini review presents a brief overview of pharmaceutical co crystals with particular focus on co crystal design, characterization techniques and impacts on drug bioavailability.
https://crimsonpublishers.com/abb/fulltext/ABB.000514.php
This document discusses solubility of drugs from the perspectives of a medicinal chemist and pharmaceutical scientist. From the medicinal chemist perspective, it discusses Lipinski's rule of five for predicting solubility and permeability. It also discusses methods for calculating absorption parameters and predicting aqueous solubility, such as the Moriguchi method for calculating logP. From the pharmaceutical scientist perspective, it outlines various techniques for enhancing drug solubility, including particle size reduction through micronization or nanosuspension, modifying crystal habit through polymorphs or complexes, and chemical modifications through prodrugs or buffer systems. Overall, the document provides an overview of key considerations and approaches for optimizing drug solubility from different scientific viewpoints.
The document discusses several physical properties that are important for drug design, including ionization, lipophilicity, hydrogen bonding, and molecular size. It explains how these properties impact key processes in the body like absorption, distribution, metabolism, and excretion of an oral drug. Specifically, it notes that the ionized and un-ionized forms of a drug affect its solubility, binding interactions, and ability to cross membranes in different parts of the body. The optimal lipophilicity and ability to form hydrogen bonds are also important for a drug to effectively reach its target site of action. Understanding these physical chemistry principles can help guide lead optimization and identification in drug discovery programs.
This document discusses concepts and approaches in drug design. It describes how drug design involves developing analogues and prodrugs through chemical modifications to a lead molecule. Analogues can be synthesized by changing substitution groups or carbon skeletal structure. Prodrugs are active metabolites formed from parent compounds through biotransformation. Lead discovery involves exploring new molecules and exploiting leads through assessment and extension. Random and nonrandom screening are used to identify potential leads. Pharmacokinetic and pharmacodynamic studies of metabolites can also lead to new leads. Drug design approaches include molecular hybridization, conjunction, and disjunction of structural elements as well as rational approaches considering physicochemical properties and electronic features.
The document provides an overview of preformulation studies, which are conducted to determine the physicochemical properties of new drug substances prior to formulation development. Key aspects covered include definition of preformulation, factors considered, objectives, outcomes, common tests like solubility and stability studies, and techniques involved. Specifically, the document discusses solubility analysis methods, factors affecting solubility like pH and temperature, and importance of solubility determination. It also covers common degradation pathways like oxidation and hydrolysis, and approaches to prevent or minimize degradation.
This document discusses analog design in drug development. It begins by defining analog design as the modification of a drug molecule or bioactive compound to create new molecules that are chemically and biologically similar. The goals of analog design are to retain or improve pharmacological effects while reducing unwanted properties. Analogs are categorized based on their chemical and pharmacological similarities. Common design strategies include bioisosteric replacement, altering stereochemistry, and modifying functional groups. Bioisosterism involves substituting groups with similar physicochemical properties to modify biological activity. Both classical and non-classical bioisosteres are discussed.
This document summarizes strategies for analog design of lead compounds in drug discovery. It discusses various types of modifications that can be made including bioisosteric replacements, rigid analogs, alterations of chain branching, changes in ring size or position, use of fragments of lead molecules, and variations in interatomic distances. Examples are provided to illustrate how each type of modification can impact pharmacological activity. The overall goal of analog design is to develop new compounds with similar or improved biological and chemical properties as the lead molecule.
This document describes the development of standardized protocols and optimized precursor sets for applying automated parallel synthesis to lead optimization using the Mitsunobu reaction. Sets of aliphatic alcohols and phenols were designed as precursors for the reaction. The alcohols were selected to probe hydrophobic interactions while the phenols aimed for diversity. An automated protocol using resin-supported triphenylphosphine and di-tert-butylazodicarboxylate achieved yields comparable to manual reactions. 48 reactions identified several unreactive precursors that were replaced to better suit the Mitsunobu conditions.
Sanjo College of Pharmaceutical Studies, Physical Pharmaceutics I , 3rd semester B.Pharm, Complexation & protein binding, Classification in detail, determination methods, application of complexes in pharmacy.
Bioisosterism is a strategy used in drug design that involves replacing one chemical group with another that has similar physical or chemical properties. This is done to improve properties like potency, selectivity, toxicity, and pharmacokinetics without significantly changing the chemical structure. Common bioisosteric replacements include replacing hydrogen with fluorine, replacing carboxylic acids with amides or esters, or replacing phenyl rings with heteroaromatic or saturated rings. The application of bioisosterism has been an important concept in medicinal chemistry for nearly 80 years and will continue to play a role in drug discovery and optimization.
1. Undergraduate Research Award Application, Spring 2015
Synthesis of Pharmacologically Active Analogs of Salvinorin A
Proposal by Logan Abbott
Mentored by Dr. Thomas E. Prisinzano
Abstract: Addiction is a complex disorder of the brain in which we see a developing
adaptation upon subsequent exposures to drugs of abuse. A fundamental aspect of drug
abuse involves the body’s reward system, or its response to pleasurable stimuli from
drugs of abuse. One notable system involved within the body’s natural reward process is
the opioid system. The opioid system, including the mu (MOR), delta (DOR), and kappa
(KOR) opioid receptors interacting with a large family of endogenous opioid peptides, is
broadly distributed along the neurocircuitry of addiction2
. As a result of its extensive
distribution, the opioid system is a popular target for the treatment of drug abuse.
Salvinorin A, the major active component in the hallucinogen Salvia divinorum, is a
potent and selective agonist at the KOR. As a natural product, salvinorin A provides a
unique but fertile opportunity for the synthesis of active analogs with the potential to
serve as novel therapies in the treatment of drug abuse.
Background and Introduction:
The total cost of drug abuse in the United States is estimated to exceed $600 billion annually. This
estimation includes loss of productivity and both health and crime-related costs. This includes
approximately $193 billion for illicit drugs and $235 billion for alcohol1
. With such staggering numbers
concerning the cost of drug abuse, researchers have turned toward finding an answer. For example,
Naloxone, Methadone, and Buprenorphine serve as treatment options currently available for opioid abuse.
As therapies for opioid abuse, these agents all act at opioid receptors, namely, the Mu opioid receptor
(MOR). The MOR is essential to mediating the rewarding properties of opiates, as well as non-opioid
drugs of abuse and natural stimuli2
. In addition to MOR, the human body is also known to possess both
Kappa opioid receptors (KOR) and Delta opioid receptors (DOR). Together, the family of opioid
receptors has shown the ability to regulate the reward system while also contributing to cognitive
dysfunction that predisposes individuals to the development of addiction.
In addiction research, KOR agonism is definitely considered a major anti-reward system,
producing dysphoric effects and antagonizing rewarding effects of drugs of abuse and social stimuli2
.
However, as previously shown, the current treatment approaches for drug abuse all target the MOR.
Taken together, this information has led to the investigation of other opioid receptors, specifically the
KOR, as potential pharmacologic targets in the treatment of drug abuse. Due to the growing interest in the
KOR as a therapeutic target, the neoclerodane diterpene salvinorin A has surfaced as a candidate for
researching the KOR and its role in the drug reward pathway.
First and foremost, salvinorin A offers an enticing compound for research because it acts as a
potent and selective agonist at the KOR with a rapid onset and short duration of action. In other words, as
a potential therapeutic agent, one can recognize the favorable pharmacodynamic parameters this
compound possesses, while exerting its effects at a site that differs from existing treatment options.
Further, salvinorin A is an investigational candidate because it serves as an atypical opioid. While
salvinorin A is a potent and selective KOR agonist, it does not structurally resemble many of the known
non-peptide opioid receptor ligands (See Figure 1). The most astonishing of these structural differences is
the lack of a basic nitrogen atom in the chemical structure of salvinorin A. Up until the discovery of
salvinorin A, the presence of a basic nitrogen atom was proposed to be a necessary structural requirement
for opioid receptor affinity4
. Conversely, salvinorin A also possesses many undesirable pharmacokinetic
properties. Salvinorin A, as suggested by its chemical structure, is a poorly water-soluble molecule. As a
compound with a poor solubility profile, it is reasonable to expect the compound to be poorly bioavailable
when orally administered. This is evidenced by the fact that salvinorin A has a historical niche in Mexican
culture as a smoked agent used in divination rituals. Due to its poor water solubility and bioavailability,
one can deduce that salvinorin A will require extensive formulation changes in order to achieve any
2. Undergraduate Research Award Application, Spring 2015
potential therapeutic benefit. In summation, as a compound with both positive and negative structural
characteristics that culminate its pharmacological profile, the nonalkaloid salvinorin A offers a potential
scaffold for chemical modification to allow further investigation into the therapeutic potential of this
agent as a treatment for drug abuse.
Figure 1: Chemical Structures of Various Opioids
Approach and Timeline:
Upon choosing salvinorin A as the compound of interest, I will investigate the C17 position of the
compound as my project over the course of the upcoming semester. Previous investigation has shown that
the C17 lactone can be reduced to the lactol without a significant loss of KOR activity3
. Further,
preliminary results from the Prisinzano laboratory have shown that modification at the C17 position to
form the acetol again maintains activity with one hundred percent efficacy. Conversely, if we modify the
chemical structure at the C17 position by adding an allyl group off of C17, we see a modest reduction in
activity. This indicates that there may be some hydrogen bonding interactions with the KOR active site
and the C17 position that are important to maintain for activity and potency. The synthesis of these
compounds begins with the selective reduction of salvinorin A to the lactol compound, followed by the
acetylation of the lactol to produce the acetol compound (See Scheme 1). Further derivation of the acetol
can be accomplished in the presence of a Lewis acid and a silyl-protected nucleophile (conditions for the
formation of the allyl compound are shown below). Thus far, this step has proven fairly robust to
accommodate a wide variety of nucleophiles.
Scheme 1: Synthetic Scheme of C17-substituted analogs
HO
O
HO
N
Morphine
H
O
O
O
O
H
CO2Me
H
O
O
N
N
O
Fentanyl
Salvinorin A
O
OH
O
O
H
CO2Me
H
O
O
O
O
O
O
H
CO2Me
H
O
O
O
O
O
O
H
CO2Me
H
O
O
O
OH
O
O
H
CO2Me
H
HO
Salvinorin A
O
SVA Lactol SVB Lactol
SVA Acetol
OO
O
H
CO2Me
H
O
O
DIBAL, THF, -78°C
Mixture of SVA and
SVB Lactols,
controlled by DIBAL
equivalents
+
(mixture of Lactols)
Ac2O, DMAP
DCM, rt
85%
Allyl TMS
BF3
.Et2O
DCM, -78°C
C17-substituted SVA analogs
3. Undergraduate Research Award Application, Spring 2015
The specific aim of my research project is to modify the C17-lactone of the KOR agonist
salvinorin A through semi-synthetic modifications in order to synthesize compounds that retain activity at
the KOR. My goal for this semester-long project is to synthesize five compounds, following the synthetic
Scheme 2, that retain pharmacologic activity. The proposed analogs have various groups appended to a
C17 amide. We chose to investigate a C17 amide due to the previously mentioned possibility that
hydrogen-bonding may play a role in affecting potency at the KOR. As the ultimate goal of this project is
to develop KOR agonists, I will then use my training in pharmacologic assays to assess these analogs for
KOR activity with the intent of identifying a potent KOR agonist.
To achieve these goals, I will begin my project by utilizing the previously optimized reactions to
convert salvinorin A into the acetol compound. With the acetol synthesized, I will then begin to make the
test bioisosteres that I have proposed. The acetol will be converted into the azide through treatment with
TMSN3 in CH2Cl2 in the presence of BF3
.
Et2O5
. While this reaction is the first proposed reaction that has
not already been optimized, I anticipate that it will be successful due to its similarity to the allylation
reaction shown in Scheme 2, as well as its well documented precedence in the literature. Following
successful conversion to the azide analog, I will synthesize the amide analog using a Traceless Staudinger
reaction6
as outlined in Scheme 2. I will then test the pharmacological activity of the analogs that I make;
the Prisinzano laboratory is already equipped to evaluate KOR activity in vitro.
Scheme 2: Synthesis of Proposed Amides
While I anticipate the synthesis of these compounds to be successful based upon literature
protocol and the preliminary reactions that have already been completed successfully in the Prisinzano
laboratory, there are alternative methods for both proposed reactions. The fundamental conversion of an
acetol to azide is a highly precedented reaction. The formation of the amide bond from the azide analog
can be performed in an alternative fashion via reaction of the azide in the presence of a thio acid reagent7
.
The C17 position of the potent and natural hallucinogen salvinorin A is a relatively unexplored
functional modification site. While it is accepted that the carbonyl lactone substituent retains activity
upon being reduced to the lactol, the impact of further structural modification represents a relatively novel
structure-activity relationship. Moreover, little research has taken place toward investigating the amount
and nature of the requirements to retain activity at this site. Throughout the span of my proposed project, I
will be contributing to the understanding of the structure-activity relationships by synthesizing
bioisosteres of salvinorin A that differ only at the C17 position of the compound. The selective
modification of the compound will add new insight to an underexplored area of the compound that has a
desirable structural activity profile for possible employment as a therapeutic option.
Significance to Applicant:
This award is significant to me as an applicant because it would allow me an opportunity to conduct
contemporary drug discovery research. Further, I would be able to explore many of the concepts that I
have been introduced to as a pharmacy student in a firsthand setting. As previously mentioned, I am
currently a 3rd
year student in the School of Pharmacy at the University of Kansas, and upon completing
my PharmD, I plan to attend graduate school in order to receive my PhD in medicinal chemistry. The
OO
O
H
CO2Me
H
O
O
N3
O
O
O
O
H
CO2Me
H
O
O
O
SVA Acetol
TMSN3
BF3
.Et2O
DCM
PPh2
O R
O
C17-Azide
OO
O
H
CO2Me
H
O
O
N
H
R
O
DMA/DPU;
then H2O
70°C
Proposed Amide Analogs
4. Undergraduate Research Award Application, Spring 2015
privilege to collaborate with a first-class mentor in Dr. Prisinzano on an involved research project will be
beneficial for my graduate school aspirations.
Applicant Qualifications:
As a pharmacy student, I had the opportunity to take an elective in undergraduate research as a part of my
curriculum. I chose to work in Dr. Prisinzano’s medicinal chemistry laboratory, where I have been
performing research for the past year. In carrying out my research in the Prisinzano laboratory over the
past year, I have already been trained in many organic chemistry techniques through the use of equipment
such as rotary evaporators, NMR spectroscopy, and mass spectrometry. I am also proficient in column
chromatography, high performance liquid chromatography, and purification techniques. Moreover, I have
had the opportunity to be involved in some aspect of this C17 site-modification project, including the first
two steps in my proposed scheme—the reduction and the acetylation. My familiarity with both the
chemistry and the technique involving my proposed research project provides a foundation from which to
develop my project over the course of the semester.
References:
1
"DrugFacts: Understanding Drug Abuse and Addiction." National Institute on Health. National Institute
on Drug Abuse (NIDA), 1 Nov. 2012. Web. 27 Oct. 2014.
2
Lutz P-E, Kieffer BL. “The multiple facets of opioid receptor function: implications for addiction.”
Current Opinion in Neurobiology, 2013. http://dx.doi.org/10.1016/jconb.2013.02.005.
3
Saylor, Rachel and Prisinzano, Thomas E. “Synthesis of C12- and C17- Modified Analogs of Salvinorin
A as Kappa Opioid Receptor Agonists.” University of Kansas, Lawrence, KS 66045. 2014.
4
Prisinzano, Thomas E. “Neoclerodanes as Atypical Opioid Receptor Ligands.” Journal of Medicinal
Chemistry. 2013, 56, 3435-3443. https://dx.doi.org/10.1021/jm400388u.
5
Guo, Zhongwu and Wu, Qiuye. “Synthesis and Antifungal Activities of Glycosylated Derivatives of the
Cyclic Peptide Fungicide Caspofungin.” ChemMedChem. 2012, 7, 1496-1503.
https://dx.doi.org/10.1002/cmdc.201200214.
6
Bernardi, Anna. “Stereoselective Synthesis of a- and b-Glycofuranosyl Amides by Traceless Ligation of
Glycofuranosyl Azides.” Chem. Eur. J. 2012, 18, 6895-6906.
https://dx.doi.org/10.1002/chem.201200309.
7
Williams, Lawrence J. “The Reaction of Thio Acids with Azides: A New Mechanism and New Synthetic
Applications.” J. Am. Chem. Soc. 2003, 125, 7754-7755. https://dx.doi.org/10.1021/ja0294919.