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Anti-Cancer Drugs-Medicinal Chemistry

Dr.Narmin Hamaamin Hussen Anti-metabolites, Anthracyclines and natural products

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Anti-Cancer Drugs
Antimetabolites, Anthracyclines
& Natural products
Medicinal Chemistry IV / 2nd Semester / 4th Class
Lectures 4 & 5
Dr.Narmin Hamaamin Hussen
2022-2023
1
2-Antimetabolites
A. Pyrimidine Analogues : 5-Fluorouracil , Capecitabine, cytarabine,Gemcitabine
B. Purine Analogues : 6-Mercaptopurine
C. Folic acid antagonist( anti folate) : Methotrexate
▪ Antimetabolites are drugs that are structurally related to naturally occurring compounds, such as vitamins,
amino acids, and nucleotides. These drugs can compete for binding sites on enzymes or can themselves
become incorporated into DNA or RNA and thus interfere with cell growth and proliferation.
Block nucleic acid (DNA, RNA) biosynthesis
➢ Pyrimidine analogues: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine)
➢ Purine anlogues: inhibit interconversion of purine nucleotide (6- mercaptopurine and 6-thioguanine)
➢ Folic acid antagonist: inhibit dihydrofolate reductase (methotrexate)
2
A. Anticancer drugs based on pyrimidine and related compounds
3
Pyrimidine
➢ 5-Fluorouracil (5-Fu)
▪ The drug is available in a 500-mg or 10-mL vial for IV use and as a 1% and 5% topical cream. 5-FU is used in
the treatment of several carcinoma types including breast cancer colorectal cancer, stomach cancer,
pancreatic cancer, and topical use in basal cell cancer of the skin.
▪ This official compound is prepared by the direct fluorination of uracil with fluoroxytrifluoromethane.
▪ Fluorine, at the 5-position of uracil, blocks the conversion of uridylate to
thymidylate, thus diminishing DNA biosynthesis
4
▪ The pyrimidine derivative 5-fluorouracil (5-FU) was
designed to block the conversion of uridine to thymidine.
▪ The normal biosynthesis of thymidine involves methylation
of the 5-position of the pyrimidine ring of uridine
▪ The replacement of the hydrogen at the 5-position of uracil
with fluorine results in an antimetabolite drug, leading to
the formation of a stable covalent ternary complex
composed of 5-FU, thymidylate synthase (TS), and cofactor
(a tetrahydrofolate species). The normal pathway for the
formation of thymidine from uridine is catalyzed by the
enzyme TS.
▪ Anticancer drugs targeting this enzyme should selectively
inhibit the formation of DNA because thymidine is not a
normal component of RNA.
▪ TS is responsible for the reductive methylation of
deoxyuridine monophosphate (dUMP) by 5,10-
methylenetetrahydrofolate to yield dTMP and
dihydrofolate. Because thymine is unique to DNA, the TS
enzyme system plays an important role in replication and
cell division.
5
Mechanism of inhibition of TS by 5-fluorouracil.
Mechanism
▪ bioactivated to 5F-dUMP
▪ covalently complexes to folic acid
▪ complex inhibits thymidylate synthase
▪ ↓ dTMP → ↓ DNA and ↓ protein synthesis
▪ The mechanism of action includes inhibition of the
enzyme TS by the deoxyribose monophosphate
metabolite, 5-FdUMP. The triphosphate metabolite is
incorporated into DNA and the ribose triphosphate
into RNA. These incorporations into growing chains
result in inhibition of the synthesis and function of
DNA and RNA.
▪ Administration of 5-FU by IV yields high drug
concentrations in bone marrow and liver. The drug
does distribute into the central nervous system (CNS).
Significant drug interactions include enhanced
toxicity and antitumor activity of 5-FU following
pretreatment with leucovorin.
▪ Toxicities include dose-limiting myelosuppression,
mucositis, diarrhea, and hand-foot syndrome
(numbness, pain, erythema, dryness, rash, swelling,
increased pigmentation, nail changes, pruritus of the
hands and feet
dihydropyrimidine
dehydrogenase
5,6-dihydro-5-fluorouracil
α-fluoro-β-alanine
6
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Anti-Cancer Drugs-Medicinal Chemistry

  • 1. Anti-Cancer Drugs Antimetabolites, Anthracyclines & Natural products Medicinal Chemistry IV / 2nd Semester / 4th Class Lectures 4 & 5 Dr.Narmin Hamaamin Hussen 2022-2023 1
  • 2. 2-Antimetabolites A. Pyrimidine Analogues : 5-Fluorouracil , Capecitabine, cytarabine,Gemcitabine B. Purine Analogues : 6-Mercaptopurine C. Folic acid antagonist( anti folate) : Methotrexate ▪ Antimetabolites are drugs that are structurally related to naturally occurring compounds, such as vitamins, amino acids, and nucleotides. These drugs can compete for binding sites on enzymes or can themselves become incorporated into DNA or RNA and thus interfere with cell growth and proliferation. Block nucleic acid (DNA, RNA) biosynthesis ➢ Pyrimidine analogues: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine) ➢ Purine anlogues: inhibit interconversion of purine nucleotide (6- mercaptopurine and 6-thioguanine) ➢ Folic acid antagonist: inhibit dihydrofolate reductase (methotrexate) 2
  • 3. A. Anticancer drugs based on pyrimidine and related compounds 3 Pyrimidine
  • 4. ➢ 5-Fluorouracil (5-Fu) ▪ The drug is available in a 500-mg or 10-mL vial for IV use and as a 1% and 5% topical cream. 5-FU is used in the treatment of several carcinoma types including breast cancer colorectal cancer, stomach cancer, pancreatic cancer, and topical use in basal cell cancer of the skin. ▪ This official compound is prepared by the direct fluorination of uracil with fluoroxytrifluoromethane. ▪ Fluorine, at the 5-position of uracil, blocks the conversion of uridylate to thymidylate, thus diminishing DNA biosynthesis 4
  • 5. ▪ The pyrimidine derivative 5-fluorouracil (5-FU) was designed to block the conversion of uridine to thymidine. ▪ The normal biosynthesis of thymidine involves methylation of the 5-position of the pyrimidine ring of uridine ▪ The replacement of the hydrogen at the 5-position of uracil with fluorine results in an antimetabolite drug, leading to the formation of a stable covalent ternary complex composed of 5-FU, thymidylate synthase (TS), and cofactor (a tetrahydrofolate species). The normal pathway for the formation of thymidine from uridine is catalyzed by the enzyme TS. ▪ Anticancer drugs targeting this enzyme should selectively inhibit the formation of DNA because thymidine is not a normal component of RNA. ▪ TS is responsible for the reductive methylation of deoxyuridine monophosphate (dUMP) by 5,10- methylenetetrahydrofolate to yield dTMP and dihydrofolate. Because thymine is unique to DNA, the TS enzyme system plays an important role in replication and cell division. 5 Mechanism of inhibition of TS by 5-fluorouracil.
  • 6. Mechanism ▪ bioactivated to 5F-dUMP ▪ covalently complexes to folic acid ▪ complex inhibits thymidylate synthase ▪ ↓ dTMP → ↓ DNA and ↓ protein synthesis ▪ The mechanism of action includes inhibition of the enzyme TS by the deoxyribose monophosphate metabolite, 5-FdUMP. The triphosphate metabolite is incorporated into DNA and the ribose triphosphate into RNA. These incorporations into growing chains result in inhibition of the synthesis and function of DNA and RNA. ▪ Administration of 5-FU by IV yields high drug concentrations in bone marrow and liver. The drug does distribute into the central nervous system (CNS). Significant drug interactions include enhanced toxicity and antitumor activity of 5-FU following pretreatment with leucovorin. ▪ Toxicities include dose-limiting myelosuppression, mucositis, diarrhea, and hand-foot syndrome (numbness, pain, erythema, dryness, rash, swelling, increased pigmentation, nail changes, pruritus of the hands and feet dihydropyrimidine dehydrogenase 5,6-dihydro-5-fluorouracil α-fluoro-β-alanine 6
  • 7. ▪ Resistance can occur as a result of increased expression of TS, decreased levels of reduced folate substrate 5,10-methylenetetrahydrofolate, or increased levels of dihydropyrimidine dehydrogenase. Dihydropyrimidine dehydrogenase is the main enzyme responsible for 5-FU catabolism. Catabolic inactivation of 5-FU by dihydropyrimidine dehydrogenase 7
  • 8. ▪ Fluorouracil when given alone stays in the body for only a short time. ▪ When given in combination with Leucovorin, Leucovorin can enhance the binding of fluorouracil to an enzyme inside of the cancer cells. As a result, fluorouracil may stay in the cancer cell longer and exert its anti-cancer effect on the cells. ▪ Leucovorin can enhance the cytotoxicity of fluorouracil in vitro, evidently by enhancing the inhibition of the key enzyme, thymidylate synthetase ▪ Leucovorin is usually administered just prior to fluorouracil. ▪ Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating cancers such as; colon and rectal, head and neck, esophageal, and other cancers of the gastrointestinal tract. ▪ In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase. ▪ 5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate. How does leucovorin enhance 5-fluorouracil? 8
  • 9. ➢ Capecitabine (Xeloda) ▪ The drug is available in 150- and 500-mg tablets for oral use. This drug is a fluoropyrimidine carbamate prodrug form of 5-fluorouracil (5-FU). It is used to treat breast cancer and colorectal cancer. The drug is converted to 5-FU by the enzyme thymidine phosphorylase following esterase activity to hydrolyze the carbamate moiety and deamination. ▪ Capecitabine is readily absorbed by the GI tract, and peak plasma levels of 5-FU occur about 2 hours after oral administration. ▪ Indications, drug interactions, and toxicities are equivalent to those of 5-FU Metabolic activation of capecitabine to 5-FU. 9 Liver Tumor
  • 10. B. Anticancer drugs based on purines and related compounds 10 Purine
  • 11. ➢ Mercaptopurine (6-MP): ▪ The drug is available as a 50-mg tablet for oral use. The primary uses of mercaptopurine are in the treatment of lymphoblastic leukemia, acute lymphocytic leukemia, and Crohn disease. Mechanism of action ▪ The mechanism of action includes the incorporation of mercaptopurine into DNA and RNA via the triphosphate metabolite. This incorporation inhibits the synthesis and function of the resulting modified DNA or RNA. The parent drug is inactive and requires phosphorylation for activity. ▪ 6-Mercaptopurine is activated by a hypoxanthine-guanine phosphoribosyltransferase(HGPRT)-catalyzed reaction with 5-phosphoribosylpyrophosphate. The nucleotide inhibits several enzymes in the purine nucleotide biosynthetic pathway, but the most prominent site is one of the early enzymes in the de novo pathway, namely, phosphoribosyl pyrophosphate amidotransferase, which catalyzes the conversion of phosphoribosyl pyrophosphate to phosphor ribosylamine. ▪ The toxicities for mercaptopurine include myelosuppression, immunosuppression, nausea, vomiting, diarrhea, dry skin, urticaria, and photosensitivity HGPRT 11 phosphoribosyl pyrophosphate amidotransferase X 6-thioinosine 5'-monophosphate(6-MPMP)
  • 12. Metabolism of Purine analogs : ▪ The antineoplastic activity of these purines as well as most antimetabolites depends on the relative rates of enzymatic activation and inactivation of these compounds in various tissues and cells. Drug resistance in certain cell lines may be caused by lower activity of activating enzymes or higher activity of catabolic enzymes. ▪ For the classic purine antimetabolites 6-MP major pathways of inactivation include S-methylation via thiopurine-Smethyl- transferase (TPMT) and oxidation by the enzyme xanthine oxidase (XO). Xanthine oxidase converts the drugs to the inactive thiouric acid, and inhibition of the enzymes responsible for the catabolic breakdown of the purine drugs can potentiate the drug’s antineoplastic activity. ▪ Allopurinol is a potent inhibitor of xanthine oxidase and is often used as an adjuvant in purine anticancer drug therapy. Allopurinol increases both the potency and the toxicity of 6- mercaptopurine. Its main importance is that it prevents the uric acid kidney toxicity caused by the release of purines from destroyed cancer cells Conversion of 6-MP to active 6-thioinosine-5- monophosphate (6-MPMP) by HPGRT and inactivation by xanthine oxidase and thiopurine methyl transferase 12
  • 13. C. Structures of folic acid and antifolate anticancer drugs 13 5-formyl tetrahydro folic acid
  • 14. ➢ Methotrexate (MTX): ▪ The drug is available in 50-, 100-, 200-, and 1,000-mg vials for IV use. Methotrexate is used to treat several cancer types including breast cancer, bladder cancer, colorectal cancer, and head and neck cancer. ▪ Oral bioavailability varies with dose because of saturable uptake processes, and high doses are required to reach therapeutic levels in the CNS ▪ The mechanism of action of methotrexate involves inhibition of dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis ,leading to a depletion of critical reduced folates. The reduced folates are necessary for biosynthesis of several purines and pyrimidines.DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Finally depressed DNA, RNA, and protein synthesis and, ultimately, to cell death ▪ Methotrexate enhances 5-FU antitumor effects when given 24 hours prior to the fluoropyrimidine. 14
  • 15. ▪ The majority of drug dosage is excreted unchanged in the urine. The renal excretion of methotrexate is inhibited by several carboxylic acid drugs such as penicillins, probenecid, nonsteroidal anti-inflammatory agents, and aspirin. ▪ Methotrexate toxicity includes myelosuppression, mucositis, nausea, vomiting, severe headaches, renal toxicity. ▪ Methotrexate is a type of medicine that stops cells from dividing. It can be used as a way (other than surgery) to treat a pregnancy that’s impla​nted outside the uterus (ectopic pregnancy). It’s given by injection, and usually just 1 dose is given. ▪ Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. ▪ Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system 15
  • 16. ▪ Methotrexate is one of anticancer agent that acts as antimetabolite and inhibits dihydrofolate reductase enzyme. This results in folic acid deficiency leading to megaloblastic anemia. Folinic acid/ leucovorin: ▪ Leucovorin can be given as rescue therapy as it antagonises the methotrexate thereby controls folic acid deficiency. ▪ As an antidote to effects of certain chemotherapy drugs such as methotrexate ▪ Chemically leucovorin is 5-formyl tetrahydrofolic acid that can act as source of tetrahydrofolate. ▪ Folinic acid is given following methotrexate as part of a total chemotherapeutic plan, where it may protect against bone marrow suppression or gastrointestinal mucosa inflammation. ▪ Initiated after 24 hrs of treatment of methotrexate Folic acid deficiency by methotrexate 16
  • 17. 3. Antibiotics(mycin/bicin) ▪ Many of the antineoplastic antibiotics are produced by the soil fungus Streptomyces. Both the antibiotic and natural product classes have multiple inhibitory effects on cell growth; however, they primarily act to disrupt DNA function and cell division. ▪ There are several mechanisms by which these agents target DNA, including intercalation, alkylation, and strand breakage either directly or as a result of enzyme inhibition Classification of Antibiotics(Cell cycle specific drugs) : A. Anthracyclines B. Actinomycin-D C. Bleomycin D. Mitomycin C 17
  • 18. ▪ Initially discovered in the early 1960s when they were isolated from Streptomyces peucetius, hundreds of compounds belonging to this class have subsequently been discovered of which five are used clinically in the United States (doxorubicin, daunorubicin, idarubicin, epirubicin, and valrubicin). ▪ DOX and DNR are natural compounds , EPI (4'-epidoxorubicin) and IDA (4-demethoxy daunorubicin) are synthetic analogues (second generation anthracyclines) of DOX and DNR, respectively, from which the former two drugs differ by relatively small chemical modifications ▪ The conjugated systems found in these molecules impart a red color, which is reflected in the name. ▪ Doxorubicin is probably the most important anticancer drug available because of its relatively broad spectrum of activity Anthracyclines 18
  • 19. First generation anthracyclines Second generation anthracyclines Third generation anthracyclines Disaccharide Anthracyclines Morpholinyl-Anthracycline Derivatives 19
  • 20. ➢ Doxorubicin ▪ Doxorubicin is available as both the conventional dosage form and a liposomal preparation, both of which are administered by infusion. Doxorubicin HCl powder is available in 10-, 20-, 50-, and 150-mg vials. ▪ Doxorubicin is widely prescribed for the treatment of solid tumours (e.g., breast, ovary and gastrointestinal) and haematologic malignancies (e.g., lymphoma and leukemia) in both adults and children. ▪ The agent is rapidly taken up into tissues following injection with a distributive half-life of 5 minutes followed by a slow elimination half-life of 20 to 48 hrs. The primary route of elimination is in the bile and feces. Metabolism involves reduction of the C-13 ketone to yield doxorubicinol (active) along with cleavage of the amino sugar to give the aglycone. The aglycones are also capable of undergoing redox cycling and producing ROS. ▪ While an effective anti-tumor agent, doxorubicin causes cumulative and dose-dependent cardiotoxicity, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive heart failure that may result in cardiac transplantation or death 20
  • 21. Mechanism of action : ▪ Bind to DNA and inhibit both DNA and RNA synthesis. ▪ Produces breaks in DNA strands by inhibiting topoisomerase II ▪ The anthracyclines are considered specific for the S phase of the cell cycle. ✓ The Doxorubicin –DNA complex is stabilized by the stacking interactions of rings B and C(Semiquinone radicals reduce molecular oxygen to superoxide ions and H2O2 that mediates single-strand scission of DNA) and by hydrogen bonding involving the hydroxyl group at C-9 of ring A, which acts as a donor to N-3 of guanine and as an acceptor from the amino group of the same guanine ✓ Ring D protrudes into the major groove and the amino sugar moiety lies in the minor groove and does not take part in the interaction with DNA, although it is crucial for antitumor activity ✓ As other antitumor intercalating agents, anthracyclines are topoisomerase II poisons because of the formation of a stable drug–DNA–topoisomerase II ternary complex and consequent inhibition of replication and transcription. ✓ The sugar unit is crucial for the stabilization of this complex, and suppression of the C-4 methoxy and C-3′ amino groups increases topoisomerase II inhibition ✓ The formation of covalent bonds between anthracyclines and DNA also is supported by several studies in which formaldehyde is produced by oxidation of cellular components or other anthracycline molecules. This oxidation results from the production of ROS such as H2O2, which are generated during redox cycling of anthracyclines . ✓ The generated formaldehyde may then form a methylene bridge between the 4- amino group of the anthracycline and the 2-amino group of guanine in DNA C9 formaldehyde formaldehyde 21
  • 23. Mechanism of anthracycline-Induced Cardiotoxicity ▪ The molecular mechanisms responsible for anthracycline-induced cardiotoxicity focusing on the pathogenic: 1. Role of Reactive Oxygen Species (ROS) 2. Anthracycline secondary alcohol metabolites ▪ Although the anthracyclines produce several adverse effects that are typical for antineoplastics, cardiotoxicity is a special concern with this class of agents. The associated cardiomyopathies and congestive heart failure (CHF) have been related to the ability of these compounds to undergo redox cycling. ▪ This is most notable in the case of daunorubicin and doxorubicin and less of a problem in the newer derivatives, idarubicin and epirubicin. ▪ However, several risk factors depending on patient and treatment characteristics may increase the incidence and severity of anthracycline-related cardiotoxicity. Age at treatment (less than 18 or more than 65 years), sex (female), race (black), genetic polymorphisms, pre-existing cardiovascular pathologies (coronary artery disease, left ventricular dysfunction, hypertension etc.), metabolic (diabetes) or genetic (trisomy 21) diseases as well as higher administration rate, concomitant radiation therapy and combination chemotherapy are known to increase the risk of developing anthracycline-induced cardiotoxicity at much lower cumulative doses 23
  • 24. ▪ Anthracyclines can generate ROS generation in two ways: through an enzymatic mechanism involving several mono-electronic oxidoreductases, and through a non- enzymatic mechanism involving anthracycline – complexes iron. ▪ Several enzymes, including NAD(P)H-oxidoreductases and CYP reductases, reduce the C ring of anthracyclines by one or two electrons, resulting in semiquinone or hydroquinone. The scheme describes the case of a single electron reduction .In futile redox cycling, this can revert to the starting quinone, resulting in the development of asuperoxide radical. ▪ The radical is normally converted to H2O2 by superoxide dismutase and H2O2 is then converted to H2O and O2 by catalase. However, the production of superoxide (O2 -.) is also associated with the release of iron from intracellular stores, which may be chelated by anthracycline. The iron then causes catalase to divert the normal detoxification pathway, resulting in the production of more active radicals such as the hydroxyl radical (. OH) .Catalase levels in myocardial cells are lower, making them less able to detoxify the H2O2 produced by redox cycling. As a result of the elevated levels of. OH, for which there is no detoxification pathway, cellular damage occurs. ▪ Reactive oxygen species, or ROS, are materials like O2 -.,. OH, and H2O2 that cause cellular damage when present in high enough concentrations. Single-strand breaks in DNA are caused by hydroxyl radicals, which activate p53 and increase apoptosis in cardiac cells. Doxorubicin administration has also been shown to activate both the intrinsic and extrinsic pathways of apoptosis in a variety of ways, which has been linked to an increase in H2O2 and hydroxyl radical production (14,15). One proposed mechanism involves damage to the mitochondrial membrane by H2O2 and. OH resulting in the release of cytochrome c, which would activate the intrinsic pathway Role of Reactive Oxygen Species (ROS) 24
  • 25. Process of anthracycline redox cycling 1. Role of Reactive Oxygen Species in Anthracycline Induced Cardiotoxicity Superoxide Doxorubicin Semiquinone 25
  • 26. 2- Role of Secondary Alcohol Metabolites in Anthracycline-Induced Cardiotoxicity Metabolism of doxorubicin ▪ Additional cardiotoxicity mechanisms have been suggested, including the metabolic reduction of the anthracycline C-13 ketone to alcohol. The resulting alcohols have been linked to a variety of pharmacological effects, including loss of Ca+2 homeostasis and inhibition of Na +/K+-ATPase in cardiac cells. ▪ The formation of doxorubicin C-13 alcohol, doxorubicinol has been associated with conversion of iron regulatory protein-1 (IRP-1) into a null protein that is no longer able to maintain iron homeostasis. It's been suggested that doxorubicin-induced cardiotoxicity is caused by a lack of iron regulation. 26
  • 27. ➢ Mitoxantrone Hcl (Dhad, Novantrone): ▪ Mitoxantrone is a synthetic agent, it is included with the natural products because it is mechanistically similar to the anthracyclines. Produced in the late 1970s, it is a derivative of a synthetic dye and is classified as an anthracenedione. ▪ Mitoxantrone is supplied as a blue aqueous solution in 10- and 20-mg vials for IV administration in the treatment of acute lymphoid leukemia, acute myeloid leukemia, breast cancer, prostate cancer, non-Hodgkin’s lymphoma, and multiple sclerosis. ▪ In this case, however, other enzymes such as myeloperoxidase are responsible for the generation of formaldehyde. Topoisomerase II is inhibited, and strand breakage occurs similar to that seen with the anthracyclines. ▪ In contrast to the anthracyclines, mitoxantrone is not a substrate for the reductase enzymes responsible for the conversion to the semiquinone so that ROS are not generated by this process. ▪ This has the effect of reducing the cardiotoxicity but not completely eliminating it, and caution should be used especially in those patients with existing cardiovascular problems. 27
  • 28. Antidot for cardiotoxicity of anthracycline (Iron chelators) ➢ Dexrazoxane((Zinecard, Cardioxane) ▪ Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as anthracyclines, such as daunorubicin or doxorubicin or other chemotherapeutic agents. ▪ However, in July 2011 the European Medicines Agency (EMA) released a statement restricting use only in adult patients with cancer who have received > 300 mg/m2 doxorubicin or > 540 mg/m2 epirubicin and general approval for use for cardioprotection. It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial drugs Mechanism: ▪ As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. ▪ Dexrazoxane binds iron before it enters cardiomyocytes which prevents the formation of the iron-anthracycline complex, thereby preventing free radical formation and thus, cardiac damage. In addition, dexrazoxane can change the configuration of topoisomerase 2β, preventing anthracyclines from binding to it, further preventing cardiomyocyte death, mitochondrial dysfunction, and the suppression of anti-oxidant gene expression. ▪ Dexrazoxane is a topoisomerase II inhibitor that, unlike anthracyclines, does not cause strand breaks. This additional property is critical for its use as an antidote for anthracycline extravasation. 28
  • 29. Actinomycin-D ▪ Dactinomycin is available in vials containing 0.5 mg of the drug for reconstitution in sterile water for IV administration This antibiotic is most effective in the treatment of rhabdomyosarcoma(skeletal muscle) and Wilms tumor(kidney) in children as well as in the treatment of choriocarcinoma(uterus), Ewing sarcoma(bone), Kaposi sarcoma, and testicular carcinoma. ▪ The actinomycins are a group of compounds that are isolated from various species of Streptomyces, all of which contain the same phenoxazone chromophore but differ in the attached peptide portion ▪ From this group emerged actinomycin D, which is known as dactinomycin and contains identical pentapeptides bound through an amide linkage utilizing the amino group of L -threonine with carbonyls at positions 1 and 9 . The pentapeptides namely L -threonine, D -valine , L -proline , sarcosine , and L - methylvaline form a lactone via the side chain hydroxyl of L- threonine and the carboxyl group of L -methylvaline 29
  • 30. Mechanism of action: Representation of the dactinomycin–DNA complex. DNA intercalation by actinomycin D. 30
  • 31. 4- Plant Products: ➢ Vinca alkaloids ➢ Taxanes ➢ Epipodophyllotoxins Vinca alkaloids ▪ The vinca alkaloids are extracted from the leaves of Catharanthus roseus (periwinkle), and were originally investigated for their hypoglycemic properties but latter found to possess antineoplastic actions. ▪ The alkaloids are composed of a catharanthine moiety containing the indole subunit and the vindoline moiety containing the dihydroindole subunit joined by a carbon–carbon bond 31
  • 32. ➢ Vincristine and vinblastine differ only in the group attached to the dihydroindole nitrogen, which is a methyl group in vinblastine and a formyl group in vincristine. ➢ Vincristine sulfate is available as a 1-mg/mL solution in 1-,2-, and 5-mL vials for IV administration in acute leukemia. ➢ Vinblastine is used in combination with other chemotherapy drugs to treat Hodgkin's lymphoma (Hodgkin's disease) and non- Hodgkin's lymphoma, and cancer of the testicles. ▪ Vinorelbine is a semisynthetic material resulting from the loss of water across the 3,4 bond. It is FDA approved for the treatment of NSCLC. The agent has also been used in treating metastatic breast cancer, cervical cancer, uterine cancer, and lung cancer, especially in older patients or those with physical difficulties ▪ Vinorelbine is the most lipophilic of the vinca alkaloids because of modifications of the catharanthine ring system and dehydration of the piperidine ring. This allows the agent to be quickly taken up into cells including lung tissue where concentrations are 300-fold higher than plasma concentrations. This is 3 to 13 times higher than the lung concentrations seen with vincristine. Structures of vinca alkaloids. 32
  • 33. Mechanism of action: ▪ They are cell-cycle specific and phase-specific because they block mitosis in metaphase (M phase). ▪ They block the ability of tubulin to polymerize to form microtubules. ▪ The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation. 33
  • 34. Taxanes ▪ The taxanes, specifically, taxol (or paclitaxel) was discovered in the 1960s as part of a large-scale screening program conducted by the National Cancer Institute on plant extracts. ▪ Taxol, isolated from the bark of the pacific yew tree, proved to be active against various cancer models, it’s used in the treatment of lung, breast, and ovarian cancer. ▪ The taxanes bind to tubulin at a site distinct from the vinca alkaloids. Bind to stabilized microtubules once they have formed, resulting in the arrest of normal mitotic cell division and subsequently cell death. ➢ Paclitaxel ➢ Docetaxel 34
  • 36. ▪ The major toxicity seen with paclitaxel is dose-limiting myelosuppression that normally presents as neutropenia. The previously mentioned hypersensitivity reactions occur but are greatly reduced by antihistamine pretreatment. ▪ The adverse effects profile for docetaxel is similar to that of paclitaxel but also includes reversible fluid retention that is dose-related. Restriction of sodium intake and pretreatment with corticosteroids is usually successful in minimizing this adverse effect. Peripheral neuropathy is seen with docetaxel but occurs less often than with paclitaxel Structures of the taxanes 36
  • 37. Epipodophyllotoxins ▪ The epipodophyllotoxins are semisynthetic derivatives of podophyllotoxin, which is isolated from the mayapple (mandrake) root and functions as an inhibitor of microtubule function. ▪ Etoposide and its analog, teniposide are semisynthetic derivatives of the plant alkaloid. The agent is approved for use in testicular cancer and small cell lung cancer ▪ They block cells in the late S to G2 phase of the cell cycle. ▪ Their major target is topoisomerase II. Binding of the drugs to the enzyme-DNA complex(The etoposide topoisomerase II complex then binds DNA, and strand cleavage occurs ) results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double strand breaks. ▪ 37
  • 38. Structures of the epipodophyllotoxins. 38 ▪ Chemical modification has led to compounds with a different mechanism of action, which involves inhibition of topoisomerase enzymes. The change in the mechanism was associated with the removal of the 4-methyl group of podophyllotoxin. Further alteration in podophyllotoxin involved the addition of the glycosidic portion of the molecules. ▪ ▪ The glycosidic moiety of the epipodophyllotoxins, which is lacking in podophyllotoxin, is associated with converting these compounds from tubulin binders to topoisomerase inhibitors. ▪ ▪ Replacement of the glycosidic 8-methyl group with thiophene gives teniposide, which is 10-fold more potent than etoposide. The glycosidic moiety is not an absolute requirement for the activity, and other more active compounds are known in which it has been replaced. The 4-OH group is important for the activity of the compounds, and loss of this functionality results in greatly reduced levels of strand breaks. ▪ ▪ Etoposide phosphate is a prodrug of etoposide and is converted to the parent by the action of phosphatases. The increased waterer solubility does not require Cremophor EL other vehicles to be used. The agent is administered IV and used in the treatment of germ cell tumors, small cell lung cancers, and NSCLCs.
  • 39. Metabolism of epipodophyllotoxins Metabolism of epipodophyllotoxins 39
  • 40. Miscellaneous compounds ➢ Asparaginase (l-asparaginase, elspar, L-asnase, cristanaspase) ▪ Asparaginase is available in 10-mL vials for intramuscular and IV use in the treatment of acute lymphocytic leukemia. ▪ Tumor cells are unable to synthesize asparagine, and therefore must utilize what is available in the extracellular environment. The agent acts by hydrolyzing extracellular asparagine to aspartate and ammonia. The tumor cells are then deprived of a necessary nutrient, and protein synthesis is inhibited leading to cell death. The agent is specific for the G1 phase of the cell cycle. ▪ Resistance occurs because of the development of the tumor cells ability to produce asparagine synthetase that allows them to synthesize the required amino acid. ▪ Myelosuppression is not generally seen. An increased risk of bleeding and clotting is seen in half of the patients taking the agent. 40
  • 41. ➢ Hydroxyurea (Droxia, Hydrea): ▪ The drug is available in a 500-mg capsule for oral use. Hydroxyurea is often considered an antimetabolite drug, and it is used alone or with other medications or radiation therapy to treat a certain type of chronic myelogenous leukemia (CML; a type of cancer of the white blood cells) ovarian cancer, and essential thrombocytosis. ▪ The mechanism of action of hydroxyurea involves inhibition of DNA biosynthesis by inhibition of the enzyme ribonucleotide reductase. Ribonucleotide reductase (RNR) is a key enzyme that mediates the synthesis of deoxyribonucleotides, the DNA precursors, for DNA synthesis. ▪ The oral bioavailability is quite high approaching 100% and the drug is distributed to all tissues. Hydroxyurea readily enters the CNS and distributes to human breast milk. A major portion of the total dose is excreted unchanged in the urine. ▪ The drug has been shown to increase the toxicity of 5-FU, and hydroxyurea may increase the effectiveness of some antimetabolite HIV drugs. 41