Anticancer Drugs Part II 2024 PDF

 Faculty of Pharmacy Department of Medicinal Chemistry Level 5 Medicinal Chemistry-III PD-513 Fall Semester 2024/2025 Anticancer Drugs_Part II  Hi 2- Antimetabolites  Anticancer 2- Antimetabolites Antimetabolites are c...

 Faculty of Pharmacy Department of Medicinal Chemistry Level 5 Medicinal Chemistry-III PD-513 Fall Semester 2024/2025 Anticancer Drugs_Part II  Hi 2- Antimetabolites  Anticancer 2- Antimetabolites Antimetabolites are compounds that prevent biosynthesis or utilization of normal cellular metabolites. They are usually closely related in structure to the metabolites (e.g. DNA and RNA templates) that are antagonized. They are categorized by the class of nucleotide they inhibit: 1 Purine Antagonists 2 Pyrimidine Antagonist 3 DNA Polymerase inhibitors 4 Folate Antagonists  Antimetabolites They serve as false substrates for critical nucleotide biosynthesis enzymes  2.A. Purine Antimetabolites Inhibit the synthesis of the purine-based nucleotides: Adenylate MonoPhosphate (AMP) and Guanylate MonoPhosphate (GMP).  Mercaptopurine; Anticancer (6-Mercaptopurine & 6-Thiopurine) They inhibit the synthesis of the purine-based nucleotides adenylate monophosphate (AMP) and guanylate monophosphate (GMP).  It is a prodrug which is transformed in vivo to the triphosphate ribonucleotide which inhibits de novo purine synthesis.  The drug is used for treatment of acute leukemia and pediatric non-Hodgkin's lymphoma. Mercaptopurine (6-Mercaptopurine) Inactive 6- thiouric acid is excreted in the urine → uric acid toxicity HPGRT = hypoxanthine-guanine phosphoribosyl-transferase Mercaptopurine (6-Mercaptopurine) Uric acid toxicity is the most important side effect, Why????? Xanthine oxidase competes with TPMT (thiopurine methyl transferase) for mercaptopurine and converts it to inactive 6-thiouric acid, which is excreted in the urine (uric acid toxicity). Allopurinol, which inhibits xanthine oxidase and increases levels of active 6- thioinosinic acid, can be co-administered with mercaptopurine to increase its duration of action and effective antineoplastic potency and to prevent the uric acid toxicity. Mercaptopurine is an immunosuppressive agent useful in organ transplantation and autoimmune diseases. It suppresses the body’s immune response and is, therefore, useful in protecting donor grafts.  Anticancer Azathioprine  It is an imidazolyl derivative and prodrug of mercaptopurine.  The prodrug azathioprine is slowly converted to 6- mercaptopurine by being attacked by glutathione allowing a more sustained activity.  Azathioprine is an immunosuppressive drug used in organ transplantation and autoimmune diseases.  Mercaptopurine is eliminated from the body very quickly. Azathioprine (Imuran) It is an imidazolyl derivative and prodrug of mercaptopurine. The prodrug azathioprine is slowly converted to 6-mercaptopurine by being attacked by glutathione allowing a more sustained activity. The rate of conversion can be altered, depending on the electron-withdrawing ability of the heterocyclic group. The greater the EW-power, the faster the breakdown. Thus, the strongly EWD “NO2” group is present to ensure efficient conversion to 6-mercaptopurine Azathioprine is an immunosuppressive drug used in organ transplantation and autoimmune diseases. Thioguanine (6-Thioguanine, 6-Mercaptoguanine) The mechanism of action as under 6-mercaptopurine……… It is administered orally in the treatment of nonlymphocytic leukemias Co-administration of allopurinol with thioguanine is not warranted, since the impact of xanthine oxidase on its metabolic degradation is minor. Thiognanine is used orally in treatment of acute leukemia especially in combination with cytarabine  2.B. Pyrimidine Antimetabolites Stop production of pyrimidine-based nucleotides: DeoxyThymidine MonoPhosphate, dTMP (produced via C5-methylation of deoxyuridine monophosphate, dUMP) **The rate-limiting enzyme of the dTMP synthetic pathway is the SH-containing thymidylate synthase, with 5,10-methylene-THF serving as CH3-donating cofactor. All dTMP synthesis inhibitors will inhibit thymidylate synthase either directly or indirectly►►►“thymineless death” in actively dividing cells.  5-Fluorouracil, 5-FU ❑ It is metabolized by dihydropyrimidine dehydrogenase (DPD)* leading to inactive 5-fluoro-5,6-dihydrouracil. This deactivation process could be inhibited by of replacement of F-atom by ethinyl moiety to give 5-ethynyluracil which improves the therapeutic index of 5-FU by 2- to 4-fold. ❑ 5-FU is used as solution or cream for the treatment of premalignant keratosis of skin. ❑ It is administered IV in the palliative treatment of colorectal, breast, stomach, and pancreatic cancers. ❑ Mechanism of action 5-FU is bioactivated to 5-fluoro-2-deoxyuridylic acid monophosphate (5F- dUMP): a powerful competitive inhibitor of thymidylate synthetase.  Anticancer  5-fluorouracil is also metabolized by dihydropyrimidine dehydrogenase (DPD) into inactive 5-fluoro-5,6- dihydrouracil and finally to F--alanine (FBAL) which is Neurotoxic.  This deactivation process could be inhibited by 5- ethynyluracil which improves the therapeutic index of 5- FU by 2- to 4-fold. 5-Fluorouracil, 5-FU  Anticancer Tegafur ❖ Tegafur is a prodrug to 5-FU that is enzymatically converted to 5-FU in the body. ❖ It is used in combination with cisplatin for head and neck cancer, colorectal cancer, breast, pancreatic cancers  Anticancer Capecitabine  Capecitabine is prodrug of 5-fluorouracil (5-FU)  It rapidly and extensively absorbed through gastrointestinal wall as an intact molecule, and rapidly metabolized to 5-FU via a three-step enzymatic process. Fluoxuridine It is the nucleoside derivative (analog) of 5-FU It is a prodrug as is bio-converted via 2′-deoxyuridine kinase–mediated phosphorylation to active form 5-F-dUMP (generated in the multistep biotransformation of fluorouracil). It is given by intra-arterial infusion for the palliative treatment of GI adenocarcinoma Because floxuridine does not generate fluorouracil, it is not a substrate for dihydropyrimidine dehydrogenase (DPD). 2.C. Indirect thymidylate synthase inhibitors (Folate Antagonists) Methotrexate Methotrexate’s C4-NH2 substituent, along with its lack of a 7,8-double bond hold the key to its DHFR-inhibiting action*.  Methotrexate ❑ Methotrexate is a folic acid antagonist structurally designed to compete with dihydrofolic acid (DHF) for the dihydrofolate reductase (DHFR) enzyme. ❑ The direct inhibition of DHFR causes cellular levels of DHF to buildup, which in turn results in feedback (indirect) inhibition of thymidylate synthase Methotrexate is also effective in inhibiting glycine amide ribonucleotide (GAR) transformylase key enzyme in purine nucleotides synthesis.  Methotrexate ◘ Methotrexate can be given orally in the treatment of breast, head and neck, and various lung cancers and in non-Hodgkin's lymphoma. ◘ If severe methotrexate toxicity occurs, reduced folate replacement therapy with 5-formyltetrahydrofolate (leucovorin: Folinic acid) must be initiated as soon as possible. ◘ Leucovorin generates the folate cofactors needed by DHFR (and GAR transformylase) to ensure the continued synthesis of pyrimidine and purine nucleotides in healthy cells. ◘ "Leucovorin rescue" therapy often is given as prophylaxis after high-dose methotrexate therapy.  2.D. DNA polymerase inhibitors/or DNA Chain Elongation Inhibitors ❑ They must be converted invivo to triphosphate nucleotides. ❑ They action involve inhibition of chain elongation via: ❑ Miscoding after incorporation into DNA & RNA. ❑ Inhibiting DNA and RNA polymerase ❑ Inhibiting Ribonucleotide Reductase (RNR)* ❑ They are: Pyrimidine antimetabolites: Cytarabine and Gemcitabine Purine antimetabolites:- Nelarabine and (Fludarabine, Cladribine, Clofarabine)  Cytarabine (ara-C; Cytosar-D) ❑ Cytarabine is analog of cytidine nucleoside, where the normal ribose sugar is replaced by arabinose (2'-OH has a β-configuration) ❑ After conversion to triphosphate (Ara-CTP) → incorporation in DNA and hence miscoding → inhibition of:- Ribonucleotide reductase (RNR) (catalyzes the formation of deoxyribonucleotides from ribonucleotides.)→ inhibiting the conversion of cytidylic acid to 2’-deoxycytidylic acid. DNA and RNA polymerase → Inhibits DNA elongation ❑ It is rapidly metabolized by oxidative deamination to an inactive metabolite. ❑ It is used in the treatment of various leukemias. ❑ It has antiviral activity, and is used for treatment of herpesvirus infection*.  Gemcitabine “dFdC” (Gimzar) ❑ Gemcitabine is a nucleoside analog of deoxycytidine in which the 2H-atoms on the 2' carbon of the sugar base are replaced by 2F-atoms. ❑ Mechanism of action: It is activated invivo to triphosphate analogue: ✓ incorporated in DNA and RNA synthesis leading to cell death. ✓ Inhibits DNA polymerase Its diphosphate analogue is irreversible ribonucleotide reductase (RNR) inhibitor. ❑ It is rapidly metabolized by oxidative deamination to an inactive metabolite. ❑ Gemcitabine is indicated in the treatment of breast, pancreatic, and non- small cell lung cancers.  Anticancer Nelarabine  Nelarabine is a prodrug of Ara-G that was synthesized to increase its water solubility.  In October 2005, it was approved by the FDA for acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.  It is subjected to demethoxylation by adenosine deaminase (ADA) to Ara-G then to the biologically active form Ara-GTP which inhibits ribonucleotide reductase (RNR) and DNA synthesis by chain termination.  Cladribine, Clofarabine & Fludarabine ❑ They are 2-haloadenosine analogs. The C2 halogen renders the molecule resistant to deamination by ADA. ❑ In vivo, they are converted to 5'-triphosphate → inhibiting RNR and DNA polymerase and ribonucleotide reductase (RNR). Cladribine (2-CdA) is indicated in the treatment of hairy cell leukemia. Clofarabine (Cl-F-Ara-A)*: used in acute lymphoblastic leukemia patients. ✓ Advantage: arabinose fluorine group makes it more stable at a lower pH and less prone to degradation in semi-solid formulations Fludarabine* (F-Ara-A) is used in chronic lymphocytic leukemia. ✓ Remember: Vidarabine (Ara-A) is an antiviral drug  Hi 2F. Miscellaneous Antimetabolites  Anticancer Hydroxycarbamide or Hydroxyurea  Hydroxyurea is well absorbed orally and excreted in the urine as urea.  It interferes with DNA synthesis by inhibiting ribonucleotide reductase, thus, decreasing the level of deoxyribonucleotides required for DNA synthesis.  This is due to its ability to chelate with Fe2+ cofactor.  It is used against melanoma and metastatic ovarian cancer. 3- Antimitotic Agents  Antimitotic Agents ❑ Mitosis is the process by which a cell duplicates the chromosomes in its cell nucleus in order to generate two, identical, daughter nuclei. ❑ The protein Tubulin has a role in cell mobility and cell division:- When the cell starts mitosis, tubulin polymerizes to form microtubules. Once the cell stops dividing, microtubules depolymerizes and breaks down to tubulin. ❑ Microtubules are important to cell division through formation of mitotic spindle (which segregates the chromosomes) so become targets for anti- cancer agents.  Antimitotic Agents ❑ Antimitotic agents: ❑ Vinca Alkaloidas (Vinblastine and vincristine)→→Inhibit Polymerization ❑ Estramustine phosphate sodium→→ bind with and dissociates MAP-4 from microtubule → depolymerization and disassembly. ❑ Taxenes (Paclitaxel and Docetaxel) →→Inhibit depolymerization ✓►►►►inhibit tumor growth.  Estramustine phosphate (EMP) ❑ EMP is a diester of estradiol with a C3 normustine (nitrogen mustard– carbamate moiety) ester and a C17β phosphate ester. ❑ EMP is provided as the sodium or meglumine salt. ❑ It is a prodrug of estramustine and estromustine in terms of its cytostatic effects and a prodrug of estradiol in relation to its estrogenic effects ❑ Due to its hydrophilic phosphate ester moiety, EMP is a readily water-soluble compound. Unlike EMP, estramustine is highly lipophilic and non-ionizable. Phosphate ester increases its water solubility allowing IV administration  Estramustine phosphate (EMP) ❑ EMP is a dual cytostatic agent and a hormonal anticancer agent of the estrogen type. So, acts by a dual mechanism of action: direct cytostatic activity (as antimitotic agent) as a form of high-dose estrogen therapy via estrogen receptor-mediated antigonadotropic and functional antiandrogenic effects. ❑ There is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity. ❑ It binds to microtubule-associated protein (MAP-4) → dissociation of this protein from the microtubule → depolymerization and disassembly→→ inhibition of mitosis.  Estramustine phosphate (EMP) ❑ Estramustine uses an estradiol carrier to selectively deliver drug to steroid- dependent prostate tissue, and its use is limited to the treatment of progressive prostate cancer. ❑ The phosphate ester and 3-carbamate groups are readily cleaved during absorption to provide estradiol which explains that: Why this drug is not used to treat estrogen-dependent tumors (e.g., estrogen-dependent breast cancer). EMP produces thromboembolic and cardiovascular complications (toxicity) including pulmonary embolism, deep vein thrombosis, stroke, thrombophlebitis, coronary artery disease (ischemic heart disease; e.g., myocardial infarction), thrombophlebitis, and congestive heart failure with fluid retention.  Vinca Alkaloidas ❑ They bind specifically with tubulin and inhibit polymerizatin. ❑ Vincristine (Oncovin) is in the treatment of acute leukemia and various Hodgkin's and non-Hodgkin's lymphomas. ❑ It is effective member in the following chemotherapy regimen: MOPP, COPP and ABVD: →for treatment of Hodgkin lymphoma. PCV: Procarbazine, CCNU, Vincristine → treatment of brain tumors. The most significant dose-limiting adverse effect is neurotoxicity. ❑ Vinblastine is used in the treatment of advanced bladder and testicular carcinoma. MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin → treatment of advanced bladder cancer.  Taxenes (Paclitaxel and Docetaxel) ❑ Taxenes stabilizes the microtubules i.e., inhibiting depolymerization. ❑ Paclitaxel (Taxol) is indicated for IV use in combination with cisplatin as first-line therapy for advanced testicular, ovarian and lung cancer. ❑ Docetaxel (Taxotere) is used in breast cancer (not used in ovarian cancer). 4- Antitumor Antibiotics  Antitumor Antibiotics ❑ They are broad category of natural or semisynthetic compounds and due to their complex chemical structures, fermentation is still the main source for their production. ❑ They have a variety of mode of action: Interact directly with DNA: via forming strong noncovalent ionic bond with DNA bases. Inhibit topoisomerase II enzyme: which normally regulates unwinding of coiled double-stranded DNA and hence responsible for maintaining proper DNA structure during replication and transcription to RNA. Some Generate cytotoxic free radicals that cause DNA single strand breaking (prevent the uncontrolled growth of cancer cells).  Anthracyclines ❑ They are very closely related to the tetracycline antibiotics. ❑ Structurally, they are glycosides and contain; Amino sugar portion (Glycon: L-daunosamine) Non-sugar portion (Aglycone: planner anthracyclinone or anthroquinone) ❑ They have chelating ability with ions such as Ca+2 and Fe+2 by the quinone and phenolic functions (→ Fe+2 accumulation). Anthracyclines ……rubicin  Anthracyclines ❑ Mode of action: They intercalate with DNA leading to single and double stranded DNA breaks: The positively charged amino group (in the aminosugar) form non-covalent ionic bond with the negatively charged phosphate sugar in DNA. Due to planar structure they can also intercalate or slide into the double helix preventing unwinding of the DNA double helix which ►►Inhibit the topoisomerase II. The generation of Hydroxyl radicals inside the tumor cells promotes single-strand breaks in DNA. ❑ Anthracyclines are useful against acute lymphatic and myelocytic leukemia. Anthracyclines  Anthracyclines ❑ Cardiac toxicity is the major use-limiting side effect of anthracyclines due to the formation of cytotoxic free radicals. The coadministration of Dexrazoxane (cyclic EDTA derivative) (Cardioprotective agent) chelates iron, thus reduce the number of metal ions complexed with anthracycline and hence, decrease the formation of cytotoxic free radicals.  Mitoxantrone (Novantrone) ❑ Mitoxantrone is an anthracenedione with the cationic side-chain amino nitrogen which binds to the anionic phosphate residue of the DNA backbone and inhibit topoisomerase II. ❑ The enhanced stability of the quinone ring (through intra-molecular H-bonding) makes the ring highly resistant to NADPH/CYP450 reductase → No superoxide radicals → No highly toxic hydroxyl radical → No cardiac toxicity. ❑ Used with other agents in the initial treatment of acute non- lymphocytic leukemia and hormone-refractory prostate cancer.  Mitomycins ❑ Mitomycin C is isolated from Streptomycin caespitosus. ❑ Mitomycin C acts by “Bioreductive alkylation” (i.e. reductive activation followed by two N-alkylations) ❑ The quinone, the aziridine ring system and the carbamate are thought to be involved in the action of the drug. ❑ It is usually given by IV administration for treatment of pancreatic cancers. Mitomycins