DA4 Exam 3

thompk31's version from 2017-04-26 11:50

Mitosis Inhibitors MOA

Question Answer
Vinca AlkaloidsBind at the dimer of the alpha and beta tubulin subunits near the GTP-binding site. Binding blocks GTP binding and prevents tubulin polymerization. At higher concentrations, more binding sites are exposed, and the tubulin polymer disintegrates. This leads to unusual cellular pathologies featuring “clumps” or “stars” of tubulin spindle fibers. Vincristine is most tightly-bound, whereas vinblastine is the least tightly-bound.
PaclitaxelBinds to beta-tubulin subunit and inhibits disassembly. The cytotoxic effect of paclitaxel is dependent on dose and duration of exposure. Drugs that block progression of the cell cycle before M phase antagonize the effects of taxanes.
TaxanesAt therapeutic doses, taxanes exhibit 1 to 20 micromolar intracellular concentration. The taxane-tubulin binding promotes elongation of microtubules and inhibits disassembly into the mitotic spindle. Thus, the mitotic phase of cell division is disrupted. At micromolar concentrations, extensive polymerization causes formation of large structures called asters.
EpothilonesMicrotubule-stabilizing agents (same mechanism of action as taxanes).Bind to beta tubulin ~ taxanes. Epothilones bind at or near the same binding site as paclitaxel. Smaller than taxanes. Stabilization of tubulin polymerization disrupts cell cycle at G2-M interface and causes apoptosis.

Mitosis Inhibitors SAR

Question Answer
Vinca AlkaloidsHave catharanthine and vindoline portions
TaxanesTaxanes are diterpenoid molecules derived from taxadiene (C20 diterpene) with a C15-taxane core fused to an oxetane ring. The molecule is divided into “northern” (critical functional groups) and “southern” (taxane) portions. Northern portion governs proper orientation of functional groups. Southern portion governs receptor binding. Paclitaxel binds at the β-tubulin subunit in a folded-T or “butterfly” shape.
EpothilonesC3-C8 of the macrolide ring is required to maintain tubulin binding activity.

Mitosis Inhibitors Metabolism

Question Answer
Vinca AlkaloidsAll vinca alkaloids undergo O4 deacetylation and CYP3A4 modifications before biliary excretion.
TaxanesCYP3A4 para hydroxylated benzyl substituents. CYP2C8 6-alpha-hydroxy paclitaxel (major metabolite).
Ixabepilonedecreases metabolism by carboxyesterases. Metabolized by CYP3A4.

Topoisomerase Inhibitors MOA

Question Answer
CamptothecinInhibits topoisomerase I by binding to the topoisomerase I-DNA covalent complex. It prevents religation of single-stranded breaks. This stabilizes the transient DNA-topoisomerase I complex.
IrinotecanProdrug metabolized by carboxyl esterase to active metabolite SN-38.
Epipodophyllotoxin bind to topoisomerase II and have NO effect on microtubular structure or function at usual concentrations
Podophyllotoxininhibits microtubule assembly and binds to tubulin at site distinct from vinca alkaloid binding (not used clinically)

Topoisomerase Inhibitors SAR

Question Answer
CamptothecinAlkaloid with a fused 5-ring backbone and pentacyclic lactone. Flat ring allows intercalation with DNA.

Topoisomerase Inhibitors Metabolism

Question Answer
TopotecanLactone = UDP glucuronyl transferase. Dihydroxyacid = CYP3A4.
IrinotecanSN-38 is inactivated by glucuronidation-UGT1A1. Once in the lumen of the intestine, SN-38G undergoes cleavage by bacterial glucuronidases and reenters the circulation through intestinal absorption. Enterohepatic recycling causes local diarrhea due to exposure of SN-38G and exposure to SN-38 (local effect).

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