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MEDICINAL CHEMISTRY 402 I. (32) Final Exam - Part A Wo (15) December 17, 2002 In. (36) Iv. a7) Please write neatly. TOTAL (100) I. _ Trinotecan hydrochloride (Camptosar®) is a relatively new antitumor agent that is being used to treat metastatic colon cancer and some lung cancers. 1. @ pts) What is the mechanism of action of irinotecan and where does it primarily act in the cell cycle? Bivels to topoisomercce TL anol tuhilvibe this enzymes activity te nick ancl veseel Dl —> Dot sterol vrecley CCS SIG, Phares 2. — Irinotecan is formulated as its hydrochloride salt for LV. use. a. (3 pts) Why is it formulated as a salt form? Tr ovder te soluloiling 4his relatively \geplats ¢ drag in oapeeus solalien Tor Ty, use 5 & sett Lomas req rv th . b. G pts) Circle all of the groups on the structure above that are ionizable at physiological pH and draw on the structure or next to it, the most prevalent monoprotonated hydrochloride salt form of the drug. See ol ote c. (pts) Estimate the pKa of this protonated form. A-\o 3. (3 pts) The stereochemistry shown is required for drug activity. What is the absolute configuration? S 4. (6 pts) Irinotecan is a prodrug that is hydrolyzed by esterases to the therapeutically active phenol. Using partial structures, show the mechanism for general-base catalyzed hydrolysis of irinotecan. ork 1 g.2 \ ot es \ VW N~ Co -O “ i) a _ mo LO Nef vt © & —> Neo Pel 
