The biosynthesis of the antitumor alkaloids camptothecin, vincaleukoblastine, and perloline is studied by feeding radiolabeled compounds to plant tissues and cell suspension cultures and determining their relative incorporation efficiency into the alkaloids. Stereochemical aspects of the biosynthetic pathway are investigated using both chiral methyl groups and cell-free systems. The catabolism of indole alkaloids and vincaleukoblastine is studied in plants for possible parallels to mammalian metabolic routes. Synthesis of (plus camptothecin and its novel analogs via secocylcopentanomonoterpenoids is developed using available natural products as starting material. Studies of the antitumor effects of camptothecin and two types of its analogs (lipophilic amide-esters and basic, water soluble amide-amines) are done to find analogs with a better therapeutic index and to elucidate its molecular mechanism of action in vitro (HeLa, L1210 cells) and in vivo. This chemistry is an extension of a simple route to such camptothecin analogs developed at UWis-Madison; the new compounds will be tested in vitro (9KB, L1210, PS388) and in vivo (L1210, PS388, B16 colon 22) for cytotoxic and antitumor activity, and in vitro for toxicity (CHO fibroblasts). Covalently-closed circular DNA (PM2, phi X174RF, Col EI) will be used to examine analogs' nicking ability in conjunction with other biochemical procedures capable of defining how the parent drug causes the fragmentation of DNA in vivo.
NIH ExPorter
NIH ExPorter