Antitumor agents. II: Regio- and stereospecific syntheses of 1-beta-alkyl-1-desoxypodophyllotoxin derivatives and biological activity.
1-beta-Alkyl derivatives of 1-desoxypodophyllotoxin were synthesized, and their cytotoxicity and inhibitory effects on DNA topoisomerase II (Topo-II) and tubulin polymerization were examined. The reaction of epipodophyllotoxin derivatives (1a-c) with trimethylallylsilane in the presence of boron trifluoride etherate gave 1-beta-allylated compounds (2a-c). The regiochemistry and the beta-stereochemistry of the 1-allyl group were confirmed by comparison of the 13C-NMR spectra and NOE's (%) of 2c, podophyllotoxin (POD) and epipodophyllotoxin (1b). 1-beta-Alkyl-1-desoxypodophyllotoxin derivatives (3-8) were prepared from 2b. None of the tested compounds (3-8) showed any inhibitory effect on Topo-II. 1-beta-Propyl compound (3) and its 4'-demethyl compound (4) inhibited tubulin polymerization and the cytotoxicities of these compounds were equal to that of VP-16. 1-beta-(2,3-Dihydroxypropyl) compounds (5 and 8) and 1-beta-(2,3-diacetoxypropyl) compounds (6 and 7) showed no inhibitory effect on tubulin polymerization. Although 5 did not inhibit either Topo-II activity or tubulin polymerization, it showed a high cytotoxicity against sarcoma 180.
Terada
T
T
Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Saitama, Japan.
Fujimoto
K
K
Nomura
M
M
Yamashita
J
J
Wierzba
K
K
Kobunai
T
T
Takeda
S
S
Minami
Y
Y
Yoshida
K
K
Yamaguchi
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D014404:Tubulin; D011034:Podophyllotoxin