ANTITUMOR AGENTS .3. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BETA-ALKYL DERIVATIVES CONTAINING HYDROXY, AMINO, AND AMIDO GROUPS OF 4'-O-DEMETHYL-4-DEOXYPODOPHYLLOTOXIN AS ANTITUMOR AGENTS

A series of 4beta-alkyl (7-10), 4beta-aminoalkyl (12a-y), and 4beta-am idoalkyl derivatives (14a-g) of 4'-O-demethyl-4-desoxypodophyllotoxin have been synthesized, and their cytotoxicity, inhibition of DNA topoi somerase II (Topo II), and tubulin polymerization were evaluated. All derivatives of 12a-y and 14a-g did not inhibit tubulin polymerization. Many compounds exhibited cytotoxicity and inhibition of Topo II. In p articular, 12o, 12s, 12t, and 12u strongly inhibited Topo II (IC50 (mu M) 32.5, 60.9, 58.8, and 33.6, respectively) and were strong cytotoxic ity against P388 cells (IC50 (M) 1.0, 4.1, 3.3, and 3.0 x 10(-9), resp ectively), compared with VP-16 (IC50 (muM) 59.2, IC50 (M) 1 X 10(-8), respectively). These compounds were nearly equal to or superior to VP- 16 in antitumor activity in vivo (L1210, P388, and Lewis lung) and wer e more cytotoxic against various human cell lines in vitro than VP-16.