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New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetals. Part 4

2003; Elsevier BV; Volume: 11; Issue: 20 Linguagem: Inglês

10.1016/s0968-0896(03)00454-1

1464-3391

Yasuyuki Takeda, Kouichi Uoto, Jun Chiba, Takao Horiuchi, Michio Iwahana, Ryo Atsumi, Chiho Ono, Hirofumi Terasawa, Tsunehiko Soga,

Microbial Natural Products and Biosynthesis

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.