A novel class of CC-1065 and duocarmycin analogues subject to mitomycin-related reductive activation

被引:34
作者
Boger, DL
Garbaccio, RM
机构
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1021/jo991301y
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A new class of DNA alkylating agents is described that incorporate the quinone of the mitomycins, which is thought to impart tuner cell selectivity as a result of preferential reduction and activation in hypoxic tumors, into the AT-selective binding framework of the duocarmycins capable of mitomycin-like reductive activation and duocarmycin-like spirocyclization and subsequent DNA alkylation. Consistent with this design, the guinone prodrugs fail to alkylate DNA unless reductively activated and then do so with an adenine N3 alkylation sequence selectivity identical to that of the duocarmycins. Additionally, the agents exhibit a selectivity toward DT-Diaphorase (NQO1)-containing versus DT-Diaphorase-deficient (resistant) tumor cell lines, and they were shown to be effective substrates for reduction by recombinant human DT-Diaphorase. As such, the agents constitute effective duocarmycin and CC-1065 analogues subject to reductive activation. In addition, the solvolysis pH rate dependence of a series of reactive spirocyclopropanes revealed a unique and inverted order of reactivity at pH 7 versus pH 3. This behavior and the structural features responsible for it are consistent with an acid-catalyzed reaction at pH 3, but a direct uncatalyzed S(N)2 reaction at; pH 7 that is not subject to acid catalysis.
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页码:8350 / 8362
页数:13
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