A Novel Class of CC-1065 and Duocarmycin Analogues Subject to Mitomycin-Related Reductive Activation.
A new class of DNA alkylating agents is described that incorporate the quinone of the mitomycins, which is thought to impart tumor 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 quinone 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.
Boger
Dale L.
DL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
Garbaccio
Robert M.
RM