Synthesis and evaluation of duocarmycin and CC-1065 analogues incorporating the 1,2,9,9a-tetrahydrocyclopropa c benz e -3-azaindol-4-one (CBA) alkylation subunit

Academic Article
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related to degree

  • Kastrinsky, David, Ph.D. in Synthetic Organic Chemistry, Scripps Research 2000 - 2005

publication date

  • November 2003

abstract

  • An efficient eight-step synthesis (53% overall) and the evaluation of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-4-one (CBA) and its derivatives containing an aza variant of the CC-1065/duocarmycin alkylation subunit are detailed. This unique deep-seated aza modification provided an unprecedented 2-aza-4,4-spirocyclopropacyclohexadienone that was characterized chemically and structurally (X-ray). CBA proved structurally identical with CBI, the carbon analogue, including the stereoelectronic alignment of the key cyclopropane, its bond lengths, and the bond length of the diagnostic C3a-N2 bond, reflecting the extent of vinylogous amide (amidine) conjugation. Despite these structural similarities, CBA and its derivatives were found to be much more reactive toward solvolysis and hydrolysis, much less effective DNA alkylating agents (1000-fold), and biologically much less potent (100- to 1000-fold) than the corresponding CBI derivatives.