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.
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.
Parrish
Jay P
JP
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kastrinsky
David B
DB
Hwang
Inkyu
I
Boger
Dale L
DL
D000478:Alkylation; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry
C482964:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)-3-azaindol-4-one; D003521:Cyclopropanes; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; C018782:CC 1065