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.
J Org Chem
; 68(23): 8984-90, 2003 Nov 14.
Article
em En
| MEDLINE
| ID: mdl-14604371
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirrolidinonas
/
Ciclopropanos
/
Indóis
Tipo de estudo:
Evaluation_studies
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article