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Novel (S) - (-) - and R- (+) -seco-iso-cyclopropylfurano[e]indoline-5,6,7-trimethoxyindole-2-carboxamide (iso-CFI) analogs of duocarmycin C2: synthesis and biological evaluation

Purnell, B.; Lingerfelt, B.; Scott, A.; Townes, H.; Summerville, K.; Hudson, S.; Kiakos, K.; Hartley, J.A.; Lee, M.

Medicinal Chemistry 2(2): 139-146

2006

ISSN/ISBN: 1573-4064
PMID: 16787363
Accession: 049715032
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Racemic seco-iso-CFI (cyclopropylfurano[e]indoline) analogs of the duocarmycins and CC-1065 have recently been reported by our group. These compounds covalently react with AT-rich sequences of DNA, and they exhibit potent cytotoxicity against cancer cells but are less toxic to normal bone marrow cells. This article details the synthesis of enantiomerically pure (S)-(-)- and R-(+)-seco-iso-CFI (cyclopropylfurano[e]indoline)-5,6,7-trimethoxyindole-2-carboxamide analogs, (S)-(-)-1 and (R)-(+)-1, respectively. The covalent DNA binding properties and cytotoxicity of both enantiomers against L1210 murine leukemia and B16 murine melanoma cells grown in culture are reported and compared to racemate (+/-)-1. The natural (S)-(-)-enantiomer of 1 is more reactive with DNA and more cytotoxic than its unnatural mirror image and the racemic mixture.

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