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

Title: 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

Volume: 2 Issue: 2

Author(s): John A. Hartley, Moses Lee, Konstantinos Kiakos, Stephen Hudson, Heather Townes, Kaitlin Summerville, Adrienne Scott, Brian Lingerfelt and Bethany Purnell

Affiliation:

Keywords: sequence specificity, cytotoxicity, DNA alkylation, CC1065, Duocarmycins

Abstract: 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.

Cite this article as:

Hartley A. John, Lee Moses, Kiakos Konstantinos, Hudson Stephen, Townes Heather, Summerville Kaitlin, Scott Adrienne, Lingerfelt Brian and Purnell Bethany, 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, Medicinal Chemistry 2006; 2 (2) . https://dx.doi.org/10.2174/157340606776056188