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.
Publication types
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Evaluation Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents, Alkylating / chemical synthesis*
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Antineoplastic Agents, Alkylating / pharmacology*
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Base Sequence
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Cell Proliferation / drug effects*
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DNA / chemistry
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DNA / drug effects
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DNA / metabolism
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Drug Screening Assays, Antitumor
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Duocarmycins
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Indoles / chemical synthesis*
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Indoles / pharmacology*
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Leukemia L1210 / pathology
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Melanoma, Experimental / pathology
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Mice
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Models, Chemical
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Pyrroles / chemical synthesis
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Pyrroles / pharmacology
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Stereoisomerism
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents, Alkylating
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Duocarmycins
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Heterocyclic Compounds, 3-Ring
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Indoles
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Pyrroles
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pyrindamycin A
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DNA