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.
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.
Purnell
Bethany
B
Department of Chemistry, Furman University, Greenville, SC 29613, USA.
Lingerfelt
Brian
B
Scott
Adrienne
A
Townes
Heather
H
Summerville
Kaitlin
K
Hudson
Stephen
S
Kiakos
Konstantinos
K
Hartley
John A
JA
Lee
Moses
M
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology*; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008956:Models, Chemical; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D011758:Pyrroles; C057900:pyrindamycin A; D004247:DNA