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.
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.
authors.affiliation: Department of Chemistry, Furman University, Greenville, SC 29613, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Purnell
authors.forename: Brian
authors.initials: B
authors.lastname: Lingerfelt
authors.forename: Adrienne
authors.initials: A
authors.lastname: Scott
authors.forename: Heather
authors.initials: H
authors.lastname: Townes
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Summerville
authors.forename: Stephen
authors.initials: S
authors.lastname: Hudson
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: 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
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D011758:Pyrroles; C057900:pyrindamycin A; D004247:DNA