Novel furano analogues of duocarmycin C1 and C2: design, synthesis, and biological evaluation ofseco-iso-Cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-Cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) analogues
Howard, T. T.; Lingerfelt, B. M.; Purnell, B. L.; Scott, A. E.; Price, C. A.; Townes, H. M.; McNulty, L. M.; Handl, H. L.; Summerville, K.; Hudson, S. J.; Bowen, J. P.; Kiakos, K.; Hartley, J. A.; Lee, M. Novel furano analogues of duocarmycin C1 and C2: design, synthesis, and biological evaluation ofseco-iso-Cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-Cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) analogues. Bioorg. Med. Chem. 2002, 10, 2941-2952.
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The design, synthesis and biological evaluation of novel seco-iso-cyclopropylfurano2,3-e]indoline (seco-iso-CFI) and the seco-cyclopropyltetrahydrofurano2,3-f]quinoline (seco-CFQ) analogues of the duocarmycins are described. These novel analogues (4-7) were designed on the premise that the lone pair of electrons on the furano-oxygen atom could enter into conjugation with the isocyclopropylfuranoe]indolone (iso-CFI) alkylating moiety, formed from the loss of HCl in compounds 4-7. The seco-iso-CFI DNA alkylating pharmacophore was synthesized through a well precedented approach of 5-exo-trig aryl radical cyclization with a vinyl chloride. In our studies, in addition to the formation of the seco-iso-CFI product, an equal amount of an unexpected seco-CFQ product was also generated during the radical cyclization reaction. Like CC-1065 and adozelesin, using Taq DNA polymerase stop and thermal cleavage assays, the seco-iso-CFI compounds (4 and 6) and the seco-CFQ compounds (5 and 7) were shown to preferentially alkylate the adenine-N3 position within the minor groove of long stretches of A residues. A MM2 energy optimized molecular model of a 1:1 complex of compound 6 with DNA reveals that the iso-CFI compound fits snugly within the minor groove. Using a MTT based experiment, the cytotoxicity of compounds 4-7 were determined against the growth of murine leukemia (L1210), mastocytoma (P815) and melanoma (B16) cell lines. The concentrations of compounds required to inhibit the growth of these tumor cells by 50% is in the range of 10-ˆ’8M. These compounds were also tested against a panel of human cancer cells by the National Cancer Institute, demonstrating that the compounds exhibited a high level of activity against selected solid tumors. At a concentration of 0.0084Î¼M (based on the IC50 of compound 17 (seco-CBI-TMI) against the growth L1210 cells), while compounds 4 and 17 were toxic against murine bone marrow cells as judged by a colony forming study of freshly isolated murine progenitor hematopoeitic cells, compound 5, a seco-CFQ compound, was significantly less toxic. Flow cytometric analysis of P815 cells that had been incubated for 24h with compounds 4 and 5 at their cytotoxic IC50 concentrations indicated the induction of apoptosis in a large percentage of cells, thereby suggesting that this might be the mechanism by which the iso-CFI compounds kill cells.
Bioorganic & Medicinal Chemistry