Antitumor effects of synthetic 6,7-annulated-4-substituted indole compounds in L1210 leukemic cells in vitro

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dc.contributor.author Perchellet, Jean-Pierre H.
dc.contributor.author Waters, Andrew M.
dc.contributor.author Perchellet, Elisabeth M.
dc.contributor.author Thornton, Paul D.
dc.contributor.author Brown, Neil
dc.contributor.author Hill, David
dc.contributor.author Neuenswander, Ben
dc.contributor.author Lushington, Gerald H.
dc.contributor.author Santini, Conrad
dc.contributor.author Chandrasoma, Nalin
dc.contributor.author Buszek, Keith R.
dc.date.accessioned 2013-03-20T14:43:12Z
dc.date.available 2013-03-20T14:43:12Z
dc.date.issued 2013-03-20
dc.identifier.uri http://hdl.handle.net/2097/15379
dc.description.abstract Background: Because annulated indoles have almost no representation in the PubChem or MLSMR databases, an unprecedented class of an indole-based library was constructed, using the indole aryne methodology, and screened for antitumor activity. Sixty-six novel 6,7-annulated-4-substituted indole compounds were synthesized, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions, and tested for their effectiveness against murine L1210 tumor cell proliferation in vitro. Materials and Methods: Various markers of tumor cell metabolism, DNA degradation, mitotic disruption, cytokinesis and apoptosis were assayed in vitro to evaluate drug cytotoxicity. Results: Most compounds inhibited the metabolic activity of leukemic cells in a time- and concentration-dependent manner but only 9 of them were sufficiently potent to inhibit L1210 tumor cell proliferation by 50% in the low-μM range after 2 (IC[subscript 50]: 4.5-20.4 μM) and 4 days (0.5-4.0 μM) in culture. However, the antiproliferative compounds that were the most effective at day 4 were not necessarily the most potent at day 2, suggesting different speeds of action. A 3-h treatment with antiproliferative annulated indole was sufficient to inhibit, in a concentration-dependent manner, the rate of DNA synthesis measured in L1210 cells over a 0.5-h period of pulse-labeling with [superscript 3]H-thymidine. Four of the antiproliferative compounds had weak DNA-binding activities but one compound reduced the fluorescence of the ethidium bromide-DNA complex by up to 53%, suggesting that some annulated indoles might directly interact with double-stranded DNA to disrupt its integrity and prevent the dye from intercalating into DNA base pairs. However, all 9 antiproliferative compounds induced DNA cleavage at 24 h in L1210 cells, containing [superscript 3]H-thymidine-prelabeled DNA, suggesting that these antitumor annulated indoles might trigger an apoptotic pathway of DNA fragmentation. Indeed the antiproliferative annulated indoles caused a time-dependent increase of caspase-3 activity with a peak at 6 h. Interestingly, the compounds with the most potent antiproliferative IC50 values at day 2 were consistently the most effective at inhibiting DNA synthesis at 3 h and inducing DNA fragmentation at 24 h. After 24-48 h, antiproliferative concentrations of annulated indoles increased the mitotic index of L1210 cells and stimulated the formation of many bi-nucleated cells, multi-nucleated cells, apoptotic cells and micronuclei, suggesting that these antitumor compounds might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis to induce apoptosis. Conclusion: Although annulated indoles may have interesting bioactivity, novel derivatives with different substitutions must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action. en_US
dc.language.iso en_US en_US
dc.relation.uri http://ar.iiarjournals.org/content/32/11/4671.abstract en_US
dc.rights Permission to archive granted by the International Institute of Anticancer Research (IIAR), February 22, 2013. en_US
dc.subject Annulated indoles en_US
dc.subject Tumor cell proliferation en_US
dc.subject DNA synthesis en_US
dc.subject Interaction and fragmentation en_US
dc.subject Cells with mitotic figures en_US
dc.subject Several nuclei and micronuclei en_US
dc.subject Cytokinesis en_US
dc.subject Apoptosis en_US
dc.title Antitumor effects of synthetic 6,7-annulated-4-substituted indole compounds in L1210 leukemic cells in vitro en_US
dc.type Article (publisher version) en_US
dc.date.published 2012 en_US
dc.citation.epage 4684 en_US
dc.citation.issue 11 en_US
dc.citation.jtitle Anticancer Research en_US
dc.citation.spage 4671 en_US
dc.citation.volume 32 en_US
dc.contributor.authoreid jpperch en_US
dc.contributor.authoreid enperch en_US
dc.contributor.authoreid watand en_US


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