Antitumor effects of synthetic 6,7-annulated-4-substituted indole compounds in L1210 leukemic cells in vitro
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.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.contributor.authoreid | jpperch | en_US |
dc.contributor.authoreid | enperch | en_US |
dc.contributor.authoreid | watand | en_US |
dc.date.accessioned | 2013-03-20T14:43:12Z | |
dc.date.available | 2013-03-20T14:43:12Z | |
dc.date.issued | 2013-03-20 | |
dc.date.published | 2012 | en_US |
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.identifier.uri | http://hdl.handle.net/2097/15379 | |
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 |