Abstract #5573: New anti-cancer quinoxalinyl-piperazine compounds: G2/M-specific microtubule inhibitor

Abstract

A series of novel quinoxalinyl-piperazine compounds, 1-[(substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives were synthesized and evaluated as an anti-cancer-agent. From screening of quinoxalinyl-piperazine compound library, we identified that many compounds inhibited proliferation of various human cancer cells at nanomolar concentrations. Among them, one of the fluoro quinoxalinyl-piperazine derivatives showed its IC₅₀ values ranging from 0.011 uM to 0.025 uM in the growth inhibition of cancer cells. This compound also displayed a more potent effect against gemcitabine, paclitaxel or cisplatin-resistant cancer cell lines than the original cytotoxic cancer drugs. The potency of this novel compound was further confirmed with the synergistic cytotoxic effect with several known cancer drugs such as paclitaxel, doxorubicin, cisplatin, gemcitabine or 5-fluorouracil in cancer cells. This strong cell killing effect was derived from the induction of apoptosis. Mechanistic studies have shown that the quinoxalinyl-piperazine compound is a G2/M-specific cell cycle inhibitor and inhibits tubulin polymerization with p21 induction by a unique mechanism. This suggests that the anticancer mechanism of this compound is quite different from that of paclitaxel that is a microtubule stabilizer and the quinoxalinyl-piperazine compound is a unique and new therapeutic anti-cancer drug candidate. This compound inhibited the growth of various human tumors in mouse xenograft models, including renal and pancreas human tumors after oral administration. Pharmacokinetic studies in animal showed good oral bioavailability and no significant accumulation when given intravenously and orally.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5573.