TQ-B3203, a potent proliferation inhibitor derived from camptothecin
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To develop topoisomerase I targeted drug candidates with sophisticated liposolubility, a series of novel camptothecin derivatives were synthesized through structure-based molecular hybridization and prodrug design approach. The compounds were used as compositions in micellar emulsion preparations, and the antiproliferative efficacy of these preparations were evaluated in two cancer cell lines (A2780s and A549) in vitro. The designed molecules were afterwards optimized for better potency by modifications at the aliphatic chain, the linker and the camptothecin-yl group to reach the optimal structure 7c (TQ-B3203), an SN-38 (camptothecin derivative, 7-ethyl-camptothecin-10-yl) containing compound. 7c showed excellent capacity of inhibiting cell proliferation with IC50 value at nanomolar level, and the potency was further confirmed in other human cancer cell lines (HT-29 and HePG2) superior to the positive reference irinotecan. 7c can be a promising candidate as antitumor drug. Its micellar emulsion preparation has succeeded in the preclinical studies and is in process for investigational new drug(IND) application.
KeywordsCamptothecin Trolox SN-38 Antiproliferative activity Liposoluble
This work was supported by the National Key Basic Research Program of China (2011CB933503), the National High-tech Research and Development Project (863 Project, 2013AA032205), the National Natural Science Foundation of China for Key Project of International Cooperation (61420106012), the Industry Project of Jiangsu Science-technology Support Plan (BE2013840), Science and Technology Development Program of Suzhou (ZXY201412) and the Collaborative Innovation Center of Suzhou Nano Science and Technology.
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Conflict of interest
The authors declare that they have no competing interests.
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