Quinoxalinehydrazines represent a novel class of compoundswith excellent potency in a panel of cancer cell lines. A prototypecompound, SC144, showed significant in vivo efficacy in micexenograft models of human breast cancer cells. The subsequentstructure–activity relationship study resulted in the discovery ofSC161 with better potency in cancer cell lines. Further exploringthe possible conformational space by a 10 ns molecular dynamicssimulation as presented herein, resulted in various pharmacophoreorientations. The trajectory analysis indicated that in mostof the simulation time, the molecule stays favorably in a compactplanarlike orientation. We therefore built a pharmacophoremodel based on the cluster containing the highest number offrames to represent the most probable orientation. The modelwas used to screen a subset of our small molecule database containing350,000 compounds. We selected 35 compounds for theinitial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazineand quinoline class displayed cytotoxicity invarious cancer cell lines. Five of them, compounds 2, 6, 15, 16,and 19, all bearing an oxadiazolopyrazine scaffold, showed IC50values <3 mm in certain tumor cell lines. The most potent compound,2, showed IC50 values <2 mm in HCT116 p53+/+, HCT116p53/, and HEY cells, and 8 mm in NIH3T3 cells. This study showsthat conformational sampling of a lead small molecule followedby representative pharmacophore model development is an efficientapproach for the rational design of novel anticancer agentswith similar or better potency than the original lead but with differentphysicochemical properties.[a] J. Deng, L. Taheri, F. Grande, F. Aiello, N. NeamatiDepartment of Pharmacology and Pharmaceutical SciencesSchool of Pharmacy, University of Southern California, 1985 Zonal AvenueLos Angeles, California 90089 (USA)Fax: (+1) 323-442-1390E-mail: neamati@usc.edu[b] F. Grande, F. Aiello, A. GarofaloDipartimento di Scienze FarmaceuticheUniversit della Calabria, 87036 Arcavacata di Rende (Cs) (Italy)ChemMedChem 2008,
Discovery of Novel Anticancer Compounds Based on Quinoxalinhydrazide Pharmacophore
F. GRANDE;AIELLO F;A. GAROFALO;
2008-01-01
Abstract
Quinoxalinehydrazines represent a novel class of compoundswith excellent potency in a panel of cancer cell lines. A prototypecompound, SC144, showed significant in vivo efficacy in micexenograft models of human breast cancer cells. The subsequentstructure–activity relationship study resulted in the discovery ofSC161 with better potency in cancer cell lines. Further exploringthe possible conformational space by a 10 ns molecular dynamicssimulation as presented herein, resulted in various pharmacophoreorientations. The trajectory analysis indicated that in mostof the simulation time, the molecule stays favorably in a compactplanarlike orientation. We therefore built a pharmacophoremodel based on the cluster containing the highest number offrames to represent the most probable orientation. The modelwas used to screen a subset of our small molecule database containing350,000 compounds. We selected 35 compounds for theinitial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazineand quinoline class displayed cytotoxicity invarious cancer cell lines. Five of them, compounds 2, 6, 15, 16,and 19, all bearing an oxadiazolopyrazine scaffold, showed IC50values <3 mm in certain tumor cell lines. The most potent compound,2, showed IC50 values <2 mm in HCT116 p53+/+, HCT116p53/, and HEY cells, and 8 mm in NIH3T3 cells. This study showsthat conformational sampling of a lead small molecule followedby representative pharmacophore model development is an efficientapproach for the rational design of novel anticancer agentswith similar or better potency than the original lead but with differentphysicochemical properties.[a] J. Deng, L. Taheri, F. Grande, F. Aiello, N. NeamatiDepartment of Pharmacology and Pharmaceutical SciencesSchool of Pharmacy, University of Southern California, 1985 Zonal AvenueLos Angeles, California 90089 (USA)Fax: (+1) 323-442-1390E-mail: neamati@usc.edu[b] F. Grande, F. Aiello, A. GarofaloDipartimento di Scienze FarmaceuticheUniversit della Calabria, 87036 Arcavacata di Rende (Cs) (Italy)ChemMedChem 2008,I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
