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Bioorg Med Chem Lett. 2011 Aug 15;21(16):4879-83. doi: 10.1016/j.bmcl.2011.06.027. Epub 2011 Jun 22.

Discovery of 1,2,4-thiadiazolidine-3,5-dione analogs that exhibit unusual and selective rapid cell death kinetics against acute myelogenous leukemia cells in culture.

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  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 501A 725 Rose Street, Lexington, KY 40536, USA.


4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was previously identified as an antileukemic agent exhibiting no evident toxicity toward normal hematopoietic cells. An SAR study has been carried out to examine the effect of varying the C-2 and C-4- substituents on the thiadiazolidinone ring of TDZD-8 on antileukemic activity. These studies resulted in the identification of more druglike analogs that exhibited comparable potency to TDZD-8 in killing acute myelogenous leukemia (AML) cells in culture. Surprisingly, the cell death kinetics induced by several of these novel analogs on MV-411 cells were extremely fast, with commitment to death occurring within 30 min. At a concentration of 10 μM, 3f (LD(50)=3.5 μM) completely eradicated cell viability of MV-411 cells within 2h, while analog 3e (LD(50)=2.0 μM) decimated cell viability within 30 min at a concentration of 10 μM and effectively abolished cell viability at 5 μM within 1-2h.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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