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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Authors: | Nasim Shama Guzman Monica L Jordan Craig T Crooks Peter A |
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Institution: | a Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 501A 725 Rose Street, Lexington, KY 40536, USA b Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA c James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA |
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Abstract: | 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 (LD50 = 3.5 μM) completely eradicated cell viability of MV-411 cells within 2 h, while analog 3e (LD50 = 2.0 μM) decimated cell viability within 30 min at a concentration of 10 μM and effectively abolished cell viability at 5 μM within 1-2 h. |
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Keywords: | 1 2 4-Thiadiazolidine-3 5-diones Antileukemic Rapid cell death kinetics Acute myelogenous leukemia (AML) |
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