title: 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.
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 (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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 501A 725 Rose Street, Lexington, KY 40536, USA.
authors.forename: Shama
authors.initials: S
authors.lastname: Nasim
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D013830:Thiadiazoles