Synthesis and in vitro cytotoxic evaluation of novel diazaspiro bicyclo hydantoin derivatives in human leukemia cells: A SAR study
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To study the structure activity relationship (SAR) on the cytotoxic activity and probe the structural requirement for the potent antitumor activity, a series of novel diazaspiro bicyclo hydantoin derivatives were designed and synthesized. Their structures were confirmed by 1H NMR, LCMS and IR analyses. The antiproliferative effect of these compounds were determined against human leukemia, K562 (chronic myelogenous leukemia) and CEM (T-cell leukemia) cells using trypan blue and MTT assay, and the SAR associated with the position of N-terminal substituents in diazaspiro bicyclo hydantoin have also been discussed. It has been observed that these compounds displayed strong, moderate and weak cytotoxic activities. Interestingly, compounds having electron withdrawing groups at third and fourth position of the phenyl ring displayed selectively cytotoxic activities to both the cell lines tested with IC50 value lower than 50 μM. In addition, the cytotoxic activities of the compounds 7(a–o) bearing the substituents at N−3 position of diazaspiro bicyclo hydantoin increases in the order alkene > ester > ether and plays an important role in determining their antitumor activities. The position and number of substituents in benzyl group attached to N−8 of diazaspiro bicyclo hydantoin nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.
KeywordsDiazaspiro bicyclo hydantoin Cytotoxic activities Trypan blue dye exclusion assay MTT assay Leukemia SAR
The authors are grateful to UGC, Govt. of India for financial support to K.S.R. under the project UGC-SAP (Phase I) vide No. F. 540/10/DRS/2004-05 (SAP I). Grants from DBT India (BT/PRS129/GBD/27/-7/2006) and Lady Tata Memorial Trust, London, UK for SCR is also acknowledged.
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