Cytotoxic Mannich Bases of 1-Arylidene-2-tetralones |
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Authors: | JR DIMMOCK MP PADMANILAYAM U DAS GA ZELLO RK SHARMA A SHRIVASTAV |
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Institution: | 1. College of Pharmacy and Nutrition, University of Saskatchewan, S7N 5C9, Saskatoon, Saskatchewan, Canadadimmock@skyway.usask.ca;3. College of Pharmacy and Nutrition, University of Saskatchewan, S7N 5C9, Saskatoon, Saskatchewan, Canada;4. Health Research Division, Department of Pathology, College of Medicine and Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, S7N 4H4, Saskatoon, Saskatchewan, Canada |
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Abstract: | Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2–10?μM range. QSAR using the cytotoxicity data for 2a–e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a–f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate antineoplastic agents serving as prototypes for future development. |
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Keywords: | Mannich bases 2-Tetralones Cytotoxicity N-myristoyltransferase |
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