Title: Cytotoxic mannich bases of 1-arylidene-2-tetralones
Authors: Dimmock, J R ×
Padmanilayam, M P
Das, U
Zello, G A
Sharma, R K
Shrivastav, A
Selvakumar, P
Pasha, M K
Nienaber, K H
Lee, J S
Allen, T M
Santos, C L
Balzarini, Jan
De Clercq, Erik #
Issue Date: 28-Oct-2003
Series Title: Journal of enzyme inhibition and medicinal chemistry vol:18 issue:4 pages:313-24
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 microM 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 anti-neoplastic agents serving as prototypes for future development.
ISSN: 1475-6366
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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