Cytotoxic and Topographical Properties of 6-Arylidene-2-dimethylaminomethylcyclohexanone Hydrochlorides and Related Compounds

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 19; no. 1; pp. 1 - 10
• Main Authors: Dimmock, J.R., Chamankhah, M., Das, U., Zello, G.A., Quail, J.W., Yang, J., Nienaber, K.H., Sharma, R.K., Selvakumar, P., Balzarini, J., De Clercq, E., Stables, J.P.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.02.2004; Taylor & Francis
• Subjects: Acyltransferases - metabolism; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Crystallography, X-Ray; Cyclohexanones - chemistry; Cyclohexanones - pharmacology; Cytotoxicity; Drug Screening Assays, Antitumor; Human N-myristoyltransferase; Humans; Inhibitory Concentration 50; Mannich bases; Mannich Bases - chemistry; Mannich Bases - pharmacology; Mice; Molecular modeling; Molecular Structure; Protein-Tyrosine Kinases - metabolism; QSAR; Quantitative Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tumor Cells, Cultured; Tyrosine kinase; X-ray crystallography
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756360310001624975

A number of 2-arylidenecyclohexanones (1a-h) were converted into the corresponding Mannich bases (2a-h) and (3a,f). Evaluation against murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed the marked cytotoxicity of the Mannich bases and also the fact that almost invariably these compounds were more potent than the precursor enones (1a-h). Further evaluation of most of the Mannich bases towards a panel of nearly 60 human tumour cell lines confirmed their utility as potent cytotoxins. In this assay, the compounds showed growth-inhibiting properties greater than the anticancer alkylator melphalan. QSAR studies revealed that in some cell lines compounds possessing small electron-attracting aryl substituents showed the greatest potencies. Molecular modeling and X-ray crystallography demonstrated that various interatomic distances and torsion angles correlated with cytotoxicity. A representative compound (2a) demonstrated weak inhibiting properties towards human N-myristoyltransferase and stimulated a tyrosine protein kinase. A single dose of 100 mg/kg of most of the compounds did not prove to be lethal in mice.