Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography

Jonathan R. Dimmock, Cheryl L. Santos, Jan Balzarini, Erik De Clereq, James P. Stables, Gordon A. Zello, Eliud O. Oloo, J. Wilson Quail, Heinz Bernhard Kraatz, Pál Perjési, Ferenc Aradi, Krisztina Takács-Novák, Theresa M. Allen

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Abstract

Three series of 2-arylidenebenzocycloalkanones 1-3 were prepared in order to compare the topography of the molecules with cytotoxicity. These compounds contain two aryl rings whose spatial relationships to each other were influenced by the size of the alicyclic ring and the nature of the substituents in the arylidene aryl rings. All compounds were evaluated against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. From these results, 1l and 2c,l emerged as useful lead molecules and 11 was shown to significantly inhibit macromolecular DNA, RNA, and protein syntheses in L1210 cells. Various interatomic distances, bond angles, and a torsion angle of 19 representative compounds were determined by X-ray crystallography, and correlations between these data and the cytotoxicity were noted in nearly 40% of the cases examined. Structure-activity relationships revealed that in general, the steric properties of the groups in the arylidene aryl ring, as revealed by measurements of the molar refractivity values, contributed more to bioactivity than the electronic and hydrophobic properties of the aryl substituents. The compounds displayed little murine toxicity, which favors the decision to develop these molecules as cytotoxic and anticancer agents.

Original languageEnglish
Pages (from-to)3103-3111
Number of pages9
JournalJournal of Medicinal Chemistry
Volume45
Issue number14
DOIs
Publication statusPublished - Jul 4 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Dimmock, J. R., Santos, C. L., Balzarini, J., De Clereq, E., Stables, J. P., Zello, G. A., Oloo, E. O., Quail, J. W., Kraatz, H. B., Perjési, P., Aradi, F., Takács-Novák, K., & Allen, T. M. (2002). Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography. Journal of Medicinal Chemistry, 45(14), 3103-3111. https://doi.org/10.1021/jm010559p