Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones

Jonathan R. Dimmock, N. Murthi Kandepu, Adil J. Nazarali, Travis P. Kowalchuk, Narasimhan Motaganahalli, J. Wilson Quail, Patricia A. Mykytiuk, Gerald F. Audette, Lata Prasad, P. Perjési, Theresa M. Allen, Cheryl L. Santos, Jen Szydlowski, Erik De Clercq, Jan Balzarini

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Abstract

Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2- arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4- methoxyphenylmethylene)-1- benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2- arylidene-1-cycloheptanones 4 which had approximately one-third of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the σ values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,k-n) revealed differences in the locations of the aryl rings which may have contributed to the, variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1-benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.

Original languageEnglish
Pages (from-to)1358-1366
Number of pages9
JournalJournal of Medicinal Chemistry
Volume42
Issue number8
DOIs
Publication statusPublished - Apr 22 1999

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Quantitative Structure-Activity Relationship
Cytotoxicity
Melphalan
Jurkat Cells
X Ray Crystallography
Cytotoxins
Tumor Cell Line
RNA
Apoptosis
T-Lymphocytes
Molecular modeling
Pharmaceutical Preparations
T-cells
X ray crystallography
Bioactivity
Proteins
Tumors
Cells
benzosuberone
cycloheptanone

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Dimmock, J. R., Kandepu, N. M., Nazarali, A. J., Kowalchuk, T. P., Motaganahalli, N., Quail, J. W., ... Balzarini, J. (1999). Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones. Journal of Medicinal Chemistry, 42(8), 1358-1366. https://doi.org/10.1021/jm9806695

Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones. / Dimmock, Jonathan R.; Kandepu, N. Murthi; Nazarali, Adil J.; Kowalchuk, Travis P.; Motaganahalli, Narasimhan; Quail, J. Wilson; Mykytiuk, Patricia A.; Audette, Gerald F.; Prasad, Lata; Perjési, P.; Allen, Theresa M.; Santos, Cheryl L.; Szydlowski, Jen; De Clercq, Erik; Balzarini, Jan.

In: Journal of Medicinal Chemistry, Vol. 42, No. 8, 22.04.1999, p. 1358-1366.

Research output: Contribution to journalArticle

Dimmock, JR, Kandepu, NM, Nazarali, AJ, Kowalchuk, TP, Motaganahalli, N, Quail, JW, Mykytiuk, PA, Audette, GF, Prasad, L, Perjési, P, Allen, TM, Santos, CL, Szydlowski, J, De Clercq, E & Balzarini, J 1999, 'Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones', Journal of Medicinal Chemistry, vol. 42, no. 8, pp. 1358-1366. https://doi.org/10.1021/jm9806695
Dimmock, Jonathan R. ; Kandepu, N. Murthi ; Nazarali, Adil J. ; Kowalchuk, Travis P. ; Motaganahalli, Narasimhan ; Quail, J. Wilson ; Mykytiuk, Patricia A. ; Audette, Gerald F. ; Prasad, Lata ; Perjési, P. ; Allen, Theresa M. ; Santos, Cheryl L. ; Szydlowski, Jen ; De Clercq, Erik ; Balzarini, Jan. / Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 8. pp. 1358-1366.
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