title: Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography.
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 1l 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.
authors.affiliation: College of Pharmacy and Nutrition, Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada. dimmock@skyway.usask.ca
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Zello
authors.forename: Eliud O
authors.initials: EO
authors.lastname: Oloo
authors.forename: J Wilson
authors.initials: JW
authors.lastname: Quail
authors.forename: Heinz-Bernhard
authors.initials: HB
authors.lastname: Kraatz
authors.forename: Pál
authors.initials: P
authors.lastname: Perjési
authors.forename: Ferenc
authors.initials: F
authors.lastname: Aradi
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Novák
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Allen
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Santos
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D018360:Crystallography, X-Ray; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm