title: Synthesis and antitumor activity of sulfur-containing 9-anilinoacridines.
abstract: A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer potential. Among the compounds, both diol-containing compounds, 2a and 3, were the most cytotoxic of the sulfide series against V-79 cells in vitro (IC(90) = 2.1 microM and 1.9 microM, respectively). Among the non-alkyl-substituted compounds (7-9), compounds with electron-donating substitution para to the sulfide (7 and 9) were more cytotoxic than the electron-withdrawing nitro-substituted compound 8. The limited SAR suggested the importance of hydroxyl functionality along with its location for the cytotoxicity in the series. A preliminary anticancer screening against P388 leukemia showed that 2a is highly active in vivo as well. Topoisomerase II inhibitory activity appeared to be involved in the cytotoxicity of compound 2a. Sulfoxide compound 2b, which is 6-7-fold less cytotoxic than its sulfide 2a, appears to be a potential bioreductive anticancer prodrug on the basis of its bioreductive metabolism findings.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Chen
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Tang
authors.forename: Zhong-Yue
authors.initials: ZY
authors.lastname: Sun
authors.forename: Chul-Hoon
authors.initials: CH
authors.lastname: Kwon
mesh_terms: D000677:Amsacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006224:Cricetinae; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005347:Fibroblasts / Q000187:drug effects; D000860:Hypoxia; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008956:Models, Chemical; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D013455:Sulfur / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C022202:9-anilinoacridine; D013455:Sulfur; D004250:DNA Topoisomerases, Type II