title: Synthesis of flexible sulfur-containing heteroarotinoids that induce apoptosis and reactive oxygen species with discrimination between malignant and benign cells.
abstract: Regulation of growth, differentiation, and apoptosis by synthetic retinoids can occur through mechanisms that are dependent and independent of their ability to bind and activate nuclear retinoic acid receptors. The objective of this study was to determine if increasing flexibility of the heteroarotinoid structure would affect the specificity of the synthetic retinoids for the receptors and for their regulation of cancerous and nonmalignant cells. Methods were developed to produce the first examples of heteroarotinoids 15a-15h, which contain urea and/or thiourea linking groups between two aryl rings. Substituents at the para position of the single phenyl ring were either an ester, a nitro group, or a sulfonamide group. Ovarian cancer cell lines Caov-3, OVCAR-3, SK-OV-3, UCI-101, and 222 were utilized, and the inhibitory prowess of the heteroarotinoids was referenced to that of 4-HPR (25). Similar to 4-HPR (25), the heteroarotinoids inhibited growth of all cell lines at micromolar concentrations. Although the heteroarotinoids did not activate retinoic acid receptors, the agents induced potent growth inhibition against the cancer cells with weak activity against normal and benign cells. The growth inhibition was associated with cell loss and induction of reactive oxygen species.
authors.affiliation: Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA.
authors.forename: Shengquan
authors.initials: S
authors.lastname: Liu
authors.forename: Chad W
authors.initials: CW
authors.lastname: Brown
authors.forename: K Darrell
authors.initials: KD
authors.lastname: Berlin
authors.forename: Aridam
authors.initials: A
authors.lastname: Dhar
authors.forename: Suresh
authors.initials: S
authors.lastname: Guruswamy
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Ginger J
authors.initials: GJ
authors.lastname: Gardner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Doris M
authors.initials: DM
authors.lastname: Benbrook
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry; D014508:Urea / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014508:Urea; D013890:Thiourea