title: A non-calcemic sulfone version of the vitamin D(3) analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin.
abstract: Novel side-chain diene sulfones 5, analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9-->10) and Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1alpha,3beta-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 microg/kg of rat body weight.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA. ghp@jhu.edu
authors.forename: G H
authors.initials: GH
authors.lastname: Posner
authors.forename: K R
authors.initials: KR
authors.lastname: Crawford
authors.forename: S
authors.initials: S
authors.lastname: Peleg
authors.forename: J E
authors.initials: JE
authors.lastname: Welsh
authors.forename: S
authors.initials: S
authors.lastname: Romu
authors.forename: D A
authors.initials: DA
authors.lastname: Gewirtz
authors.forename: M S
authors.initials: MS
authors.lastname: Gupta
authors.forename: P
authors.initials: P
authors.lastname: Dolan
authors.forename: T W
authors.initials: TW
authors.lastname: Kensler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D013450:Sulfones; D002762:Cholecalciferol; D004317:Doxorubicin; D002117:Calcitriol; C078903:seocalcitol