title: Synthesis and antiproliferative properties of a new ceramide analog of varacin.
abstract: A benzopentasulfane was synthesized in 8 steps with a ceramide attached through an amide bond to the 7-position of the heterocycle structure. The anticancer activity of this synthetic ceramide-benzopolysulfane drug conjugate was analyzed against five human cancer cell lines MDA-MB-231 (breast), DU145 (prostate), MIA PaCa-2 (pancreas), HeLa (cervix), and U251 (glioblastoma). The ceramide-benzopolysulfane conjugate had IC50 values ranging from 10 to >20 μM with complete cell killing at 12.5 μM for MDA-MB-231 and 20 μM for DU145 and HeLa cells. The ceramide-benzopolysulfane conjugate had IC50 values 1.8 and 4.0 times lower than a PEG benzopolysulfane, N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzo[f][1,2,3,4,5]-pentathiepine-7-carboxamide, for MDA-MB-231 and DU145 cells, respectively. The parent "unsubstituted" benzopolysulfane, o-C6H4S5, had IC50 values 4.2 times lower and 2.7 times higher than the ceramide benzopolysulfane for MDA-MB-231 and DU145 cells, respectively. The results indicate that the polysulfur linkage is needed for activity since benzenedithiol, o-C6H4(SH)2, had IC50 values greater than 30 μM with little effect on MDA-MB-231 and DU145 cells. Thus, to account for the bioactivity, a bimolecular reaction of cellular thiol with the ceramide benzopolysulfane is a proposed followed by thiozone (S3) extrusion.
authors.affiliation: Department of Chemistry and Graduate Center, Brooklyn College of the City University of New York, Brooklyn, New York 11210, USA.
authors.forename: Adaickapillai
authors.initials: A
authors.lastname: Mahendran
authors.affiliation: Department of Chemistry and Graduate Center, Brooklyn College of the City University of New York, Brooklyn, New York 11210, USA.
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Ghogare
authors.affiliation: Department of Chemistry and Biochemistry, and Graduate Center, Queens College of the City University of New York, Flushing, New York 11367, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Arthur
authors.affiliation: Department of Chemistry and Graduate Center, Brooklyn College of the City University of New York, Brooklyn, New York 11210, USA. Electronic address: agreer@brooklyn.cuny.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Greer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D005021:Ethylamines; D013440:Sulfides; C093885:varacin A
keywords: Ceramide drug conjugate; Pentathiepin toxicity; Polysulfur ring; Reactive sulfur species