title: Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity.
abstract: Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.
authors.affiliation: Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Keizo
authors.initials: K
authors.lastname: Sugasawa
authors.forename: Onur
authors.initials: O
authors.lastname: Atasoylu
authors.forename: Chia-Ping Huang
authors.initials: CP
authors.lastname: Yang
authors.forename: Susan Band
authors.initials: SB
authors.lastname: Horwitz
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D008870:Microtubules / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
chemical_list: D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; D012996:Solutions; D014404:Tubulin; C071229:discodermolide; D017239:Paclitaxel