title: Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids.
abstract: Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.
authors.affiliation: Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Xudong
authors.initials: X
authors.lastname: Geng
authors.forename: Raphaël
authors.initials: R
authors.lastname: Geney
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lauher
authors.forename: Shujun
authors.initials: S
authors.lastname: Xia
authors.forename: Susan B
authors.initials: SB
authors.lastname: Horwitz
authors.forename: Jean M
authors.initials: JM
authors.lastname: Veith
authors.forename: Paula
authors.initials: P
authors.lastname: Pera
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008870:Microtubules / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D043823:Taxoids / Q000138:chemical synthesis* / Q000494:pharmacology; D014404:Tubulin / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D047028:Macrocyclic Compounds; D043823:Taxoids; D014404:Tubulin