title: Design, synthesis, and biological evaluation of new-generation taxoids.
abstract: Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.
authors.affiliation: Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA. iojima@notes.cc.sunysb.edu
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Borella
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Michael L
authors.initials: ML
authors.lastname: Miller
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.forename: Xudong
authors.initials: X
authors.lastname: Geng
authors.forename: Larisa
authors.initials: L
authors.lastname: Kuznetsova
authors.forename: Chuanxing
authors.initials: C
authors.lastname: Qu
authors.forename: David
authors.initials: D
authors.lastname: Gallager
authors.forename: Xianrui
authors.initials: X
authors.lastname: Zhao
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanardi
authors.forename: Shujun
authors.initials: S
authors.lastname: Xia
authors.forename: Susan B
authors.initials: SB
authors.lastname: Horwitz
authors.forename: Jon
authors.initials: J
authors.lastname: Mallen-St Clair
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Guerriero
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
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
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D017354:Point Mutation; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001704:Biopolymers; D043823:Taxoids; D014404:Tubulin; D017239:Paclitaxel