title: New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models.
abstract: During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. bruce.g.szczepankiewicz@abbott.com
authors.forename: B G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: H S
authors.initials: HS
authors.lastname: Jae
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: I W
authors.initials: IW
authors.lastname: Gunawardana
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: S L
authors.initials: SL
authors.lastname: Gwaltney
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
authors.forename: L
authors.initials: L
authors.lastname: Gehrke
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: R B
authors.initials: RB
authors.lastname: Credo
authors.forename: J D
authors.initials: JD
authors.lastname: Alder
authors.forename: M A
authors.initials: MA
authors.lastname: Nukkala
authors.forename: N A
authors.initials: NA
authors.lastname: Zielinski
authors.forename: K
authors.initials: K
authors.lastname: Jarvis
authors.forename: K W
authors.initials: KW
authors.lastname: Mollison
authors.forename: D J
authors.initials: DJ
authors.lastname: Frost
authors.forename: J L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Y H
authors.initials: YH
authors.lastname: Hui
authors.forename: A K
authors.initials: AK
authors.lastname: Claiborne
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C442803:A 259745; D000970:Antineoplastic Agents; D010080:Oxazoles; D003078:Colchicine