title: Synthesis and antitumor activity of ester-modified analogues of bengamide B.
abstract: Bengamide B, a novel sponge-derived marine natural product with broad spectrum antitumor activity, was not suitable for further preclinical development because of its difficult synthesis and very poor water solubility. Bengamide B produced a 31% T/C at its solubility-limited maximum intravenous dose of 33 micromol/kg in MDA-MB-435 breast carcinoma implanted subcutaneously as a xenograft in nude mice. Compound 8a, a bengamide B analogue with three structural changes (t-Bu alkene substituent, unsubstituted lactam nitrogen, and inverted lactam 5'-myristoyloxy group), was as potent as bengamide B in vitro and more efficacious than bengamide B in vivo. A series of ester-modified analogues based on 8a were synthesized and tested in vitro and in vivo (MDA-MB-435). The cyclohexyl- and phenethyl-substituted esters, 8c and 8g, respectively, had in vitro and in vivo activities similar to that of 8a and enhanced water solubility (ca. 1 mg/mL). Consequently, 8c and 8g were tested in the MDA-MB-435 xenograft model at 100 micromol/kg and produced 29% and 57% tumor regression, respectively.
authors.affiliation: Oncology Department, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901-1398, USA. frederick.kinder@pharma.novartis.com
authors.forename: F R
authors.initials: FR
authors.lastname: Kinder
authors.forename: R W
authors.initials: RW
authors.lastname: Versace
authors.forename: K W
authors.initials: KW
authors.lastname: Bair
authors.forename: J M
authors.initials: JM
authors.lastname: Bontempo
authors.forename: D
authors.initials: D
authors.lastname: Cesarz
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Crews
authors.forename: A M
authors.initials: AM
authors.lastname: Czuchta
authors.forename: C T
authors.initials: CT
authors.lastname: Jagoe
authors.forename: Y
authors.initials: Y
authors.lastname: Mou
authors.forename: R
authors.initials: R
authors.lastname: Nemzek
authors.forename: P E
authors.initials: PE
authors.lastname: Phillips
authors.forename: L D
authors.initials: LD
authors.lastname: Tran
authors.forename: R M
authors.initials: RM
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Weltchek
authors.forename: S
authors.initials: S
authors.lastname: Zabludoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012995:Solubility; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C438869:3,4,5-trihydroxy--2-methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl)non-6enamide; C438868:3,4,5-trihydroxy-2--methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl)non-6-enamide; C438867:3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(tridecylcarbonyl)oxy-2H-azepin-3-yl)non-6enamide; D000970:Antineoplastic Agents; D001381:Azepines; C427480:bengamide B