Synthesis and antitumor activity of ester-modified analogues of bengamide B.
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.
Kinder
F R
FR
Oncology Department, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901-1398, USA. frederick.kinder@pharma.novartis.com
Versace
R W
RW
Bair
K W
KW
Bontempo
J M
JM
Cesarz
D
D
Chen
S
S
Crews
P
P
Czuchta
A M
AM
Jagoe
C T
CT
Mou
Y
Y
Nemzek
R
R
Phillips
P E
PE
Tran
L D
LD
Wang
R M
RM
Weltchek
S
S
Zabludoff
S
S
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
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