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: F R Kinder Jr, R W Versace, K W Bair, J M Bontempo, D Cesarz, S Chen, P Crews, A M Czuchta, C T Jagoe, Y Mou, R Nemzek, P E Phillips, L D Tran, R M Wang, S Weltchek, S Zabludoff
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 22 Pg. 3692-9 (Oct 25 2001) ISSN: 0022-2623 [Print] United States
• PMID: 11606134 (Publication Type: Journal Article)

Chemical References

• 3,4,5-trihydroxy--2-methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl)non-6enamide
• 3,4,5-trihydroxy-2--methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl)non-6-enamide
• 3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-(hexahydro-2-oxo-6-(tridecylcarbonyl)oxy-2H-azepin-3-yl)non-6enamide
• Antineoplastic Agents
• Azepines
• bengamide B

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Azepines (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Mice, Nude
• Solubility
• Structure-Activity Relationship
• Transplantation, Heterologous
• Tumor Cells, Cultured