Synthesis and antitumor activity of ester-modified analogues of bengamide B

Bengamide B, a novel sponge-derived marine natural product with broad spect rum antitumor activity, was not suitable for further preclinical developmen t because of its difficult synthesis and very poor water solubility. Bengam ide B produced a 31% T/C at its solubility-limited maximum intravenous dose of 33 mu mol/kg in MDA-MB-435 breast carcinoma implanted subcutaneously as a xenograft in nude mice. Compound Sa, a bengamide B analogue with three s tructural 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-mod ified analogues based on 8a were synthesized and tested in vitro and in viv o (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 a nd enhanced water solubility (ca. 1 mg/mL). Consequently, 8c and Sg were te sted in the MDA-MB-435 xenograft model at 100 mu mol/kg and produced 29% an d 57% tumor regression, respectively.