Synthesis and structure-activity relationship of botryllamides that block the ABCG2 multidrug transporter

Abstract

In previous work, botryllamides discovered from the marine ascidian Botryllus tyreus were characterized as selective inhibitors of the ABCG2 multidrug transporter. However, the structural basis for this activity could not be established. In this study, botryllamide F, the core botryllamide structure, and botryllamide G, the most potent botryllamide ABCG2 inhibitor, were synthesized along with a series of structural variants for evaluation of structure-activity relationships. The biological activity of synthetic botryllamide analogs implied that the 2-methoxy-p-coumaric acid portion, and the degree of double bond conjugation within this group, were critical for inhibition of ABCG2. However, variations in the substituents on the two aryl groups did not appear to significantly impact the potency or degree of inhibition.

Figure 1

Strategy for the SAR study of botryllamides.

Scheme 1

Reagents and conditions a) NaOMe, MeOH, reflux, overnight, 75%; b) Octopamine HCl (bis-brominated octopamine for 10), WSCI, HOBt, Et₃N, r.t., 4h.; c) Ac₂O, Pyridine, r.t., 2h, 2steps 58%; d) K₂CO₃, DMSO, 98°C, 2h. 45%