Synthesis and evaluation of bifunctional sGC regulators

Abstract

Background Our previous studies identified dicyanocobinamide as a novel sGC regulator that targets the catalytic region and synergistically enhances activation of sGC by NO-independent regulators. As proof-of-concept study, we designed and synthesized a set of bifunctional sGC regulators, which consist of cobinamide analog conjugated to a protoporphyrin IX derivative through linkers of varying length and composition (Figure 1). Results The length and composition of the linker was proved to be crucial for sGC activation. Our results indicate that only hybrid molecules containing a 13-16 atom chain linker benefited from synergistic engagement of both heme-binding region and catalytic domain. The hybrid compounds containing linkers connected through an ester bond were not only more stable, but also were more effective than those connected though an amide. Hybrids with shorter or longer linkers, or with different linker composition, were much less potent and were no more active than the cobyrinic acid component alone. The most effective compound was conjugated through an ester bond, contained a 13 atom chain linker and a triazole group close to the cobyrinate moiety. This compound displayed more than 60 fold activation of purified sGC.