New vitamin B₁₂ derivatives activates sGC

Background

Protoporphyrin IX (PPIX) was shown to strongly activate in vitro the soluble guanylate cyclase enzyme (sGC), which makes it an interesting drug candidate for treatment of hypertension [1, 2]. In order to overcome the problem of PPIX poor bioavailability (especially in the case of oral administration), we decided to exploit the specific uptake pathway of vitamin B₁₂, which was frequently used for delivering biologically active substances from the digestive system into the body cells. To this end, we embarked on the synthesis of a series of hybrid molecules, containing PPIX and vitamin B₁₂ moieties, linked via chains of different length and chemical character [3].

Methods and results

Our synthetic approach is based on the synthesis of linking molecules containing a primary -NH₂ group and -N₃ or alkyne group at the other end. Amine functionality allows us to connect these linkers to vitamin B₁₂, and to PPIX, finally, the union of the two parts is possible using Cu-catalyzed azide alkyne cycloaddition (the “click reaction”) [4].