Vitamin B₁₂Derivatives as Activators of Soluble Guanylyl Cyclase

Abstract

Various newly prepared and previously known vitamin B12 derivatives have been studied as potential soluble guanylyl cyclase (sGC) activators. All compounds tested were found to activate the sGC enzyme, although to differing extents. The best results were obtained with the derivatives synthesized from c-lactone and possessing aliphatic amides in the c- and d-positions.

Recent trends in the development of vitamin B12derivatives for medicinal applications

“…Base-off forms of Cob(III)-, and Cob(II)alamins can also be obtained by substituting the intramolecularly bound Dmbz base with competitive ligands, for example with water. This derivative was initially developed as a hydrophobic B 12 mimic in the group of Eschenmoser (Figure 4) 23,24 and has nowadays found new applications as photocatalyst, [25][26][27] chemosensor (see chapter 2.1), 17, 28-31 enzyme activators (see chapter 2.4) 32,33 and is also used for fundamental studies 8, 16, 34-38 . In this equilibrium (Figure 3), 13 a low pK base-off value reflects a favoured intramolecular coordination of the Dmbz base to the metal-centre, e.g.…”

Small Alterations in Cobinamide Structure Considerably Influence sGC Activation

“…To further elaborate the effect of such interactions on the potency of sGC activation, cobyrinic acid was compared with hexacobyrinic acid 6 (Figure 1 B). As previously described,11 cobryinic acid has a bell‐shaped curve instead of a typical S‐shaped saturation curve, and is less potent than heptamethyl cobyrinate 1 . Elimination of the d ‐position results in only a slight decrease in activity, confirming that the d ‐position is nonfunctional in hydrophilic cobalamins.…”

“…Subsequently, hydrophobic heptamethyl cobyrinate 1 and its derivatives were tested (Figure 1 C). Heptamethyl cobyrinate 1 is a good sGC activator, displaying high activity at low concentrations 11. In the case of compound 5 , in which the d ‐position is removed, a significant drop in activity was observed, even though the shape of the curve is similar to that of heptamethyl cobyrinate 1 , suggesting that compound 5 is positioned or interacts with sGC in a similar manner to derivative 1 .…”

“…Following the synthesis of these derivatives, we evaluated their effect on sGC activity. As in previous studies,11–13 the activity of purified sGC was tested after pre‐incubation with cobinamide derivatives at various concentrations. First, we examined the influence of the c ‐ and d ‐positions by comparing hexaamide 8 with (CN) 2 Cbi and heptaamide 2 .…”

“…It was recently reported that dicyanocobinamide ((CN) 2 Cbi) and its derivatives can directly activate sGC by targeting sites outside the heme‐binding region 11–13. Introduction of other hydrophilic amides to the peripheral side chains dramatically improves sGC activation.…”