Over the past decade there has been much interest in NO-independent soluble guanyl cyclase (sGC) activators. sGC operates via activation of nitric oxide (NO) and plays an important role in cardiovascular homeostasis, platelet function, angiogenesis and neurotransmission.¹ Currently, sGC regulation is achieved by using various NO releasing organic nitrates or nitrovasodilators such as nitroglycerine, trinitrate, isosobide dinitrate and isosobide-5- mononitrate. NO-activators although effective, are known to rapidly induce tolerance and have a limited mode of delivery. However, it has been discovered that natural tetrapyrroles, such as protophorphyrin IX (PPIX) and vitamin B₁₂ derived cobainamide ((CN)₂Cbi), can act as NO-independent sGC acitivators.^2-4 Moreover, modes of activation differ for each compound; PPIX activates through the regulatory domain while (CN)₂Cbi activates via the catalytic domain.⁴

Hence our goal was to synthesise novel hydrophobic and hydrophilic cobinamide derivatives via aminolysis of cobalamin and examine their potential as sGC activators. Moreover, since both PPIX and vitamin B₁₂ derivatives can stimulate sGC enzyme via different domain activation. In order to achieve a synergistic effect a series of hybrid molecules were obtained using two synthetic strategies: copper (I) catalyzed alkyne–azide 1,3 dipolar cycloaddition (CuAAC, ’click’ reaction) and selective amide formation between vitamin B₁₂ and PPIX derivatives.

References:

[1] Waldman, S. A. et al. Pharmacol. Rev. 2000, 52, 373.

[2] Ignarro, L. J. J. Physiol. Pharm. 2002, 53, 503.

[3] Waldman, S. A.; Murad F. et al. J. Biol. Chem. 1984, 259, 4038.

[4] Martin, E., Gryko, D. et al. J. Pharmacol Exp Ther. 2012, 340, 723-732.

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