Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery.

Hélène Carreyre,Sébastien Thibaudeau,Claudiu T Supuran,Maurice Ouedraogo,Grégoire Carré,Clarisse Vandebrouck,Jocelyn Bescond

doi:10.3390/molecules22060915

Abstract

Dodoneine (Ddn) is one of the active compounds identified from Agelanthus dodoneifolius, which is a medicinal plant used in African pharmacopeia and traditional medicine for the treatment of hypertension. In the context of a scientific program aiming at discovering new hypotensive agents through the original combination of natural product discovery and superacid chemistry diversification, and after evidencing dodoneine’s vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III) and L-type Ca2+ current inhibition. These derivatives can now be considered as new lead compounds for vasorelaxant therapeutics targeting these two proteins.

Highlights

The narrowing of therapeutic focus, the expansion of biotechnologies and bio-based therapies, and the necessity to hit the target accurately but very quickly are trends that characterize the present pharmaceutical environment [1,2]
After evidencing its vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III and L-type Ca2+ current inhibition and can be considered as new lead compounds for vasorelaxant therapeutics synergistically targeting two proteins
In developing countries, where it affects a significant part of the population [28], hypertension is usually treated by plant decoctions or extracts such as infusions of Agelanthus dodoneifolius

Summary

Introduction

The narrowing of therapeutic focus, the expansion of biotechnologies and bio-based therapies, and the necessity to hit the target accurately but very quickly are trends that characterize the present pharmaceutical environment [1,2]. To fully exploit the potential of natural products, chemo and site-selective chemical modifications are required to tailor physicochemical properties, to modify metabolism, or to improve the ADME (Absorption, Distribution, Metabolism, and Excretion) properties or selectivity of a drug [19] To this end, late-stage functionalization is recognized as an especially efficient strategy and the available synthetic arsenal for molecular function optimization is growing tremendously [20,21]. That allows for direct modification in positions that cannot be accessible by using conventional media Under these conditions, natural products can be selectively and directly functionalized (ketones, phenols, terpenes, steroids, alkaloids) [24,25] to generate new bioactive compounds. After evidencing its vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III) and L-type Ca2+ current inhibition and can be considered as new lead compounds for vasorelaxant therapeutics synergistically targeting two proteins

Structure Elucidation of a Dihydropyranone from Tapinanthus dodoneifolius

Dodoneine and Its Analogues Also Inhibit Human Carbonic Anhydrases

Chemical

Conclusions