Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes As Drug Candidates for the Treatment of Sickle Cell Disease

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Oct 27

PMID 36296435

Authors

Boshi Huang

Mohini S Ghatge

Akua K Donkor

Faik N Musayev

Tanvi M Deshpande

Mohammed Al-Awadh

Rana T Alhashimi

Hongmei Zhu

Abdelsattar M Omar

Marilyn J Telen

Yan Zhang

Tim J McMahon

Osheiza Abdulmalik

Martin K Safo

Affiliations

Soon will be listed here.

Abstract

Sickle cell disease (SCD) is caused by a single-point mutation, and the ensuing deoxygenation-induced polymerization of sickle hemoglobin (HbS), and reduction in bioavailability of vascular nitric oxide (NO), contribute to the pathogenesis of the disease. In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits.

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