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

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

Blog Article

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 tg02-0325m 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 ceiling fan with 18 inch downrod 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.