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Journal Article Epublish 5 citations

PubMed: 36296435 DOI: 10.3390/molecules27206835

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

Molecules 27(20)

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

  • Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Vertex Pharmaceutical Incorporated, Boston, MA 02210, USA.
  • Department of Medicine, Duke University Health System, Durham NC 27710, USA.
  • Department of Medicine, Durham VA Health Care System, Durham NC 27705, USA.
  • Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
  • Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
  • Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

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.

MeSH

Cells, Tissue Adhesions, Hemoglobins, Anemia, Sickle Cell, Pharmaceutical Preparations, Aldehydes, Therapeutics, Drug Candidate

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