Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease
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
Boshi Huang
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Mohini S. Ghatge
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Akua K. Donkor
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Faik N. Musayev
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Tanvi M. Deshpande
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Mohammed Al-Awadh
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Rana T. Alhashimi
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Hongmei Zhu
Department of Medicine, Duke University Health System, Durham NC 27710, USA
Abdelsattar M. Omar
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia
Marilyn J. Telen
Department of Medicine, Duke University Health System, Durham NC 27710, USA
Yan Zhang
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
Tim J. McMahon
Department of Medicine, Duke University Health System, Durham NC 27710, USA
Osheiza Abdulmalik
Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Martin K. Safo
Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
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.
