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Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease.
Huang, Boshi; Ghatge, Mohini S; Donkor, Akua K; Musayev, Faik N; Deshpande, Tanvi M; Al-Awadh, Mohammed; Alhashimi, Rana T; Zhu, Hongmei; Omar, Abdelsattar M; Telen, Marilyn J; Zhang, Yan; McMahon, Tim J; Abdulmalik, Osheiza; Safo, Martin K.
Afiliación
  • Huang B; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Ghatge MS; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Donkor AK; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Musayev FN; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Deshpande TM; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Al-Awadh M; Vertex Pharmaceutical Incorporated, Boston, MA 02210, USA.
  • Alhashimi RT; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Zhu H; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
  • Omar AM; Department of Medicine, Duke University Health System, Durham NC 27710, USA.
  • Telen MJ; Department of Medicine, Durham VA Health Care System, Durham NC 27705, USA.
  • Zhang Y; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
  • McMahon TJ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
  • Abdulmalik O; Department of Medicine, Duke University Health System, Durham NC 27710, USA.
  • Safo MK; Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Molecules ; 27(20)2022 Oct 12.
Article en En | MEDLINE | ID: mdl-36296435
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemoglobina Falciforme / Anemia de Células Falciformes Límite: Animals Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemoglobina Falciforme / Anemia de Células Falciformes Límite: Animals Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza