Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Nitrate Ester %Derivatives of TD7 (TD7-NO) and VZHE039 (VZHE039-NO) Are Capable of Releasing NO
2.3. VZHE039-NO Exhibits Favorable Pharmacologic Effect In Vitro and In Vivo
2.4. VZHE039-NO Showed Antiadhesive Effect
2.5. VZHE039-NO Binds Hb Similarly as VZHE039 to Stabilize Liganded Hb
3. Discussion
4. Experimental Section
4.1. Study Approvals
4.2. Chemistry
4.2.1. Materials and General Procedures
4.2.2. Synthesis of (6-((2-Formyl-4-methoxyphenoxy)methyl)pyridin-2-yl)methyl Nitrate (TD7-NO)
4.2.3. Synthesis of (6-((2-formyl-3-hydroxyphenoxy)methyl)pyridin-2-yl)methyl Nitrate (VZHE039-NO)
4.3. Study of NO Release from the Nitrate Esters in Whole Blood In Vitro
4.4. Study of NO Release from the Nitrate Esters in Whole Blood from Wild-Type Mice Dosed with the Compounds
4.5. In Vitro Hb Modification, Oxygen Equilibrium and Antisickling Studies Using Human Homozygous Sickle Cell (SS) Blood
4.6. In Vivo Pharmacologic Study of VZHE039-NO in Wild-Type Mice
4.7. Study of VZHE039 and VZHE039-NO on Adhesivity of SS RBCs
4.8. Crystallographic Study of Hb in Complex with VZHE039-NO
4.9. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Huang, B.; Ghatge, M.S.; Donkor, A.K.; Musayev, F.N.; Deshpande, T.M.; Al-Awadh, M.; Alhashimi, R.T.; Zhu, H.; Omar, A.M.; Telen, M.J.; et al. Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease. Molecules 2022, 27, 6835. https://doi.org/10.3390/molecules27206835
Huang B, Ghatge MS, Donkor AK, Musayev FN, Deshpande TM, Al-Awadh M, Alhashimi RT, Zhu H, Omar AM, Telen MJ, et al. Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease. Molecules. 2022; 27(20):6835. https://doi.org/10.3390/molecules27206835
Chicago/Turabian StyleHuang, Boshi, 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, and et al. 2022. "Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease" Molecules 27, no. 20: 6835. https://doi.org/10.3390/molecules27206835