Structural basis for the potent antisickling effect of a novel class of five-membered heterocyclic aldehydic compounds

Journal of Medicinal Chemistry
Martin K SafoDonald J Abraham

Abstract

Naturally occurring five-membered heterocyclic aldehydes, including 5-hydroxymethyl-2-furfural, increase the oxygen affinity of hemoglobin (Hb) and strongly inhibit the sickling of homozygous sickle red blood (SS) cells. X-ray studies of Hb complexed with these compounds indicate that they form Schiff base adducts in a symmetrical fashion with the N-terminal alphaVal1 nitrogens of Hb. Interestingly, two cocrystal types were isolated during crystallization experiments with deoxygenated Hb (deoxyHb): one crystal type was composed of the low-affinity or tense (T) state Hb quaternary structure; the other crystal type was composed of high-affinity or relaxed state Hb (with a R2 quaternary structure). The R2 crystal appears to be formed as a result of the aldehydes binding to fully or partially ligated Hb in the deoxyHb solution. Repeated attempts to crystallize the compounds with liganded Hb failed, except on rare occasions when very few R state crystals were obtained. Oxygen equilibrium, high performance liquid chromatography (HPLC), antisickling, and X-ray studies suggest that the examined heterocyclic aldehydes may be acting to prevent polymerization of sickle hemoglobin (HbS) by binding to and stabilizing liganded Hb in the form...Continue Reading

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Citations

Jul 20, 2011·Journal of Medicinal Chemistry·Jean Leandro dos SantosManChin Chung
Nov 22, 2011·Acta Crystallographica. Section D, Biological Crystallography·Osheiza AbdulmalikMartin K Safo
Dec 1, 2012·Anemia·Sunday J AmehBenjamin U Ebeshi
Jul 25, 2006·Expert Opinion on Investigational Drugs·Iheanyi Okpala
Mar 5, 2014·Hematology/oncology Clinics of North America·Martin K Safo, Gregory J Kato
Mar 15, 2011·Biochimica Et Biophysica Acta·Martin K SafoTelih Boyiri
Feb 3, 2005·British Journal of Haematology·Osheiza AbdulmalikToshio Asakura
Feb 10, 2006·Journal of Molecular Biology·Priyamvada AcharyaSeigo Shima
Mar 7, 2014·Blood Cells, Molecules & Diseases·A HannemannJ S Gibson
Aug 17, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abdelsattar M OmarMartin K Safo
Jan 28, 2017·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Xinran LuDavid K Wood
May 9, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Man Chin ChungLorena Blau
Apr 6, 2018·Chemistry Central Journal·Ummay Mahfuza ShaplaSiew Hua Gan
Nov 21, 2007·Chemistry & Biodiversity·Shilpa S KharalkarMartin K Safo
Sep 26, 2008·Chemistry & Biodiversity·Ijeoma N NnamaniMartin K Safo
Oct 9, 2013·Acta Crystallographica. Section D, Biological Crystallography·Martin K SafoJ Eric Russell
Jan 12, 2019·Annual Review of Biochemistry·Adolfo Cuesta, Jack Taunton
Mar 14, 2020·Annals of Hematology·Cristiane O RenóHérica L Santos
Oct 6, 2018·Acta Crystallographica. Section D, Structural Biology·Tanvi M DeshpandeMartin K Safo
Apr 16, 2018·Bioorganic & Medicinal Chemistry·Piyusha P PagareMartin K Safo
Apr 3, 2021·Therapeutic Advances in Hematology·Alexander K GlarosAhmar U Zaidi
Dec 29, 2020·Journal of Medicinal Chemistry·Ariamala GopalsamyHatice G Yayla
Mar 25, 2017·ACS Medicinal Chemistry Letters·Brian MetcalfZhe Li

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