title: Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin.
abstract: Hemoglobin (Hb) modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD), specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series) for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen). The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia. asmansour@kau.edu.sa.|Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. asmansour@kau.edu.sa.
authors.forename: Abdelsattar M
authors.initials: AM
authors.lastname: Omar
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. mahranmona@yahoo.com.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Mahran
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. msghatge@vcu.edu.
authors.forename: Mohini S
authors.initials: MS
authors.lastname: Ghatge
authors.affiliation: Department of Biochemistry, Faculty of Medicine, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia. fbamane@yahoo.com.
authors.forename: Faida H A
authors.initials: FH
authors.lastname: Bamane
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. ahmedmh@vcu.edu.
authors.forename: Mostafa H
authors.initials: MH
authors.lastname: Ahmed
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia. alamka@gmail.com.|Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt. alamka@gmail.com.
authors.forename: Moustafa E
authors.initials: ME
authors.lastname: El-Araby
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. abdulmalik@email.chop.edu.
authors.forename: Osheiza
authors.initials: O
authors.lastname: Abdulmalik
authors.affiliation: Department of Medicinal Chemistry, and The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. msafo@vcu.edu.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Safo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000986:Antisickling Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002995:Clofibric Acid / Q000737:chemistry / Q000494:pharmacology; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000986:Antisickling Agents; D006454:Hemoglobins; D002995:Clofibric Acid
keywords: antisickling; aryloxyalkanoic acids; crystal structure; halogenated benzene; hemoglobin; high affinity; imidazole; low affinity; oxygen equilibrium curve; sickle cell disease