Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin

• Published in: Molecules (Basel, Switzerland) Vol. 21; no. 8; p. 1057
• Main Authors: Omar, Abdelsattar M, Mahran, Mona A, Ghatge, Mohini S, Bamane, Faida H A, Ahmed, Mostafa H, El-Araby, Moustafa E, Abdulmalik, Osheiza, Safo, Martin K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 13.08.2016; MDPI AG
• Subjects: Allosteric Regulation - drug effects; antisickling; Antisickling Agents - chemical synthesis; Antisickling Agents - chemistry; Antisickling Agents - pharmacology; aryloxyalkanoic acids; Binding Sites; Clofibric Acid - chemistry; Clofibric Acid - pharmacology; crystal structure; halogenated benzene; hemoglobin; Hemoglobins - chemistry; Hemoglobins - metabolism; high affinity; imidazole; low affinity; Models, Molecular; Molecular Conformation; oxygen equilibrium curve; Protein Binding; sickle cell disease; Structure-Activity Relationship; aryloxyalkanoic acids; high affinity; imidazole; low affinity; crystal structure; oxygen equilibrium curve; halogenated benzene; antisickling; hemoglobin; sickle cell disease
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules21081057

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.