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Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents. 1991

R S Randad, and M A Mahran, and A S Mehanna, and D J Abraham
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond 23298-0581.

Three isomeric series of 2-(aryloxy)-2-methylpropionic acids were prepared and studied for their ability to decrease the oxygen affinity of human hemoglobin A. The isomeric aryloxy groups included 4-[[(aryloyl)amino]methyl]phenoxy, 4-(arylacetamido)phenoxy, and 4-[[(arylamino)carbonyl]methyl]phenoxy. A total of 20 compounds were synthesized and tested. Structure-activity relationships are presented. Several of the new compounds were found to be strong allosteric effectors of hemoglobin. The two most active compounds are 2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]- 2-methylpropionic acid and the corresponding 3,5-dimethyl derivative. The latter two compounds have been compared to other known potent allosteric effectors in the same assay and show greater activity. Both compounds also exhibit a right shift in the oxygen equilibrium curve when incubated with whole blood. The new compounds may be of interest in clinical or biological areas that require or would benefit from a reversal of depleted oxygen supply (i.e., ischemia, stroke, tumor radiotherapy, blood storage, blood substitutes, etc.). They are also structurally related to several marketed antilipidemic agents.

UI MeSH Term Description Entries
D010100 Oxygen An element with atomic symbol O, atomic number 8, and atomic weight [15.99903; 15.99977]. It is the most abundant element on earth and essential for respiration. Dioxygen,Oxygen-16,Oxygen 16
D011422 Propionates Derivatives of propionic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxyethane structure. Propanoate,Propanoic Acid,Propionate,Propanoates,Propanoic Acid Derivatives,Propanoic Acids,Propionic Acid Derivatives,Propionic Acids,Acid, Propanoic,Acids, Propanoic,Acids, Propionic,Derivatives, Propanoic Acid,Derivatives, Propionic Acid
D002621 Chemistry A basic science concerned with the composition, structure, and properties of matter; and the reactions that occur between substances and the associated energy exchange.
D006441 Hemoglobin A Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000494 Allosteric Regulation The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES. Regulation, Allosteric,Allosteric Regulations,Regulations, Allosteric
D000814 Aniline Compounds Compounds that include the aminobenzene structure. Phenylamine,Phenylamines,Anilines,Compounds, Aniline
D000986 Antisickling Agents Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions. Desickling Agents,Agents, Antisickling,Agents, Desickling
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D055598 Chemical Phenomena The composition, structure, conformation, and properties of atoms and molecules, and their reaction and interaction processes. Chemical Concepts,Chemical Processes,Physical Chemistry Concepts,Physical Chemistry Processes,Physicochemical Concepts,Physicochemical Phenomena,Physicochemical Processes,Chemical Phenomenon,Chemical Process,Physical Chemistry Phenomena,Physical Chemistry Process,Physicochemical Phenomenon,Physicochemical Process,Chemical Concept,Chemistry Process, Physical,Chemistry Processes, Physical,Concept, Chemical,Concept, Physical Chemistry,Concept, Physicochemical,Concepts, Chemical,Concepts, Physical Chemistry,Concepts, Physicochemical,Phenomena, Chemical,Phenomena, Physical Chemistry,Phenomena, Physicochemical,Phenomenon, Chemical,Phenomenon, Physicochemical,Physical Chemistry Concept,Physicochemical Concept,Process, Chemical,Process, Physical Chemistry,Process, Physicochemical,Processes, Chemical,Processes, Physical Chemistry,Processes, Physicochemical

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