Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents.
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.
Randad
R S
RS
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond 23298-0581.
Mahran
M A
MA
Mehanna
A S
AS
Abraham
D J
DJ
D000494:Allosteric Regulation / Q000187:drug effects; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000986:Antisickling Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006441:Hemoglobin A / Q000378:metabolism; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D000986:Antisickling Agents; D011422:Propionates; D006441:Hemoglobin A; C067396:efaproxiral; D010100:Oxygen