Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin.
A series of allosteric effectors of hemoglobin, 2-(aryloxy)-2-alkanoic acids, was prepared to investigate the effect of the stereocenter on allosteric activity. The chiral analogues were based on the lead compound, RSR13 (3b), with different alkyl/alkanoic and cycloalkyl/cycloalkanoic groups positioned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 were selected for resolution based on structure-activity relationships. One chiral analogue, (-)-(1R,2R)-1-[4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentane carbox ylic acid (11), exhibited greater in vitro activity in hemoglobin solutions than its antipode, racemate, and RSR13. Compound (-)-(1R, 2R)-11 was equipotent with RSR13 in whole blood, is a candidate for in vivo animal studies, and if efficacious and safe has a potential for use in humans. In general, it was found that chirality affects allosteric effector activity with measurable differences observed between enantiomers and the racemates.
Phelps Grella
M
M
Department of Medicinal Chemistry, School of Pharmacy, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0133, USA.
Danso-Danquah
R
R
Safo
M K
MK
Joshi
G S
GS
Kister
J
J
Marden
M
M
Hoffman
S J
SJ
Abraham
D J
DJ
D000085:Acetates / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000097:blood / Q000737:chemistry*; D001555:Benzene Derivatives; D018360:Crystallography, X-Ray; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D011422:Propionates / Q000097:blood / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C418112:1-(4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy)-2-methylcyclopentanecarboxylic acid; D000085:Acetates; D000814:Aniline Compounds; D001555:Benzene Derivatives; D006454:Hemoglobins; D011422:Propionates; C067396:efaproxiral; D010100:Oxygen