Synthesis and X-ray studies of chiral allosteric modifiers of hemoglobin.
This study was designed to investigate the effect of chirality on the allosteric activity of a series of Hb allosteric modifiers. The chiral analogues were based on the lead compound (4), JP7, [1-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]cyclopentanecarboxylic acid] with different D- and L-amino acids conjugated to the JP7 acid moiety. The D-isomers were the most potent in vitro effectors in Hb solutions as well as with whole blood. In general, this study demonstrated that the chirality of extended amino acid side chains in JP7 conjugates plays an important role in observed degree of allosteric activity. The binding site interactions for four analogues were determined by single crystallographic diffraction studies. Conclusions show that the chiral configuration of some of the D-isomers enable the effectors to bind with a greater number of interactions with the protein residues. D- and L-isomers with equivalent or near equivalent allosteric activity did not show any significant differences or interactions between their amino acid side chains and the protein. The most potent effectors, in vitro, were compounds 15 and 19, D-isomers of leucine and phenylalanine, respectively. Compounds 21, 22, 30, and32 were more potent in vitro in Hb solutions than JP7.
Youssef
Amal Mamdouh
AM
Department of Medicinal Chemistry, School of Pharmacy, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0133, USA.
Safo
Martin K
MK
Danso-Danquah
Richmond
R
Joshi
Gajanan S
GS
Kister
Jean
J
Marden
Michael C
MC
Abraham
Donald J
DJ
D000494:Allosteric Regulation / Q000187:drug effects; D000596:Amino Acids / Q000138:chemical synthesis / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D003461:Crystallography; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D013237:Stereoisomerism
D000596:Amino Acids; D002264:Carboxylic Acids; D003517:Cyclopentanes; D006454:Hemoglobins