Induction of fetal hemoglobin by propionic and butyric acid derivatives: correlations between chemical structure and potency of Hb F induction.
Short-chain fatty acids (C2-C9) induce fetal hemoglobin synthesis in primary cell cultures, primates, and patients. We carried out experiments to test whether relationships exist between chemical structure and the Hb F-inducing potential of several short-chain fatty acid derivatives. BFUe cultures were performed in the presence of propionic and butyric congeners, covering the full spectrum of substitutions of these molecules, including polar and non-polar groups, esters, and double bonds. We found that the fetal hemoglobin inducibility is related to the chemical structure of the inducing compound. This structure-activity relation depends on the length of carbon chain, the nature of the substitutions, and the position of more potent substitutions on the carbon chain. It appears that substitutions enhancing the inducibility of these compounds are (with decreasing potency): methyl > phenyl > hydroxy >> amino groups. Placement of these substitutions at a position distal to the carboxyl group enhances gamma-globin inducibility. Presence of the carboxyl group is prerequisite for gamma-globin inducibility.
Liakopoulou
Effie
E
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195-7720, USA.
Li
Qiliang
Q
Stamatoyannopoulos
George
G
D002087:Butyrates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000737:chemistry / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics; D006801:Humans; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013329:Structure-Activity Relationship
D002087:Butyrates; D005232:Fatty Acids, Volatile; D011422:Propionates; D012333:RNA, Messenger; D005914:Globins; D005319:Fetal Hemoglobin