Selective inhibitors of human lactate dehydrogenases and lactate dehydrogenase from the malarial parasite Plasmodium falciparum.
Derivatives of the sesquiterpene 8-deoxyhemigossylic acid (2, 3-dihydroxy-6-methyl-4-(1-methylethyl)-1-naphthoic acid) were synthesized that contained altered alkyl groups in the 4-position and contained alkyl or aralkyl groups in the 7-position. These substituted dihydroxynaphthoic acids are selective inhibitors of human lactate dehydrogenase-H (LDH-H) and LDH-M and of lactate dehydrogenase from the malarial parasite Plasmodium falciparum (pLDH). All inhibitors are competitive with the binding of NADH. Selectivity for LDH-H, LDH-M, or pLDH is strongly dependent upon the groups that are in the 4- and 7-positions of the dihydroxynaphthoic acid backbone. Dissociation constants as low as 50 nM were observed, with selectivity as high as 400-fold.
Deck
L M
LM
Departments of Chemistry and of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131.
Royer
R E
RE
Chamblee
B B
BB
Hernandez
V M
VM
Malone
R R
RR
Torres
J E
JE
Hunsaker
L A
LA
Piper
R C
RC
Makler
M T
MT
Vander Jagt
D L
DL
D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D019344:Lactic Acid / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology*; D019289:Pyruvic Acid / Q000378:metabolism; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000378:metabolism
C114815:8-deoxyhemigossylic acid; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; D009243:NAD; D019344:Lactic Acid; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase