Selective active site inhibitors of human lactate dehydrogenases A(4), B-4, and C-4

Human lactate dehydrogenases (LDH-A(4), -B-4, and -C-4) are highly homologo us with 84-89% sequence similarities and 69-75% amino acid identities. Acti ve site residues are especially conserved. Gossypol, a natural product from cotton seed, is a non-selective competitive inhibitor of NADH binding to L DH, with K-i values of 1.9, 1.4, and 4.2 muM for LDH-A(4), -B-4, and -C-4, respectively. However, derivatives of gossypol and structural analogs of go ssypol in the substituted 2,3-dihydroxy-1-naphthoic acid family exhibited m arkedly greater selectivity and, in many cases, greater potency. For gossyp ol derivatives, greater than 35-fold selectivity was observed. For dihydrox ynaphthoic acids with substituents at the 4- and 7-positions, greater than 200-fold selectivity was observed. Inhibition was consistently competitive with the binding of NADH, with dissociation constants as low as 30 nM. By c omparison, a series of N-substituted oxamic acids, which are competitive in hibitors of the binding of pyruvate to LDH, exhibited very modest selectivi ty. These results suggest that substituted dihydroxynaphthoic acids are goo d lead compounds for the development of selective LDH inhibitors. Selective inhibitors of LDH-C, targeted to the dinucleotide fold may hold promise as male antifertility drugs. Selective inhibitors of LDH-A(4) and -B-4 may be useful for studies of lactic acidemia associated with ischemic events. Mor e broadly, the results raise the question of the general utility of drug de sign targeted at the dinucleotide binding sites of dehydrogenases/reductase s. (C) 2001 Elsevier Science Inc. All rights reserved.