TY - JOUR
T1 - Design, syntheses and evaluation of a selective inhibitor of lactate dehydrogenase C 4 (LDHx)
AU - Cabrera Hernández, A.
AU - Estrada Hernández, T.
AU - Rodríguez Paez, L.
AU - Farfán, N.
AU - Baeza, I.
AU - Wong, C.
PY - 1998
Y1 - 1998
N2 - In this investigation we designed, synthesized and studied three N-substituted oxamates as possible inhibitors of mouse LDH isozymes. The inhibitors were DL-N-secbutyl oxamic acid and N-isobutyl oxamic acid with a nonpolar substituent, and the Na + salt of the N-hydroxy-ethyl oxamate with a polar substituent. Kinetic studies of these substances on the activity of mouse LDH isozymes showed that DL-N-secbutyl oxamic acid was a competitive inhibitor, having high selectivity for LDHx, as this inhibitor had 31 x more affinity for LDHx (Kj 0.4 mM) than for LDH-5 (K i 12.5 mM) and 36x more affinity for LDHx than for LDH-1 (K i 14.5 mM). N-isobutyl oxamic acid was also a competitive inhibitor. However, the K i value for LDHx (K i 2.0 mM) was only one third the values for LDH-1 (K i 6.0 mM) and LDH-5 (K i7.0 mM). During the evaluation of the inhibitory effect of N-hydroxy-ethyl oxamate on LDH isozymes, we found that it produced a noncompetitive inhibition in the three isozymes. However, this inhibitor also showed selectivity for LDHx because it showed 20x more inhibitory effect on LDHx (K i0.07mM) than on LDH-5 (K i 1.4 mM) and LDH-1 (K, 1.45 mM). Nevertheless, whereas the DL-N-secbutyl oxamic acid is a competitive inhibitor directed against the active site of LDHx, N-hydroxy-ethyl oxamate exerts its inhibitory effect on a different site, outside the active site of the LDH isozymes.
AB - In this investigation we designed, synthesized and studied three N-substituted oxamates as possible inhibitors of mouse LDH isozymes. The inhibitors were DL-N-secbutyl oxamic acid and N-isobutyl oxamic acid with a nonpolar substituent, and the Na + salt of the N-hydroxy-ethyl oxamate with a polar substituent. Kinetic studies of these substances on the activity of mouse LDH isozymes showed that DL-N-secbutyl oxamic acid was a competitive inhibitor, having high selectivity for LDHx, as this inhibitor had 31 x more affinity for LDHx (Kj 0.4 mM) than for LDH-5 (K i 12.5 mM) and 36x more affinity for LDHx than for LDH-1 (K i 14.5 mM). N-isobutyl oxamic acid was also a competitive inhibitor. However, the K i value for LDHx (K i 2.0 mM) was only one third the values for LDH-1 (K i 6.0 mM) and LDH-5 (K i7.0 mM). During the evaluation of the inhibitory effect of N-hydroxy-ethyl oxamate on LDH isozymes, we found that it produced a noncompetitive inhibition in the three isozymes. However, this inhibitor also showed selectivity for LDHx because it showed 20x more inhibitory effect on LDHx (K i0.07mM) than on LDH-5 (K i 1.4 mM) and LDH-1 (K, 1.45 mM). Nevertheless, whereas the DL-N-secbutyl oxamic acid is a competitive inhibitor directed against the active site of LDHx, N-hydroxy-ethyl oxamate exerts its inhibitory effect on a different site, outside the active site of the LDH isozymes.
UR - http://www.scopus.com/inward/record.url?scp=33748177422&partnerID=8YFLogxK
M3 - Artículo
SN - 0083-8969
VL - 41
SP - 273
JO - Proceedings of the Western Pharmacology Society
JF - Proceedings of the Western Pharmacology Society
ER -