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Chem Biol Drug Des. 2015 Jul;86(1):114-21. doi: 10.1111/cbdd.12469. Epub 2014 Nov 28.

Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5-Lipo-Oxygenase.

Author information

1
Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago, Chile, Casilla 442, Correo 2, Santiago, Chile.
2
Laboratorio de Investigación Científica Emory Black, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago, Chile, Casilla 442, Correo 2, Santiago, Chile.
3
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064.

Abstract

Continuing our search to find more potent and selective 5-LOX inhibitors, we present now the enzymatic evaluation of seventeen isoflavones (IR) and nine isoflavans (HIR), and their in vitro and in cellulo potency against human leukocyte 5-LOX. Of the 26 compounds tested, 10 isoflavones and 9 isoflavans possessed micromolar potency, but only three were selective against 5-LOX (IR-2, HIR-303, and HIR-309), with IC50 values at least 10 times lower than those of 12-LOX, 15-LOX-1, and 15-LOX-2. Of these three, IR-2 (6,7-dihydroxy-4-methoxy-isoflavone, known as texasin) was the most selective 5-LOX inhibitor, with over 80-fold potency difference compared with other isozymes; Steered Molecular Dynamics (SMD) studies supported these findings. The presence of the catechol group on ring A (6,7-dihydroxy versus 7,8-dihydroxy) correlated with their biological activity, but the reduction of ring C, converting the isoflavones to isoflavans, and the substituent positions on ring B did not affect their potency against 5-LOX. Two of the most potent/selective inhibitors (HIR-303 and HIR-309) were reductive inhibitors and were potent against 5-LOX in human whole blood, indicating that isoflavans can be potent and selective inhibitors against human leukocyte 5-LOX in vitro and in cellulo.

KEYWORDS:

IC50 values, structure-activity relationship; human lipo-oxygenase; isoflavans derivative; steered molecular dynamics

PMID:
25359714
DOI:
10.1111/cbdd.12469
[Indexed for MEDLINE]
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