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  • Derivatives of pyrimidine, phthalimide and anthranilic acid as inhibitors of human hydroxysteroid dehydrogenase AKR1C1
    Brožič, Petra ...
    Human hydroxysteroid dehydrogenase (HSD) AKR1C1 is a member of the aldo-keto reductase superfamily, and it functions mainly as a 20_-HSD. It catalyzes the reduction of the potent progesterone to the ... weak 20_-hydroxyprogesterone, and of 3_,5_-tetrahydroprogesterone (5_-THPč allopregnanolone) to 5_-pregnane-3_,20_-diol. AKR1C1 thus decreases the levels of progesterone and 5_-THP in peripheral tissue. Progesterone inhibits cell proliferation, stimulates differentiation of endometrial cells, and is also important for maintenance of pregnancy, while 5_-THP allosterically modulates the activity of the _-aminobutyric acid receptor. Inhibitors of AKR1C1 are thus potential agents for treatment of endometrial cancer and endometriosis, as well as other diseases like premenstrual syndrome, catamenial epilepsy and depressive disorders.We have synthesized a series of pyrimidine, phthalimido and athranilic acid derivatives, and have here examined their inhibitory properties towards AKR1C1. A commonaldo- keto reductase substrate, 1-acenaphthenol,was used to monitor theNAD+-dependent oxidation catalyzed by AKR1C1. The most potent inhibitors of AKR1C1 were the pyrimidine derivative N-benzyl- 2-(2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetamide (Ki=17_M) and the anthranilic acid derivative 2-(((2_,3-dichlorobiphenyl-4-yl)carbonyl)(methyl)amino)benzoic acid (Ki =33_M), both of which are non-competitive inhibitors.
    Vrsta gradiva - prispevek na konferenci
    Leto - 2009
    Jezik - angleški
    COBISS.SI-ID - 2480497