Reduced Reproduction with Increased Abortion Rate in Transgenic Mice That Overexpress 15-Lipoxygenase

Abstract

15-Lipoxygenase (15-LOX) is a lipid-oxidizing enzyme that is involved in cell cycle regulation. To evaluate the effect of 15-LOX on reproduction, we studied transgenic mice that overexpress 15-LOX. The transgene was introduced over the genetic background of the low density lipoprotein receptor deficient mice (LDL-R^–/–) and reproduction was compared to LDL-R^–/– mice. We found a lower pregnancy rate in the 15-LOX/LDL-R^–/– mice as compared to the LDL-R^–/– mice (62.74 vs. 79.1%, p < 0.01). Additionally, a remarkably higher number of resorptions per pregnancy was found in the 15-LOX/LDL-R^–/– mice (16.7 vs. 3.27%, p < 0.001) and it was accompanied by a significantly higher activity of the 15-LOX enzyme in these resorptions as compared to other tissues. These findings may implicate a role for 15-LOX in the development of spontaneous abortions.

Synthesis of Optically Active 6‐Alkynyl‐ and 6‐Alkylpurines as Cytokinin Analogs and Inhibitors of 15‐Lipoxygenase; Studies of Intramolecular Cyclization of 6‐(Hydroxyalkyn‐1‐yl)purines

“…The alkynylpurines 9 were synthesized by Sonogashira coupling and deprotected under standard acidic conditions (Scheme 2). The allene oxide 11a was obtained directly after deprotection of compound 9a by a "disfavored" 3-exo-dig cyclization, [12] and the elusive 10a could not be isolated. NOESY spectroscopy showed that the (Z)-isomer was formed and that cyclization under acidic conditions resulted in an intramolecular anti-addition of the hydroxy group.…”

6‐Substituted Purines as Inhibitors of 15‐Lipoxygenase; a Structure‐Activity Study

“…In our study of biological activities of cytokinins and synthetic analogs [1Ϫ4], we identified certain 6-alkenyland 6-alkynylpurines as potent inhibitors of 15-lipoxygenase (15-LO) from soybeans [3]. The active compounds did not exhibit significant scavenging of the radical diphenylpicrylhydrazyl (DPPH) and we proposed that the purine derivatives were so-called non-antioxidant inhibitors; they exert their activity by a direct interaction with the enzyme.15-LO has been implicated in oxidation of low-density lipoproteins (LDL), a process believed to be important for the development of atherosclerosis [5,6], as well as for instance in prostate cancer [7,8], and spontaneous abortions [9]. Even though the clinical importance of these effects in humans is currently not known, development of potent and selective inhibitors of 15-LO appears to be an important task.…”