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Heterocyclic aminoparthenolide derivatives modulate G(2)-M cell cycle progression during Xenopus oocyte maturation - PubMed

  • ️Wed Jan 01 2014

Heterocyclic aminoparthenolide derivatives modulate G(2)-M cell cycle progression during Xenopus oocyte maturation

Venumadhav Janganati et al. Bioorg Med Chem Lett. 2014.

Abstract

Aminoparthenolide derivatives have been prepared by reaction of parthenolide with various heterocyclic amines to afford corresponding Michael addition products. These novel compounds were evaluated for their modulatory effects on Xenopus oocyte maturation. Two compounds, 6e and 6f, were identified that promote G2-M cell cycle progression.

Keywords: Heterocyclic amines; Michael addition; Oocyte maturation; Parthenolide; Progesterone.

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Figures

Figure 1
Figure 1

Structures of PTL, MMB, MCL, DMAPT, and PTL Michael adducts

Figure 2
Figure 2

The Effect of compounds 6a-6l on the rate of progression of Xenopus oocytes to germinal vesicle breakdown (GVBD) was assessed for each test compound relative to the time taken for 50% of DMSO-treated control oocytes to complete GVBD (GVBD50) (Fig. 2). A value of 1.0 indicates that the compound did not differ from DMSO-treated control oocytes. A value greater than 1.0 indicates a delay to maturation, with a value of 2.0 indicating that no maturation occurred. A value less than 1.0 indicates acceleration of maturation, with a value of 0.0 indicating spontaneous progression to GVBD without added progesterone. Only compounds differing by more than 20% from DMSO-treated control oocytes were assessed further. Compound 6e induced spontaneous maturation in the absence of added progesterone. Compound 6f inhibited progesterone-stimulated maturation. Compound 6l appeared to delay time to GVBD, but this modest effect was not reproducible. None of the other compounds tested (including PTL and DMAPT, exerted any reproducibly significant phenotypic effects upon progression to GVBD during oocyte maturation.

Figure 3
Figure 3

Compound 6e induces maturation in the absence of progesterone in a dose-dependent manner. The rate of oocyte progression to GVBD was assessed by appearance of a white spot on the animal pole over a range of 6e concentrations relative to DMSO-treated control oocytes. 6e induced GVBD in the absence of progesterone at 100 and 50 μM, and to a lesser extent at 10 μM.

Figure 4
Figure 4

Compound 6e triggers progesterone-independent activation of endogenous signaling pathways. Oocytes treated with 6e were harvested when 50% of the oocytes completed GVBD; they were segregated into those which had not (−) or had (+) completed GVBD. 6e-treated oocytes which had not completed GVBD displayed activation of MAP kinase signaling above basal, but had not activated MPF (assessed by retention of the inhibitory phosphorylation of CDK1). After GVBD, 6e-treated oocytes showed augmented MAP kinase activation and de-phosphorylation and activation of MPF.

Figure 5
Figure 5

6f inhibits maturation at high concentration, but accelerates maturation at lower concentrations. The time-matched effects of varying 6f concentration on progesterone-stimulated maturation were assessed relative to DMSO-treated oocytes (0) and scored when oocytes treated with 50 μM 6f induced maximal GVBD. At 5, 10 and 50 μM, 6f doubled the rate of progression to GVBD. The mean values are plotted for three independent experiments.

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