Progesterone utility in the synthesis of steroidal heterocyclic compounds with antitumor activity

One–pot and efficient method for the synthesis of progesteronpyridine 5a-c, 6a-c and 7a,b and/or progesteronpyran derivatives 9a-c and 10a,b by condensation reaction of progesterone 1 with different aldehydes and active methylene compounds in the presence of ammonium acetate or piperidine.  New progesteronopyrimidine derivatives 12a-d and 13a, b were synthesized via interaction of progesterone 1 with urea or thiourea and/or guanidine reagents and aldehyde. Progesterone 1 was examined to synthesize heterocyclic compound 16 containing ?-Lactone chiral carbon via the reaction of hydrazone derivative 14 with phenyl isothiocyanate followed by boiling with chloroacetic acid in benzene. The biological activity of compounds 5a, 5b, 6b, 7a, 9b, 9c, 12a, 12c, and 13a were evaluated as growth inhibitors of the liver and the breast carcinoma human cell line (HEPG2 & MCF7). Compounds 13a, 12a and 7a showed a higher potency than the standard. Key Words: Progesterone, MCR’s (multicomponents reaction), (pyridine, pyran, pyrimidine, ?-Lactone) derivatives, HEPG2 & MCF7

MIR-99a and MIR-99b Modulate TGF-β Induced Epithelial to Mesenchymal Plasticity in Normal Murine Mammary Gland Cells

Epithelial to mesenchymal transition (EMT) is a key process during embryonic development and disease development and progression. During EMT, epithelial cells lose epithelial features and express mesenchymal cell markers, which correlate with increased cell migration and invasion. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. The TGF-β pathway is regulated by microRNAs (miRNAs), which are small non-coding RNAs regulating the translation of specific messenger RNAs

The EYA Tyrosine Phosphatase Activity Is Pro-Angiogenic and Is Inhibited by Benzbromarone

Eyes Absents (EYA) are multifunctional proteins best known for their role in organogenesis. There is accumulating evidence that overexpression of EYAs in breast and ovarian cancers, and in malignant peripheral nerve sheath tumors, correlates with tumor growth and increased metastasis. The EYA protein is both a transcriptional activator and a tyrosine phosphatase, and the tyrosine phosphatase activity promotes single cell motility of mammary epithelial cells. Since EYAs are expressed in vascular endothelial cells and cell motility is a critical feature of angiogenesis we investigated the role of EYAs in this process. Using RNA interference techniques we show that EYA3 depletion in human umbilical vein endothelial cells inhibits transwell migration as well as Matrigel-induced tube formation. To specifically query the role of the EYA tyrosine phosphatase activity we employed a chemical biology approach. Through an experimental screen the uricosuric agents Benzbromarone and Benzarone were found to be potent EYA inhibitors, and Benzarone in particular exhibited selectivity towards EYA versus a representative classical protein tyrosine phosphatase, PTP1B. These compounds inhibit the motility of mammary epithelial cells over-expressing EYA2 as well as the motility of endothelial cells. Furthermore, they attenuate tubulogenesis in matrigel and sprouting angiogenesis in the ex vivo aortic ring assay in a dose-dependent fashion. The anti-angiogenic effect of the inhibitors was also demonstrated in vivo, as treatment of zebrafish embryos led to significant and dose-dependent defects in the developing vasculature. Taken together our results demonstrate that the EYA tyrosine phosphatase activity is pro-angiogenic and that Benzbromarone and Benzarone are attractive candidates for repurposing as drugs for the treatment of cancer metastasis, tumor angiogenesis, and vasculopathies

Cross-border trafficking in human beings: prevention and intervention strategies for reducing sexual exploitation

Over the years, growing attention has been given to the phenomenon of trafficking in human beings (THB). Sexual exploitation was until recently by far the most commonly identified feature of THB, followed by forced labour. Many activities to combat trafficking for the purpose of sexual exploitation have been initiated by numerous supranational, international as well as national organizations. Much is written about these initiatives, but some areas have been neglected. Knowledge on ‘what works’ is in particular limited. The growing attention to THB entails a demand for more information. The severity of the crime and the impact on its victims makes it of utmost importance to gain more insight into the working and effectiveness of anti-trafficking strategies and interventions. The main objective of this review was to assess the presently available evidence on the effects of interventions that aim to prevent and suppress trafficking in human beings

<span style="color:black;mso-bidi-language:HI">Synthesis and behaviour of 2-carboxyvinyl-6,8-dibromo-4<i>H</i>-3,1-benzoxazin-4-one <span style="color:black;mso-bidi-language:HI">towards nitrogen, carbon and sulphur nucleophiles </span></span>

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