MMP-2 Inhibitor II Classically HIF levels and consequently

Classically HIF-α levels and consequently HIF transcriptional activity have been associated with hypoxic conditions. However, some years ago, regulation by hormones of HIF transcriptional activity under normoxic conditions was demonstrated. Different stimuli such as heregulin, IGF1 and insulin, among others, were shown to elevate HIF-1α protein levels and consequently HIF transcriptional activity in several tissues and cell types [[7], [8], [9]]. In the last decade, the expression of HIF-1α and HIF-2α in Sertoli cells was demonstrated [[10], [11], [12]]. It is worth mentioning that postnatal mouse HIF-2α ablation leads to male infertility, reduced testis size and seminiferous tubule number [10]. Despite the decrease in seminiferous tubules number, only the number of Sertoli cells per tubule was analyzed, while the total number of Sertoli cells per testis was neglected. Considering that the final number of Sertoli cells is the result of the proliferative periods and that FSH regulates the proliferation of Sertoli cells, it would of interest to evaluate whether HIFs are involved in the mechanism of action of the hormone. To our knowledge, no reports are available linking FSH actions, Sertoli cell proliferation and HIF transcriptional activity. Hence, the aim of this study was to analyze the participation of HIFs in the regulation of Sertoli cell proliferation by FSH.
Materials and methods
Results and discussion
Conflicts of interest
Acknowledgements
Hypoxia-inducible factor 1α (HIF-1α) has been implicated in a variety of diseases, including cancer,, infections,, inflammatory diseases,, and Parkinson’s disease. HIF-1α expression levels are controlled by cellular oxygen concentrations. It is abundantly expressed in solid tumor cells and plays a key role in tumor cell MMP-2 Inhibitor II to hypoxic environments created by rapid tumor growth. HIF-1α is a known regulator of tumor cell proliferation, migration, and angiogenesis, and the presence of a high concentration of HIF-1α is positively correlated with cancer severity. In addition, the recurrence of cancer after resection is related to HIF-1α overexpression. Therefore, HIF-1α has become an attractive target for the development of new anti-cancer drugs., , Several recent reports have investigated various structural modifications to develop the bioactive properties of the pentacyclic triterpenoid ursolic acid (UA), with an aim to generate potent novel anti-cancer agents. Indeed, structural modifications of the UA C-28 carboxylic acid group or C-3 hydroxy group have been shown to significantly enhance its anticancer activity., , , , , , Wu et al. reported that the oxidation of the UA C-3 hydroxyl group to a carbonyl group greatly enhanced its antitumor properties, while Bai et al. showed that acetylation of the UA C-3 hydroxy group and amidation of the UA C-28 carboxyl group also resulted in an enhancement of its anticancer activity. However, studies by Gu et al. indicated that substitutions of large functional groups at the C-3 and C-28 positions are likely to decrease its anticancer activity., In our previous work, we observed that the introduction of a triazolone moiety to the C-28 position of UA increased HIF-1α inhibition with low cytotoxic effects (, compound A). Recently, we reported the design, synthesis, and screening of a series of compounds containing an aminoguanidine moiety. We revealed that compound B (, compound B) displayed the most potent inhibitory effect on HIF-1α activity. However, some of these derivatives showed significant cytotoxicity against a Hep3B cell line. As a result, we attempted to replace the triazolone moiety with other azoles at the C-28 position of UA and to shorten the distance between UA and the azole ring. In addition, we simultaneously introduced small changes at the C-3 position by acetylation and oxidation to identify further potent novel HIF-1α inhibitors with low cytotoxicity. Tetrazole derivatives have been reported to possess a broad spectrum of therapeutic activities including anti-microbial,, anti-bacterial,, antioxidant,, anti-HIV, anti-leishmanial, and anti-cancer activities., Tetrazole is also a mimetic of carboxylic acid. Several tetrazole-containing drugs have been developed for clinical use, including cefazolin, valsartan, and pentetrazole, some of which possess a tetrazolium group as a terminal moiety (). Therefore, we hypothesized that the introduction of a terminal tetrazole functional group to the C-28 of UA is likely to enhance its biological potency. In this study, we designed and synthesized eight novel series of UA derivatives containing a tetrazole moiety (31 compounds in total) and evaluated their ability to inhibit hypoxia-induced HIF-1α transcriptional activity.