Mini Reviews in Medicinal Chemistry - Volume 14, Issue 11, 2014

Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.

Repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity, cell survival, and prevention tumorigenesis. Three pathways are responsible for the repair of DNA DSBs: homologous recombination (HR), single strand annealing (SSA) and non-homologous end joining (NHEJ). DNA-dependent Protein Kinase (DNAPK), the key component of the NHEJ pathway, becomes an important target for cancer therapy. A large number of small molecules exhibit inhibitory activities against DNA-PK in an ATP-competitive manner. This paper reviews the recent developments of a diversity of small molecule DNA-PK inhibitors, with emphasis on their structural features, biological activities, and structure-activity relationships (SARs).

Among the pharmacological strategies to treat obesity, two subtypes of the neuropeptide Y (NPY) receptor family have drawn the attention of several research groups in the effort to develop efficacious and safe anti-obesity drugs. In the last two decades, different classes of non-peptide compounds exhibiting significant anti-orexigenic responses in NPY knockout and NPY receptor deficient mice have been reported as NPY Y1 and Y5 receptor antagonists. At the beginning of this century, NPY receptor antagonists were considered promising anti-obesity compounds that modulate food intake and body weight in obese patients; however, only a few antagonists are currently being evaluated in clinical trials because there are other neuronal pathways that maintain homeostasis of food intake and body weight in animals, making the design of molecules with more affinity and selectivity for the NPY Y1 and Y5 receptors necessary. The present review is a compendium of the reports that account for the design, synthesis and biological evaluation of nonpeptide compounds that selectively bind to NPY Y1 and Y5 receptors. This review presents a historic retrospective of those antagonists that have shown a high affinity and selectivity for these two NPY receptors in preclinical and clinical trials, highlighting key structural features that display more affinity, selectivity, and better pharmacokinetic profiles.

Countless bioactive constituents obtained from different medicinal plants have long been focused by the researchers of the scientific community and pharmaceutical industry. In recent years, extensive in vitro and in vivo research has been carried out with these biomolecules to develop complementary and alternative medicines. Findings revealed that these molecules may act as promising agents for almost all kinds of pathophysiological states. Further, these novel bioactive compounds are mostly not harmful in dietary doses. In this eclectic review, we highlighted the beneficial role of genistein, an isoflavone available mainly in the legumes particularly in soybean. Genistein is a potent phytoestrogen which binds with both alpha and beta estrogen receptors and regulate the divergent intracellular signaling cascades of estrogen. It also has the potential to competitively inhibit different imperative ATP utilizing enzymes. These properties help genistein in regulating various cellular and biochemical functions at different levels of structural organization in the body. Moreover, it’s very low cytotoxicity and abundance in regular aliment compared to other isoflavones makes it a more promising therapeutic option. Emerging evidence from the literature proves the competence of genistein in combating oxidative stress, cancer, diabetes, obesity, inflammation, osteoporosis, neuropathy and some other disorders. This review aims to unravel the assorted underlying mechanisms behind the multivariate properties of this unique aglycone.

The antimicrobial activity of sixteen new N-heteroarylated 1H-(benz)imidazoles was evaluated against clinically relevant bacteria (Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida, Aspergillus and dermatophyte) species according to the Clinical and Laboratory Standards Institute guidelines. None of the tested compounds were active against Gram negative bacteria, but only against S. aureus, that was particularly susceptible to N-thianthrenyl- and N-dibenzothienyl imidazole derivatives. Most of the imidazole derivatives showed a broad spectrum of antifungal activity in all tested fungal strains, including fluconazole-resistant species, with a particularly low minimum inhibitory concentration (MIC) for dermatophytes. N-(dibenzofuran-4-yl)-1H-imidazole (1) and N-(dibenzothien-4-yl)-1H-imidazole (3) showed the highest antifungal potential, being most active against Candida albicans. Some N-heteroarylated benzimidazoles showed low activity for fungi with the exception of 3-(1H-benzo [d]imidazol-1-yl)quinoline (14) which was selective against dermatophytes (MIC=4-16 µg/mL). The effect of the active compounds in the inhibition of the dimorphic transition, ergosterol biosynthesis and mitochondrial activity was evaluated in C. albicans. Compounds 1 and 3 showed the capacity to inhibit the germ tube formation in C. albicans, reduced the ergosterol production and impaired the mitochondrial function. Compounds 1 and 3 showed antimicrobial activity and low cytotoxicity, being of interest for further investigation concerning specially the development of new antifungal agents.