Abstract:The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.

The understanding of the molecular basis of yeast resistance to ethanol may guide the design of rational strategies to increase process performance in industrial alcoholic fermentations. In this study, the yeast disruptome was screened for mutants with differential susceptibility to stress induced by high ethanol concentrations in minimal growth medium. Over 250 determinants of resistance to ethanol were identified. The most significant gene ontology terms enriched in this data set are those associated with intracellular organization, biogenesis, and transport, in particular, regarding the vacuole, the peroxisome, the endosome, and the cytoskeleton, and those associated with the transcriptional machinery. Saccharomyces cerevisiae and related yeast species have been extensively used in fermentation, wine making, sake making, and brewing processes. Bioethanol production by yeast is also a growing industry due to energy and environmental demands (38). The successful performance of alcoholic fermentations depends on the ability of the yeast strains used to cope with a number of stress factors occurring during the process (45, 48). These include osmotic pressure imposed by initial high sugar concentration and stress induced by fermentation end products or subproducts such as ethanol and acetate. However, the stress induced by increasing amounts of ethanol, accumulated to toxic concentrations during ethanolic fermentation, is the major factor responsible for reduced ethanol production and, eventually, for stuck fermentations (14). Thus, yeast strains that can endure stress imposed by high ethanol concentrations are highly desired.Throughout the years many efforts to characterize the mechanisms underlying ethanol stress tolerance, aiming to increase ethanol productivity, have been made (3,16,45,53). The successful engineering of yeast transcription machinery for this purpose was recently reported (3). A number of studies based on detailed physiological and molecular analyses have contributed to increasing the understanding of the processes underlying ethanol toxicity and yeast tolerance of stress induced by this metabolite (34)(35)(36)45). These studies indicate that ethanol interferes with membrane lipid organization, affecting its function as a matrix for enzymes, perturbing the conformation and function of membrane transporters, increasing the nonspecific plasma membrane permeability, and leading to the dissipation of transmembrane electrochemical potential (36,45). Concomitantly, yeast responses to ethanol-induced stress include changes in the levels and composition of membrane phospholipids and ergosterol (1,6,53). Through its effect at the level of plasma membrane organization and function, ethanol also produces intracellular acidification (26,(34)(35)(36). In response to this effect, yeast exhibits increased plasma membrane H ϩ -ATPase activity, which is important to maintain the intracellular pH and secondary transport mechanisms, which are dependent on the proton gradient across the plasma membrane (1,29,31,34...

This is the first comprehensive study demonstrating the antiproliferative effect of vanadium complexes bearing 8-hydroxyquinoline (quinH) ligands, including the parent and –CH3 (Me), –NO2, –Cl and –I substituted ligands, on HCT116 and A2780 cancer cell lines.

Cancer is considered the most aggressive malignancy to humans, and definitely the major cause of death worldwide. Despite the different and heterogenous presentation of the disease, there are pivotal cell elements involved in proliferation, differentiation, and immortalization, and ultimately the capability to evade treatment strategies. This is of utmost relevance when we are just beginning to grasp the complexity of the tumor environment and the molecular “evolution” within. The tumor micro-environment (TME) is thought to provide for differentiation niches for clonal development that results in tremendous cancer heterogeneity. To date, conventional cancer therapeutic strategies against cancer are failing to tackle the intricate interplay of actors within the TME. Nanomedicine has been proposing innovative strategies to tackle this TME and the cancer cells that simultaneously provide for biodistribution and/or assessment of action. These nanotheranostics systems are usually multi-functional nanosystems capable to carry and deliver active cargo to the site of interest and provide diagnostics capability, enabling early detection, and destruction of cancer cells in a more selective way. Some of the most promising multifunctional nanosystems are based on gold nanoparticles, whose physic-chemical properties have prompt for the development of multifunctional, responsive nanomedicines suitable for combinatory therapy and theranostics. Herein, we shall focus on the recent developments relying on the properties of gold nanoparticles as the basis for nanotheranostics systems against the heterogeneity within the TME.

Antisense therapy is a powerful tool for post-transcriptional gene silencing suitable for down-regulating target genes associated to disease. Gold nanoparticles have been described as effective intracellular delivery vehicles for antisense oligonucleotides providing increased protection against nucleases and targeting capability via simple surface modification. We constructed an antisense gold-nanobeacon consisting of a stem-looped oligonucleotide double-labelled with 3'-Cy3 and 5'-Thiol-C6 and tested for the effective blocking of gene expression in colorectal cancer cells. Due to the beacon conformation, gene silencing was directly detected as fluorescence increases with hybridisation to target, which can be used to assess the level of silencing. Moreover, this system was extensively evaluated for the genotoxic, cytotoxic and proteomic effects of gold-nanobeacon exposure to cancer cells. The exposure was evaluated by two-dimensional protein electrophoresis followed by mass spectrometry to perform a proteomic profile and 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, glutathione-S-transferase assay, micronucleus test and comet assay to assess the genotoxicity. This integrated toxicology evaluation showed that the proposed nanotheranostics strategy does not exhibit significant toxicity, which is extremely relevant when translating into in vivo systems.