Mini Reviews in Medicinal Chemistry - Volume 16, Issue 8, 2016

Extensive research over the past several decades has identified numerous dietary and phytochemical compounds that have chemopreventive potential and could represent an important source of anti-cancer lead molecules. In this scenario several nutritional factors have attracted considerable attention as modifiable risk factor in the prevention of breast cancer, the most frequently diagnosed cancer and a major cause of death among women worldwide. There is an immediate need for more effective and less toxic therapeutic and preventive strategies for breast cancers able also to counteract the recurrent phenomenon of resistance to hormonal and targeted therapy that represent the first-line treatment in the management of breast cancer patients. The present review focuses on chemopreventive and anti-cancer activities of different bioactive compounds obtained from dietary sources such as Omega-3 fatty acids, naturally present in fish, Resveratrol (3,5,40-trihydroxy-transstilbene), a phytoalexin found in grapes and Epigallocatechin Gallate, a polyphenolic compound found in green tea, or purified from medicinal plant (Oldenlandia Diffusa) and fruits (Ziziphus Jujube) highlighting their potential use in breast cancer treatment. Herein, we discuss the molecular mechanisms by which the bioactive compounds can inhibit carcinogenesis by regulating antioxidant enzyme activities, and inducing antiproliferative and apoptotic effects in different breast cancer cell lines. Understanding the mechanism of action of dietary compounds or traditionally used herbs having potential preventive and therapeutic effects on cancer may provide a rationale for further translational studies. This review emphasizes the importance, in the next future, of a proper scientific validation of these natural bioactive compounds for clinical use in the therapeutic portfolio for breast cancer.

Dementia is becoming a major public health problem worldwide. The most common form of dementia is Alzheimer’s disease (AD), characterized by a deficient cholinergic transmission, deposition of amyloid plaques and neurofibrillary tangles, and neuro-inflammation that result in progressive degeneration and/or death of nerve cells and cognitive impairment. At present, AD cannot be prevented or cured, so the symptomatic relief obtainable by the use of acetylcholinesterase (AChE) inhibitors is one of the therapeutic strategies. Accumulated evidence suggests that naturally occurring compounds may potentially improve memory and cognitive function, and prevent neurodegeneration. Even today the search for new neuroprotective agents of natural origin is very active. The neuroprotective effects of medicinal plants covering studies of the last years will be summarized and discussed in this review choosing a family classification with particular emphasis on extracts and isolated compounds as promising new drugs. The search of a multifunctional potential anti-AD agent able to act on different crucial targets, such as galanthamine, quercetin and timosaponin AIII, could be a useful approach to recognizing therapeutics against AD.

Elevated serum cholesterol, triglycerides and LDL levels are often associated with an increased incidence of atherosclerosis and coronary artery disease. The most effective therapeutic strategy against these diseases is based on statins administration, nevertheless some patients, especially those with metabolic syndrome fail to achieve their recommended LDL targets with statin therapy, moreover, it may induce many serious side effects. Several scientific studies have highlighted a strong correlation between diets rich in flavonoids and cardiovascular risk reduction. In particular, Citrus bergamia Risso, also known as bergamot, has shown a significant degree of hypocholesterolemic and antioxidant/radical scavenging activities. In addition, this fruit has attracted considerable attention due to its peculiar flavonoid composition, since it contains some flavanones that can act as natural statins. Hence, the study of bergamot flavonoids as metabolic regulators offers a great opportunity for screening and discovery of new therapeutic agents. Cholesterol metabolism, flavonoid composition and potential therapeutic use of C. bergamia Risso will be discussed in the following review.

Chemotherapeutics used in cancer treatment may elicit pleiotropic effects interfering, for instance, directly on DNA metabolism or on endoplasmic organelles functions. Recently there has been a trend towards the use of molecular-targeted therapies as alternative treatments of cancer, arising from the need to overcome the onset of undesired side effects or drug-resistance. Thus, a major challenge is the design and synthesis of new agents able to interact with specific cellular components, often over-expressed or altered in cancerous cells, such as telomerase and topoisomerase or protein kinases, with reduced toxicity at effective doses. The main molecular targets for the development of new anticancer drugs include: cell surface receptors, signal transduction pathways, enzymes, gene transcription, ubiquitin-proteasome/heat shock proteins, and anti-angiogenic agents. Several natural or synthetic polycyclic molecules with carbazolic nucleus, which show attractive drug-like properties, were identified with the aim to increase their biological activities and their specificity, obtaining cytotoxic agents effective in a panel of cancer cell lines. The cytotoxic profile of these compounds has been assessed using several in vitro assays as, for instance, MTT, colony formation, and flow cytometry assays and some of these compounds showed an interesting profile at sub-micromolar concentrations. The usefulness of some carbazole derivatives has been demonstrated, as well, in preclinical studies.

Design and discovery of new classes of anticancer agents with unique mechanisms of action is an urgent medical need. During the past several years, a series of salicylhydrazide class of compounds were reported to possess remarkable potency in a large panel of cancer cell lines from different tumor origins. In particular, the optimized lead compound, SC144, was further investigated and selected as a valuable drug candidate endowed with favorable pharmacokinetic and antiproliferative properties in various in vitro and in vivo xenograft models. This lead compound is active in cells resistant to conventional chemotherapies, synergistic with several standard-of-care drugs, and possesses an unique mechanism acting through the inhibition of the gp130-STAT3-survivin axis. Because of this novel mechanism, clinical development of SC144 will provide new therapeutic options for diverse cancers.

Hydrogels have received growing attention as materials for drug delivery systems (DDS) because of their biodegradable and biocompatible properties. DDS were developed to optimize the therapeutic properties of drug products and to render them more safe, effective, and reliable. In the past, drugs were frequently administered orally, as liquids or in powder forms. To avoid problems incurred through the utilization of the oral route of administration, new dosage forms, DDS, containing the drugs were introduced. They can deliver drugs directly to the intended site of action and can also improve treatment efficacy, while minimizing unwanted side effects elsewhere in the body, which often limit the long-term use of many drugs, and provide better efficacy of treatment. Biocompatible hydrogels are an example of such systems available for therapeutic use. In this review, results from recent publications concerning these systems are discussed. Hydrogels show superior effectiveness over conventional methods of treatment providing controlled release of active substances. They are of interest in medical applications such as breast cancer treatment.

Electro-responsive nanomaterials are usually made with polyelectrolytes able to undergo shrinkage or swelling by tuning on electrical fields. Nevertheless, the electrical conductivity of many polymeric materials used for the fabrication of release devices is not high enough to achieve an effective modulation of the drug release. The incorporation of conducting materials (e.g. carbon nanostructures) in polymeric networks has been proposed as a valuable strategy to overcome this limitation. In this regard, carbon nanotubes and graphene, by virtue of their unique chemical structures and attractive physiochemical properties, have been receiving exciting attention primarily in biology and medicine. By their incorporation into composite hydrogels, the biocompatibility and biodegradability of polymers can be merged with the favorable properties of carbon nanostructures, such as enhanced cellular uptake, electromagnetic, and magnetic behavior. The applicability of carbon hybrid materials to modulate release of therapeutics in response to an external current voltage, is being extensively investigated in the present review.

Nanotechnology encompasses the production and applications of physical, chemical, and biological systems at scales ranging from individual atoms or molecules to around 100 nanometres, as well as the integration of the resulting nanostructures into larger systems. Nanomaterials differ from bulk materials for their relatively larger surface-area-to-mass ratio, consequently they become more chemically reactive and can show different optical, magnetic and electrical behaviours. In recent years, engineered nanomaterials have gained a particular attention in some fields such as environmental protection (soil, air and water remediation/treatment) and medicine (bio-sensing, imaging, and drug delivery). Nanoparticles can be used to monitor in real-time some pollutants (including heavy metal ions, organic compounds, microbiological pathogens, etc.) present even at extremely low concentrations in different environments. The use of nanomaterials for waste remediation/treatment results in a technology more cost-effective and rapid than current conventional approaches thanks to their enhanced surface area, transport properties, and sequestration characteristics. In addition, the integration of molecular biology and medicine with nanotechnology has resulted in new active nanostructures able to interact with biological systems. Nanocarriers based on carbon nanotubes, fumed silica (SiO2), titanium dioxide (TiO2), and magnetite and maghemite (Fe3O4, and γ-Fe2O3) nanoparticles have a distinct advantage over other drug carriers as they can be opportunely designed to reach the desired targets. As a consequence, such nanostructures can represent an important platform for enhanced medical imaging and controlled drug delivery. Here, some applications of nanomaterials as water purifying agents and drug delivery systems are reported.

Photostability tests applied on topical commercial formulations containing non-steroidal anti-inflammatory drugs have demonstrated a clear degradation of the active compounds when exposed to light. The photodegradation profile of these drugs is usually monitored by spectrophotometric or chromatographic techniques according to the international ICH rules for photostability testing. In the last years, the data are processed ever more by multivariate analysis, as principal component analysis, partial least squares, multivariate curve resolution. These techniques have proved to be able to resolve the complex data sets from evolving chemical processes, by estimating the number of the involved components, their pure spectra and concentration profiles. When applied to the study of drug photodegradation, the multivariate approach has been able to define completely the reaction mechanisms and kinetics parameters. Several novel pharmaceutical formulations have been described to improve the photostability of NSAIDs in topical formulations. The common use of light protective packaging has recently been replaced or supplemented by incorporating suitable excipients in the drug formulations. The addition of UV absorbent agents, deactivating quench reactions that are either singlet oxygen-driven or involve free radicals, has had good success. A clear improvement in the light protection has been shown by entrapping the drugs into supramolecular matrices as cyclodextrins, liposomes, niosomes and other host-guest matrices. The present review gives an updated overview on the stability-indicating methods adopted for a series of NSAIDs in topical formulations and the supramolecular matrices designed to minimize the drug photodegradation.