Current Medicinal Chemistry - Volume 23, Issue 28, 2016

In this review, we first highlighted on C-methyl-branched nucleosides and nucleotides approved as anti-hepatitis C infection (HCV) drugs, their mechanism of action and recent progress in the development of new clinical candidates. Then, we report on our attempt to develop several C-methyl nucleosides/tides potentially useful for treatment of various diseases such cancer, pain, epilepsy and glaucoma. Design, synthesis and pharmacological screening of 1′-C-, 2′-C-, 3'-C-methyladenosine or other purine/pyrimidine nucleosides allowed us to discover some promising new molecules. 3'-C-Methyladenosine showed antitumor activity against several human tumor cell lines. We have investigated the mechanism of action of 3'-C-methyladenosine that proved to be an effective inhibitor of ribonucleotide reductase. Moreover, we will also summarize the chemical and biological properties of some of the recent N6-substituted and 5', N6-disubstituted 2'-C-methyladenosine derivatives that were synthetized in our laboratory and evaluated as A1 adenosine receptor agonists. 2-Chloro-2'- C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), 5′-chloro-5′-deoxy-N6-(±)-(endo-norborn- 2-yl)adenosine (5′Cl5′d-(±)-ENBA) and 2'-C-methyl-5'-chloro-5'-deoxy-N6-(±)-(endonorborn- 2-yl)adenosine (2'-Me-5′Cl5′d-(±)-ENBA) displayed high hA1AR affinity and selectivity. 2'-Me-CCPA and 5′Cl5′d-(±)-ENBA showed significant analgesic properties.

MicroRNAs (miRNAs), which are small non-coding RNA molecules that post-transcriptionally regulate the expression of target genes, control the vast majority of cellular events, including proliferation, differentiation, survival, senescence, autophagy, metabolism and genome stability. Even slight alterations in miRNA expression levels may induce the development of pathological states, including cancer. Several studies have already demonstrated the importance of miRNAs in the regulation of melanocytes. Upregulation of oncogenic miRNAs (oncomiRs), mainly by amplification and translocation of miRNA genes, and downregulation of oncosuppressor miRNAs (anti-oncomiRs) by deletion and other mutations, promoter methylation and abnormal processing contributes to melanoma initiation and progression. At each phase of melanoma progression, tumor cells exhibit distinct profiles of miRNA expression, as compared with normal melanocytes. Moreover, as miRNAs are stable molecules that can be identified in bodily fluids, such as blood and saliva, they can serve as potent non-invasive prognostic markers of disease progression and response to therapy. This review summarizes recent findings regarding miRNA-mediated control of melanocytes and melanoma development, and presents miRNAs as prognostic markers for this disease.

Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process.

Background: Targeted drugs modulate selective pathways activated or repressed only in cancer cells, resulting in a higher response to chemotherapy with less severe side effects. The use of a selected member of the heat shock protein 70 family (HSP70) as an effective therapeutic target in the treatment of colorectal cancer (CRC) will be the focus of this review. Methods: We generated two main questions for this study: 1) What are the current and potential future molecular therapies in CRC? 2) Can selective members of the HSP70 family advance drug design and drug discovery for treatment of CRC patients? We discuss related articles based on their significance and translational contributions to the existing literature. Results: The first part of this review discusses molecularly targeted agents that are currently used successfully in the clinic for the treatment of patients with CRC and highlights several novel targeted agents that are being investigated in ongoing trials. The second part of this review focuses on the unique tumorigenic functions of heat shock proteins, particularly mortalin-2, an essential heat shock protein for mitochondrial biogenesis in normal cells and a dominant oncoprotein in colon cancer cells. Basic and clinical studies have justified mortalin-2 as a potential molecular target, and its inhibition could dramatically improve patients’ responses to standard chemotherapies. Conclusion: Further understanding of the contributions of HSP70 family members to CRC at the molecular level, combined with translation of new concepts into effective targeted therapies, are anticipated to improve clinical outcomes and increase the therapeutic synergy with combination treatment with cytotoxic agents.

Background: Polyphenols are probably the most known and investigated molecules of nutritional interest as micronutrients present in abundance in our diet. Some of the most important food sources of polyphenols in the Mediterranean diet are olives and olive oil. A growing body of evidence from animal models to clinical studies indicates that polyphenol compounds may have neuroprotective effects in several pathologies of the nervous system through the control of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Objective: Based on the most recent scientific literature, dietary intake of polyphenols attenuates oxidative stress and reduces risk for related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis and Huntington’s disease. Also at the peripheral level, they act as antioxidant, defending tissues against oxidative damage and scavenging free radicals. Results: Recent findings in animal models and humans show that polyphenols may have a role in regulating neurotrophins levels, in particular nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF), suggesting that polyphenols may also induce their protective effects through the potentiation of neurotrophins action. NGF and BDNF, primarily known as biological mediators stimulating neuron growth, proliferation, survival and differentiation are recently studied also as metabotrophic factors, acting on glucose and energy metabolism, pancreatic beta cells and cardiovascular homeostasis. Conclusion: In this context, a better understanding of the effects of polyphenols on neurotrophins and their receptors (TrkA, TrkB, p75NTR) could certainly generate interest for drug discovery and also for the potential dietary prevention of several neurological and cardiometabolic diseases.

“Nutraceuticals” are food-derived products largely used for their presumed healthpromoting or disease-preventing effects. In the recent years, many efforts have been aimed at assessing nutraceutical efficacy and safety, but these factors are difficult to address because of the complex chemical compositions and multiple mode of actions. Thus, the study of nutraceutical ingredients poses several challenges for the medicinal chemistry field, some of which are related to extraction and chemical characterization, some to in vitro and in vivo bioactivity evaluation, and some to the bioavailability and interaction of these natural mixtures with organs and microbiota. Furthermore, because of their nature as medicinal and food products, these nutraceuticals can also be considered as a valuable source of new “lead compounds”, creating the opportunity to discover new classes of therapeutic agents. This review provides information on these themes, showing the new challenges that comprehensive medicinal chemistry research is called to answer in the field of nutraceuticals.