Mini Reviews in Medicinal Chemistry - Volume 17, Issue 11, 2017

Background: The body of evidence available from published literature during the past three decades indicates that reactive oxygen species and reactive nitrogen species can induce, promote and modulate carcinogenesis. Objective: The purpose of this review was to present the current status of knowledge on the possible role of oxidative/nitrosative stress in the development and progression of several human cancers. Moreover, we discuss briefly the formation and decomposition of oxygen and nitrogen species within cells and their physiological and damaging influences. Given that some antitumor treatments are based on the formation of ROS, we also summarize what is currently known about supplementing the diet with antioxidants. Methods: We conducted literature searches to review the recent progress toward the potential role of reactive oxygen and nitrogen species and associated oxidative stress in carcinogenesis. Results: The epidemiological and laboratory studies showed that excessive production of reactive oxygen/ nitrogen species may lead to consequent alteration in the intracellular homeostasis and cause damage to all important cellular components when the excess of oxidants is not balanced by antioxidant defence and/or DNA repair mechanisms. Chronic oxidative stress can drive carcinogenesis by altering expression of cancer-related genes causing mutation and transformation. Conclusion: There is now common agreement that reactive oxygen and nitrogen species are involved in the development and progression of several human cancers like breast, prostate, colorectal, gynecological, cervical, eye, skin, leukemia, gastric. Antioxidant supplements at low doses can promote health, while excess supplementation can be harmful and even carcinogenic.

Background & Objective: Pancreatic cancer is one of the most lethal malignancies accounting for the fourth leading cause of cancer-related deaths in the United States. Among several explored anticancer agents, Gemcitabine, a nucleoside analogue remained a front line chemotherapeutic agent for the treatment of pancreatic cancer. However, gemcitabine exerts a low response rate with limited progression free survival in patients due to cellular resistance of pancreatic tumors to this therapy. Several chemotherapeutic agents have been explored in combination with gemcitabine against pancreatic cancer with overall mixed responses and survival rates. Naturally occurring dietary agents possess promising anticancer properties and have been shown to target various oncogenic signaling pathways in in-vitro and in-vivo pancreatic cancer models. Results: Multiple studies using natural compounds have shown increased therapeutic efficacy of gemcitabine in pancreatic cancer models. Conclusion: This review is focused on recent updates on cellular, preclinical and clinical studies utilizing natural anticancer agents with gemcitabine against pancreatic cancer.

Background: Migraine is a highly prevalent neurovascular disorder. Objective: Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT;serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990’s led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies. Conclusion: This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.s.

Background & Objective: Chagas disease or American trypanosomiasis is a major parasitic disease in Latin America with restricted available treatment: nifurtimox and benznidazole. These two drugs are ineffective in the chronic phase of the disease; therefore, there is a need for the development of new, efficient and safe drugs for the treatment of this pathology. With this goal, one of the promising targets is trypanothione reductase (TR), a key enzyme in the metabolism of Trypanosoma cruzi. Conclusion: In this review, we analyse the importance of TR as a drug target, as well as the well-known and new inhibitors reported in the last decade as potential therapeutic agents for Chagas disease.

Background: GPR40, an orphan G-protein coupled receptor that is activated by medium and long-chain fatty acids and is highly expressed in pancreatic islets, adipose depots and the gastrointestinal tract are involved in energy source recognition, absorption, storage and/or metabolism. Since its deorphanization in 2003, G-protein-coupled receptor GPR40 has emerged as a potential target for type II diabetes because it has been hypothesized to participate in the adverse effects of chronic fatty acid exposure on function of β-cell. Results: This signifies that G-protein-coupled receptors have recently emerged as novel therapeutic targets in metabolic diseases, such as diabetes, obesity and the metabolic syndrome. Therefore it seems natural that GPR40 represents a potentially attractive target to best meet the need for novel treatments for Type II diabetes. Conclusion: This review describes recent advances and novel drug discovery approaches in the antidiabetic area, focusing on GPR40 modulators which have been synthesized till date and their Structure-Activity Relationship (SAR).

Background: Pyrazole is one of the excellent structural motifs in medicinal chemistry. Various physiological and therapeutic possibilities have been exploited by incorporating different pharmacophoric groups in the pyrazole moiety. Objective: This has opened a new arena of pyrazole analogs that can be developed into medicinal agents such as anti-inflammatory, analgesic, antipyretic, antiviral, antibacterial, anticancer, anticonvulsant, hypoglycemic, carbonic anhydrase inhibitors, mono amino oxidase (MAO) inhibitors, etc. Though, pyrazole analogs have proven their clinical efficacy as different pharmacological agents, a few of them have been withdrawn from the market due to their side effects. Thus, research on potential new drug candidates bearing the pyrazole moiety with lesser side effects has fairly increased over the last few years. Conclusion: This review explores diverse pharmacological activities exhibited by pyrazole analogs reported recently, which may be of great help for researchers in the area of drug discovery to understand the current scenario of pyrazole based compounds and to design and develop newer drug candidates with improved efficacy.