Mini Reviews in Medicinal Chemistry - Volume 12, Issue 13, 2012

Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds.

Covalent inhibition is an efficient molecular mechanism for inhibiting enzymes or modulating the function of proteins and is found in the action of many drugs and biologically active natural products. However, it is has been less appreciated that the formation of covalent bonds can be reversible or irreversible. This review focuses on biologically active compounds that are Michael acceptors and how the reversible nature of the Michael addition reaction influences biological activity and how this can be exploited in designing prodrugs.

Alogliptin (codenamed SYR-322) is a recently approved anti-diabetic drug in Japan, which has been under clinical development phase III in USA and Europe. Alogliptin has been developed by Takeda under the brand name “Nesina”. Alogliptin is a highly selective (> 10,000-time selectivity, potent, reversible and durable serine protease dipeptidyl peptidase IV enzyme is compared to DPP-8 and DPP-9) inhibitor, which has been developed as an alternative second-line to metformin in place of a sulphonylurea. Alogliptin has been observed to increase and prolong the action of incretin hormone by inhibiting the DPP-IV enzyme activity. Alogliptin has been observed to well absorb and show low plasma protein binding, which displays slow-binding properties to DPP-IV enzyme. The X-ray crystallography studies have been revealed that Alogliptin binds to DPP-IV active site by non-covalently and provides sustained reduction of plasma DPP-IV activity as well as lowering of blood glucose, in drug-naive patients with T2DM and inadequate glycemic control, once daily oral dosing regimen with varying levels of doses ranging from 25-800 mg. Alogliptin is approved as monotherapy and in combination with alpha-glucosidase & thiazolidinediones. The 26 week clinical study of Alogliptin revealed that Alogliptin doesn't increase the weight and well tolerated. In the present review, we have tried to cover biology of DPP-IV, molecular chemistry, chemical characterization, crystal polymorphic information, interaction studies, commercial synthesis, current patent status, adverse effects and clinical status of Alogliptin giving emphasis on the medicinal chemistry aspect.

Sydnones are mesoionic heterocyclic aromatic compounds. They have been widely studied for some important biological activities like antiviral, antitumor, antimicrobial, anti-inflammatory, anticancer, analgesic, anthelmintic and antihypertensive activities. The aim of the present article is to review the available information on sydnones and the derivatives of sydnones and also a look at the future perspectives.

The ability of grapevine to activate defense mechanisms against some pathogens has been shown to be linked to the synthesis of stilbenes by the plant (inducible viniferins). Metabolized viniferins may also be produced or modified by extracellular enzymes released by the pathogen in an attempt to eliminate undesirable toxic compounds. Due to the important properties of resveratrol, there is increasing interest in producing foods with higher contents of this compound and higher nutritional value. The production of high resveratrol-containing grapes and wines relies on quality-oriented viticulture (suitable terroirs, sustainable cultural practices) and wine-making technologies which avoid degradation of the compound. The technique of skin extraction and enzymatic hydrolysis of glucoside forms in wine-making plays an important role in resveratrol wine concentration. Other factors affecting its final concentration and balance in wine are conditions for promoting trans-cis isomerization of aglycones, the type of yeast used, and the presence of lactic bacteria with β-glucosidase activity. In general, the enological practices commonly used to stabilize wine after fermentation do not significantly affect resveratrol concentrations, which show considerable stability.

The plant-endophytic strains of the fungus Pestalotiopsis (Amphisphaeriaceae) are distributed throughout the world. Previous chemical investigation of members of the genus resulted in the discovery of various bioactive secondary metabolites including chromones, cytosporones, polyketides, terpenoids and coumarins with diverse structural features. The present report reviews the papers, which have appeared in the literature till now, concerning the isolation, structural elucidation, and biological activities of the secondary metabolites from Pestalotiopsis species.

Chalcones are the principal precursors for the biosynthesis of flavonoids and isoflavonoids. A three carbon α, β-unsaturated carbonyl system constitutes chalcones. Chalcones are the condensation products of aromatic aldehyde with acetophenones in attendance of catalyst. They go through an assortment of chemical reactions and are found advantageous in synthesis of pyrazoline, isoxazole and a variety of heterocyclic compounds. In synthesizing a range of therapeutic compounds, chalcones impart key role. They have showed worth mentioning therapeutic efficacy for the treatment of various diseases. Chalcone based derivatives have gained heed since they own simple structures, and diverse pharmacological actions. A lot of methods and schemes have been reported for the synthesis of these compounds. Amongst all, Aldol condensation and Claisen-Schmidt condensation still grasp high up position. Other distinguished techniques include Suzuki reaction, Witting reaction, Friedel-Crafts acylation with cinnamoyl chloride, Photo-Fries rearrangement of phenyl cinnamates etc. These inventive techniques utilize various catalysts and reagents including SOCl2 natural phosphate, lithium nitrate, amino grafted zeolites, zinc oxide, water, Na2CO3, PEG400, silicasulfuric acid, ZrCl4 and ionic liquid etc. The development of better techniques for the synthesis of α, β- unsaturated carbonyl compounds is still in high demand. In brief, we have explained the methods and catalysts used in the synthesis of chalcones along with their biological activities in a review form to provide information for the development of new-fangled processes targeting better yield, less reaction time and least side effects with utmost pharmacological properties.

The needs of newly developed antitubercular agents are required for the control of tuberculosis in the present time. In the discovery of new antitubercular drugs, the emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) has encouraged the researchers to intensify the efforts to discover novel antitubercular drugs. These novel drugs will predominantly target the persistent state of mycobacterium strains, which are resistant to conventional drugs including non resistant mycobacterium strains. In the last three to four decades no new effective drug has been developed for the treatment of resistant tuberculosis. However, in recent years, the research and development programs for the control of TB, there is a lot works is going on to enhancement of the anti- TB activity of new drugs particularly against resistant mycobacterium strains. Simultaneously, practical usefulness of some new targets is being identified and validated for the treatment of TB. Some compounds are presently in clinical trials, while others are being investigated in an attempt to explore new compounds for the target based treatment. The present review provides an overview of the new anti-TB agents with different molecular structures that are being clinically used and advanced stages of preclinical as well as clinical stages and also attempted to highlight the efforts that are being made in the development of new drug molecules as lead anti-TB agents.

Post-operative atrial fibrillation (AF) occurs in up to 40% of cardiac surgery patients and represents the most common post-operative arrhythmic complication. Post-operative AF is associated with impaired cardiac hemodynamics, increased incidence of serious complications (e.g. heart failure, stroke), prolonged hospitalization and increased healthcare costs. Therefore, treatment of post-operative AF would decrease health-care costs during hospitalization and improve the prognosis of patients following cardiovascular surgery. Current consensus guidelines recommend β-blockers, amiodarone and sotalol for post-operative AF prophylaxis. However, new pharmacological agents have been associated with a reduction in post-operative AF frequency, including inhibition of the renin angiotensin aldosterone system (RAAS) using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), statins, antioxidant agents, magnesium supplementation and antiarrhythmic drugs. The aim of this review is to analyse and determine the efficiency of existing therapies in the reduction of post-operative AF development.