Mini Reviews in Medicinal Chemistry - Volume 14, Issue 10, 2014

Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome (MetS) is rising among children and adolescents, leading to fears for future epidemics of type 2 diabetes mellitus and cardiovascular disease in the young. MetS includes central obesity, hypertension, low HDL cholesterol, high triglycerides, and elevated concentrations of fasting blood glucose. Nonalcoholic fatty liver disease (NAFLD), which is the most common cause of chronic liver disease both in adults and children, is currently considered as the hepatic component of MetS. Growing evidence suggests that n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) may have a beneficial role on many factors associated with MetS, including circulating lipids and low-grade chronic inflammation. Recently, there has also been growing interest in n-3 LC-PUFAs supplementation as potential treatment for NAFLD, which is pathogenically linked to insulin resistance and involves inflammation in its advanced stages. Problems of adherence to lifestyle interventions, especially in children, and side effects with pharmacological agents make the dietary fish oil supplementation a simple and practical alternative therapy. Fish oil provides a convenient source of essential n-3 LCPUFA with few side effects, and may directly decrease circulating lipids, hepatic lipogenesis and steatosis, and chronic inflammation. In this review, we examine observational and interventional studies assessing in children and adolescents the potential impact of dietary n-3 PUFA supplementation on MetS components including NAFLD, and discuss the mechanisms underlying the actions of n-3 LC- PUFA on multiple risk factors associated with MetS.

Radiation and genotoxic drugs are two of the cornerstones of current cancer treatment strategy. However, this type of therapy often suffers from radio- or chemo-resistance caused by DNA repair mechanisms. With the aim of increasing the efficacy of these treatments, there has been great interest in studying DNA damage responses (DDR). Among the plethora of signal and effector proteins involved in DDR, three related kinases ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related) and DNA-PK (DNA-dependent protein kinase) play the main roles in initiation and regulation of signaling pathways in response to DNA double and single strand breaks (DSB and SSB). ATM inhibitors, as well as those of ATR and DNA-PK, provide an opportunity to sensitize cancer cells to therapy. Moreover, they can lead to selective killing of cancer cells, exploiting a concept known as synthetic lethality. However, only a very few selective inhibitors have been identified to this date. This mini-review is focused both on the development of selective inhibitors of ATM and other inhibitors which have ATM as one of their targets.

Ionizing radiation is the more effective therapy to reduce tumor growth through damaging the DNA of cells. In response to DNA damage, cells activate the checkpoint kinases such as CHK2, which signal to initiate repair processes and cell-cycle arrest, until the damaged DNA is repaired. At present, the development of CHK2 inhibitors has provided an interesting strategy for the treatment of cancer by introducing new radiation modifier agents. CHK2 inhibitors can contribute for the improvement of cancer therapy through sensitizing cancerous cells and radioprotection of normal cells against ionizing radiation. This review describes and discusses the most recent inhibitors of CHK2 and presents an evaluation of chemical structures and biological activities. As well as their role in cell growth during exposure to ionizing radiation.

Influenza virus is an important RNA virus causing pandemics (Spanish Flu (1918), Asian Flu (1957), Hong Kong Flu (1968) and Swine Flu (2009)) over the last decades. Due to the spontaneous mutations of these viral proteins, currently available antiviral and anti-influenza drugs quickly develop resistance. To account this, only limited antiinfluenza drugs have been approved for the therapeutic use. These include amantadine and rimantadine (M2 proton channel blockers), zanamivir, oseltamivir and peramivir (neuraminidase inhibitors), favipravir (polymerase inhibitor) and laninamivir. This review provides an outline on the strategies to develop novel, potent chemotherapeutic agents against M2 proton channel. Primarily, the M2 proton channel blockers elicit pharmacological activity through destabilizing the helices by blocking the proton transport across the transmembrane. The biologically important compounds discovered using the scaffolds such as bisnoradmantane, noradamantane, triazine, spiroadamantane, isoxazole, amino alcohol, azaspiro, spirene, pinanamine, etc are reported to exhibit anti-influenza activity against wild or mutant type (S31N and V27A) of M2 proton channel protein. The reported studies explained that the adamantane based compounds (amantadine and rimantadine) strongly interact with His37 (through hydrogen bonding) and Ala30, Ile33 and Gly34 residues (hydrophobic interactions). The adamantane and the non-adamantane scaffolds fit perfectly in the active site pocket present in the wild type and the charged amino groups (ammonium) create positive electrostatic potential, which blocks the transport of protons across the pore. In the mutated proteins, larger or smaller binding pocket are created by small or large mutant residues, which do not allow the molecules fit in the active site. This causes the channel to be unblocked and the protons are allowed to transfer inside the pore. The structural analysis of the M2 proton channel blockers illustrated that the adamantane derivatives have action against both influenza A and B, but have no effect on the mutants.

In the last ten years, a high amount of genetic assays has been developed for molecular biopathology and genetic laboratories of the hospitals, mainly developed and provided by external companies. In some cases, the specialized staff members of the hospitals (doctors, biopathologists, geneticists or pharmacists) develop their own methods. The validation of these methods is required before their use in clinical testing, in order to assess its reliability. Analytical methods are validated under the requirements of International Guidelines, but validation procedures for clinical genetic tests are under study and need clarifications. In this manuscript, the main information related to the field of genetic validation is revised, including statistics, explaining the difficulty of validation for some of the developed genetic tests. The provided information is in agreement with all the International Guides. The information could be useful by the workers daily performing this kind of analysis.

MicroRNAs are evolutionary conserved single stranded non-coding RNAs with immense ability to posttranscriptionally regulate gene expression via complementary base pairing with mRNAs of more than 50% protein encoding genes. They play diverse roles in physiological and pathophysiological processes such as normal development and cancer pathogenesis respectively. Recent investigations have focused on the identification and characterization of microRNAs aberrantly expressed in cancer and their target molecules that are critically involved in the initiation, progression and development of carcinogenesis as possible diagnostic, prognostic and theranostic (Integration of biomarker use as diagnostic tools and target-specific therapies to enhance selective and individualized therapy) tools to augment conventional cancer therapeutic armamentarium. In this mini review, we bring to focus the intricate interactions between microRNAs aberrantly expressed in hepatocarcinogenesis and their interactions with the transforming growth factor beta (TGF-β)/Small mother against decapentaplegic (Smad) and the mitogen activated protein kinases (MAPKs) signaling pathways. Importantly, we highlight microRNA-Specific targets as possible biomarkers for prognosis, diagnosis and as therapeutic targets for hepatocellular carcinoma (HCC) while at the same time exploring new directions for future investigations.

Progesterone, extensively used in human as well as veterinary medicines is a progestogen type of hormone. With the aim for hunting the stable polymorph, this review examines polymorphic behavior of progesterone and stabilization of less stable form by co-crystallization. An overview of two monotropically related forms of progesterone – form-I and form-II, synthetic enantiomer, ent-progesterone and racemic progesterone is provided. Different methods reported in the literature for the formation of polymorphs of progesterone are discussed here. After extensive manual screening it has been found that, though there are few methods mentioned in the literature for the formation of form-II, there is a lack of reproducibility in the recipes. This contribution also briefly reviews three other forms of progesterone (form-III, form-IV and form-V) which appear only in equilibrium melt and cannot be structurally characterized. Finally, comparison of different physical properties of form-I and form-II are also addressed.

Ion chromatography is a well-established regulatory method for analyzing anions and cations in environmental, food and many other samples. It offers an enormous range of possibilities for selecting stationary and mobile phases. Additionally, it usually helps to solve various separation problems, particularly when it is combined with different detection techniques. Ion chromatography can also be used to determine many ions and substances in clinical and pharmaceutical samples. It provides: availability of high capacity stationary phases and sensitive detectors; simple sample preparation; avoidance of hazardous chemicals; decreased sample volumes; flexible reaction options on a changing sample matrix to be analyzed; or the option to operate a fully-automated system. This paper provides a short review of the ion chromatography applications for determining different inorganic and organic substances in clinical and pharmaceutical samples.