Mini Reviews in Medicinal Chemistry - Volume 9, Issue 6, 2009

Ras protein plays pivotal roles in control of normal and transformed cell growth. These ras genes are mutated in 30% of human cancer. For functioning of Ras protein its prenylation (farnesylation) is required. Therefore targeting Ras farnesylation is valuable approach for cancer treatment. Farnesyltransferase inhibitor (FTI) has been developed as anticancer drug and is currently evaluated in clinical trials. Different types of FTI have been identified that inhibit Ras farnesylation. FTI in combination with some cytotoxic antineoplastic drugs, exhibit additive effects.

Several studies have been published on discovering involvement of PARs receptors in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. This mini-review will focus on recent advances in the synthesis of PAR ligands highlighting their therapeutic potential in the treatment of various inflammatory diseases.

Available anti-obesity pharmacotherapy options remain very limited. The development of more effective drugs has become a priority. The potential strategies to achieve weight loss are to reduce energy intake, by stimulating anorexigenic signals or by blocking orexigenic signals, and to increase energy expenditure. This review will focus on approved obesity medications, as well as potential new pharmacological treatment options.

Trypanosomatid (order Kinetoplastida)-borne neglected tropical diseases - African and American trypanosomiasis and leishmaniasis - are amongst the most devastating health threats of underdeveloped, developing and poor countries. Climatic changes due to global warming, tourism exchange and increasing migratory fluxes are re-distributing the endemic subtropical location of these diseases to a new scenario with a rising presence in developed countries during the last decades. In addition, the proved opportunistic transmission of these diseases through contaminated syringes shared by drug users, in combination with immunosuppression processes linked to HIV infections and the poor response to the typical treatments, point to AIDS patients as a sensitive sub-population prone to suffer from these diseases. DNA topoisomerases are the “molecular engineers” that unravel the DNA during replication and transcription. The mechanism of DNA unwinding includes the scission of a single DNA strand - type I topoisomerases - or both DNA strands - type II topoisomerases - establishing transient covalent bonds with the scissile end. Camptothecin and etoposide - two natural drugs whose semi-synthetic derivatives are currently used in cancer chemotherapy - target types I and II DNA-topoisomerases respectively, stabilizing ternary topoisomerase-DNA-drug covalent complexes, which irreversibly poison the enzymes. Several differences between parasite and host DNA topoisomerases have pointed to these enzymes as potential drug targets in Trypanosomatids. The unusual localization inside the mitochondria-like organellum - the kinetoplast - linked to mini and maxicircles, as well as the uncommon heterodimeric structure of the DNA topoisomerase IB subfamily, make these proteins unquestionable targets for drug intervention against trypanosomatids.

Antimicrobial peptides, AMPs, exert their function acting mainly at the membrane level. In the wide AMPs panorama a particular position is occupied by lactoferrin derived peptides. They also possess antiviral, antifungal and antitumor activities and their parent molecules are available in several mammalian fluids and in dairy industries waste.

2-Phenyl-3-hydroxy-4(1H)-quinolinones can be considered as aza-analogues of flavones, compounds which are known for the wide-range of their biological activity. These quinolinones were studied as inhibitors of topoisomerase, gyrase and IMPDH. They were tested for anticancer activity in-vitro and were also shown to possess immunosuppressive properties. This review is the first summarizing the synthesis and activity of the mentioned quinolinones.

The lead optimization paradigm includes a team of experts that has a multitude of parameters to consider when moving from an initial lead compound through the lead optimization phase to the development phase. While in the past the team may have had only a medicinal chemist and a pharmacologist, the current team would often include experts in the areas of drug metabolism and pharmacokinetics (DMPK) as well as chemical toxicity. This review provides an overview of the some of the recent advances in the areas of DMPK screening plus a discussion of some of the assays that can be used to begin to screen for toxicity issues. The focus of this review is the major potential problem areas: oral bioavailability, half-life, drug-drug interactions and metabolism and toxicity issues.

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Impaired beta-cell function and possibly beta-cell mass appear to be reversible, particularly at early stages of the disease. Pancreatic beta-cells possess the potential to greatly expand their function and mass in both physiologic and pathologic states by several mechanisms, including hypertrophy and proliferation of existing beta-cells, increased insulin production and secretion, and formation of new beta-cells from progenitor cells. Recently a large number of factors controlling the differentiation of beta-cells has been identified and among them the parathyroid hormone-related protein (PTHrP) emerged as a strong candidate in ß-cell survival. In this review, we will hightlight our current knowledge in PTHrP physiology implicating its role into the mechanisms of beta-cell mass regulation and consequently in diabetes. Further research into mechanisms will reveal the key modulators of beta-cell failure and thus identify possible novel therapeutic targets.

Alzheimer's disease (AD) is a late-life cognitive disorder associated, among other things, to the presence of extracellular aggregates of fibrillar amyloid beta protein (Aβ). However, there is growing evidence that early stages of AD may be due to neuronal network dysfunction produced by the actions of soluble forms of Aβ. Therefore, the development of new therapeutic strategies to treat AD, at least during its first stages, may be focused on preventing or reversing, the deleterious effects that soluble Aβ exerts on neuronal circuit function. In order to do so, it is necessary to elucidate the pathophysiological processes involved in Aβ-induced neuronal network dysfunction and the molecular processes underlying such dysfunction. Over the last decades, there has been extensive research about the molecular mechanisms involved in the effects of Aβ as well as possible neuroprotective strategies against such effects. Here we are going to review some of the intracellular pathways triggered by Aβ, which involve membrane receptors such as nicotinic-R, NMDA-R, integrins, TNF-R1, RAGE, FPRL and p75NTR and their intracellular mediators such as GSK3, PKC, PI3K, Akt, FAK, MAPK family, Src family and cdk5. Several of these pathways may constitute therapeutic targets for the treatment of the Aβ-induced neuronal network dysfunction which is, at least in part, the basis for cognitive dysfunction in AD.

The silencing of genes by RNA interference (RNAi) has identified proteins involved in the resistance of cancers to chemotherapeutic drugs. Resistance is associated with defects in the apoptotic signaling pathways. In this article, we examine using RNAi to target the anti-apoptotic protein cellular FLICE-like inhibitory protein (c-FLIP) for drug development.

The concept that bioactive components in functional foods are efficacious for the improvement of health, has recently gained much importance. The cruciferous vegetables which include broccoli, cabbage and cauliflower are excellent source of phytochemicals including glucosinolates and their byproducts, phenolics and antioxidant vitamins as well as dietary minerals. Broccoli consumption mediates a variety of functions including providing antioxidants, regulating enzymes and controlling apoptosis and cell cycle. The organosulfur chemicals namely glucosinolates and the S-methyl cysteine sulphoxide found in broccoli in concert with other constituents such as vitamins E, C, K and the minerals such as iron, zinc, selenium and the polyphenols namely kaempferol, quercetin glucosides and isorhamnetin are presumably responsible for various health benefits of broccoli. There exists no comprehensive review on the health promoting effects of phytochemical compounds present in broccoli so far. This review compiles the evidence for the beneficial role of glucosinolates in conjugation with the other phytoconstituents for human health. It also gives an overview on the chemical and biological characterization of potential bioactive compounds of broccoli including the interaction of phytoconstituents on its bioactivity. Further, the molecular basis of the biological activities of the chemicals present in broccoli potentially responsible for health promotion, from chemoprevention to cardio protection, are outlined based on in vitro and in vivo studies with a note on the structure activity relationship of sulforaphane and a few other isothiocyanates.