Current Medicinal Chemistry - Volume 25, Issue 15, 2018

Background: Many impediments of current anti-cancer therapies have urged scientists to discover new agents. As a result of growing spectrums of new targets and strategies and recent biological and biotechnological progresses, many anti-cancer agents such as monoclonal antibodies, small molecule tyrosine kinase inhibitors and epigenetic drugs have been reached to clinical trials. Objectives: This review helps to understand the rationale for the development of inhibitors against major targets such as cell growth, proliferation, survival, angiogenesis and recent targets such as proteasome, heat shock proteins, and epigenetics. Methods: Recent approaches of the target-based anti-cancer drug developments were highlighted to giving some examples from approved agents. Many factors, such as metabolic change, hypoxia, cancer precursors and cancer resistant cells, and their effect on drug resistance mechanisms were discussed. The impacts of advanced computational techniques to identify targets of cancer and designing more selective inhibitors were explained. Results: Contributions of recent techniques such as a network analysis, the precise modes of action and computational methodologies especially simulation of bio-molecular processes to clarify targets, mechanism actions and reasons of lack of efficacy of anti-cancer drugs have been explained. The relationship between the several mechanisms and molecular design strategies has been discussed. Conclusion: This review provides an overview of important targets and design strategies of anti-cancer drugs, advantages and disadvantages of these methods and evaluation of some currently used anticancer targets in clinical studies.

Background: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition to the promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbil was shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk. Methods: These new results, together with the controversial effects of the drug on cardiac oxygen consumption, are critically discussed in this review in light of the current literature on omecamtiv mecarbil. Results: In therapeutically relevant concentrations the beneficial inotropic effect of the agent is not likely affected by these new results - in accordance with the good clinical data. At supratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increase arrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, observed at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtiv mecarbil. Conclusion: Further studies with definitely supratherapeutical concentrations of omecamtiv mecarbil should be designed to map the actual risk of these potentially harmful side-effects.

Coordination chemistry offers much scope for the design of novel and therapeutic agents, including metallopharmaceuticals. The widespread use of metal complexes as effective pharmaceuticals, e.g. cancer therapeutic, anti-inflammatory, antidiabetic drugs or antimicrobial and diagnostic agents, demonstrates that the cytotoxicity of metal ions can be finely controlled via the appropriate choice of ligands. The successful targeting of radioisotopes again depends on the ligand design and metal oxidation state. The complexes of platinum, ruthenium, cobalt, copper and other d-block metal ions have been used in medicine for a long time but only recent advances have been made in understanding the molecular basis of mechanism of their action. Due to the above mentioned purpose, we decided to prepare a detailed description of target-based research, directed towards a design and application possibilities, with the known mechanisms of action of metal ion complexes in the broad sense of therapy definition. The review also covers the progress, limitations and challenges of the above-mentioned approaches and emphasizes the advantages of well known and new metallopharmaceuticals in medicine and pharmacy.

Background: The endometrium is one of the most important female reproductive organs. Polycystic ovarian syndrome (PCOS) is a reproductive and endocrine pathology that affect women of reproductive age. PCOS negatively affects the endometrium, leading to implantation failure and proliferative aberrations. Methods: We conducted a search at the http://www.ncbi.nlm.nhi.gov/pubmed/electronic database using the following key words: endometrial steroid receptors, endometrium, uterine function, endometrium and PCOS, implantation window, implantation and PCOS, implantation markers, inflammation, oxidative stress. We selected the articles based on their titles and abstracts, then we analyzed the full text and classified the articles depending on the information provided according to the sections of the present review. Results: The endocrine and metabolic abnormalities displayed in women with PCOS promote complex effects on the endometrium, leading to a low rate of implantation and even infertility. Women with PCOS show alterations in the Hypothalamic-Pituitary- Ovarian axis, which results in constant circulating levels of estrogen, similar to those at the early follicular phase, and a deficiency in the withdrawal of estrogen and progesterone. Besides this deficiency in the withdrawal of estrogen and progesterone, the insulin/ glucose pathway, adhesion molecules, cytokines and the inflammatory cascade, together with the establishment of a pro-oxidative status, lead to an imbalance in the uterine function, which in turn leads to implantation failure or even endometrial cancer. Conclusion: Women with PCOS display a dysregulation of the Hypothalamic-Pituitary- Ovarian axis, which alters the steroid pathway. In addition, the deficiency in the withdrawal of estrogen and progesterone in the endometrium results in abnormal endometrial cellular proliferation. The imbalance in adipose tissue observed in PCOS patients reinforces the increase in circulating hormones. The present review describes the role of hormones, metabolites, cytokines, adhesion molecules and the insulin/glucose pathway related to the uterine endometrium in women with PCOS and their role in implantation failure and development of endometrial cancer.

Matrix metalloproteinases (MMPs) are members of calcium dependent-zinc containing endopeptidases that play a pivotal role in extracellular matrix (ECM) remodeling. MMPs are also known to cleave non-matrix proteins, including cell surface receptors, TNF-α, angiotensin-II, growth factors, (especially transforming growth factor-β1, GF- β1) plasminogen, endothelin and other bioactive molecules. The tissue inhibitors of metalloproteinases (TIMPs) inhibit the activity of MMPs and decrease ECM degradation. Various patho-physiological conditions have been linked with the imbalance of ECM synthesis and degradation. Numerous studies have reported the significance of MMPs and TIMPs in the progression of kidney pathologies, including glomerulonephritis, diabetic nephropathy, renal cancer, and nephrolithiasis. Although dysregulated activity of MMPs could directly or indirectly lead to pathological morbidities, their contribution in disease progression is still understated. Specifically, MMP activity in the kidneys and it's relation to kidney diseases has been the subject of a limited number of investigations. Therefore, the aim of the present review is to provide an updated insight of the involvement of MMPs and TIMPs in the pathogenesis of inflammatory and degenerative kidney disorders.