Current Medicinal Chemistry - Volume 19, Issue 23, 2012

A large body of evidence point out that the onset of synthetic lethality may provide a useful tool for amplifying the efficacy of drugs in anticancer regimens, to uncover interdependence between genes and to identify predictive factors that would be extremely useful to guide in the selection of more effective targeted drugs and drug combinations for each patient. Here, we provide an overview on the exploitation of synthetic let Read More

Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair pr Read More

Alkylating agents such as temozolomide (TMZ) are effective anticancer drugs for treating a variety of solid tumors including melanoma, glioma, and astrocytoma. TMZ exerts its effects mainly via the mutagenic product O6-methylguanine, a cytotoxic DNA lesion. This damage may be repaired by the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), a key player in the resistance of cancers to TMZ. Several str Read More

Available evidence demonstrates that the DNA repair machinery is involved in melanoma resistance to chemotherapeutics. Furhtermore, preclinical findings suggest that interfering with DNA repair could increase chemosensitivity of melanoma cells. However, the clinical implementation of these principles is still in its infancy and no such strategy is currently proven to be effective in patients with advanced melanoma. Since the mo Read More

Type II topoisomerases (TOPO2) are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. The class of compounds targeting TOPO2 includes some of the most active chemotherapy agents currently available for the treatment of patients with different cancer types. Therefore, understanding of the molecular mechanisms un Read More

Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select Read More

Cancer treatments often lose their effectiveness due to the development of multiple drug resistance. Thus, identification of key proteins involved in the tumorigenic process and the survival mechanism(s), coupled with the design of novel therapeutic compounds (such as small molecule inhibitors), are essential steps towards the establishment of improved anticancer treatment strategies. DNA repair pathways and their p Read More

Polo-like kinases (PLKs) are a family of serine/threonine kinases that play crucial roles in multiple stages of mitosis. PLK1 is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of PLK1 inhibitors are ATP-competitive. Despite the structural similarities among various kinases, several inhibitors are selective. Some areas of the PLK1 active sit Read More

Breast cancer is still the leading cause of cancer deaths among women worldwide, and new therapies to treat this dangerous disease are desperately needed. The serendipitously found anticancer drug cisplatin and its second-generation congener carboplatin appear to be promising drug systems for the treatment of breast tumors, in particular of multidrug resistant and highly aggressive triplenegative subtypes. In th Read More

This review presents a general overview of the subtype-selective dopamine receptor radioligands for in vivo imaging of dopamine receptor expression by positron emission tomography (PET). Besides the 11C- and 18F-labeled radioligands which are already in clinical use, a summary of subtype-selective radioligands which had been studied in vitro and in vivo is provided, which shines light onto the current status and rece Read More

This review article deals with the structure activity relationship (SAR) for a variety of palladacycles in biomedical applications. Moreover, the types of antibacterial, antifungal, antimycobacterial and antiprotozoal (antiamoebic and antitrypanosomal) activities will vary considerably from one country to another. Therefore, all efforts will be required to face such a vast diversity of problems. This study gives an up to date overvie Read More

Dipeptidyl peptidase 4 (DPP-4), a substrate-specific serine protease, has been validated as a promising drug target for the treatment of type 2 diabetes. DPP-4 inhibitors significantly lowered blood glucose levels in patients with type 2 diabetes without common body weight gain, hypoglycemia and gastrointestinal disturbance side effects. Therefore, DPP-4 inhibitors attracted more and more attention. In particular Read More

Autism spectrum disorders are complex neuro-developmental disorders whose neurobiology is proposed to be associated with oxidative stress which is induced by reactive oxygen species. The process of oxidative stress can be a target for therapeutic interventions. In this study, we aimed to review the role of oxidative stress, plasma glutathione (GSH), and related factors as the potential sources of damage to the brain as Read More

Diets in which fat is significantly provided by olive oil and are relatively rich in vegetables, have been associated with a low incidence of cardiovascular diseases, mostly due to the presence of several phenolic compounds which have anti-oxidant and antiinflammatory properties. [1]. In this work, we describe the anti-inflammatory effect of 3,4-DHPEA-EDA in a cell model that we developed to mimic inflammatory injury Read More

AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded th Read More

P38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-α and interleukin-1β pathways, and thus the inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Presently, a combined study of threedimensional quantitative structure-activity relationship, molecular docking and molecular dynamics (MD) was undertaken to explore the structural insights of 174 Read More