Current Medicinal Chemistry - Volume 24, Issue 6, 2017

Exploitation of nanotechnology advances in the cardiovascular medicine has led to new approaches for the diagnosis and therapy of vascular inflammation associated to cardiovascular diseases. Innovative nanoparticles targeted to the main players in the arterial wall inflammation in atherosclerosis (i.e. inflammatory molecules, immune or resident cells) have been already developed to diagnose and/or reduce excessive vascular inflammation and is eagerly awaited that promising preclinical and early clinical results to boost the approval of the first nanocarrier in this field. This review discusses the challenges and the steps undertaken so far to produce powerful multifunctional nanoparticles capable of raising new scenarios for future precision medicine in atherosclerosis.

Natural products have been frequently used as sources of clinical useful pharmaceuticals. However, some intrinsic characteristics of the natural drugs have limited their use, namely their solubility and chemical stability in physiologic mediums. Innovative drug delivery systems may help overcome such limitations, thus providing more effective administration of natural products. Phytosome (Indena SPA, Italy) is one of the most exciting recent delivery technologies that improves the oral bioavailability of the phytopharmaceuticals by their inclusion in equimolar complexes with dietary phospholipids with vesicular shape in aqueous environments. The purpose of this review is to characterize the state of the art of the phytosome as drug delivery system of natural products, including a discussion of the natural drug-phospholipid complex interactions, mechanisms of oral and topical delivery, methods of preparation and phytosome recent applications and patents in the 2006-2016 period.

Non-Small Cell Lung Cancer (NSCLC) is an especially aggressive cancer, the optimal drugs for which are still being developed. The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. EML4-ALK fusion gene initially identified in patients with NSCLC in 2007 is defined as a new molecular subset, which is highly sensitive to ALK inhibition. Since the first ALK inhibitor, crizotinib, was approved by the US Food and Drug Administration (FDA) for the treatment of NSCLC patients in 2011, ALK has been identified as a promising target for NSCLC therapy. However, crizotinib is not effective for various point mutations in ALK and central nervous system (CNS) metastasis. To date, there are only eight of second-and third-generation ALK inhibitors in clinical investigation and others are in preclinical research. This review summarizes recent advances of ALK inhibitors, with a focus on their biological activity, selectivity and structure-activity relationship (SAR) information. We hope this review could help medicinal chemists to discover newer ALK-inhibitors to overcome exist issues in the process of drug discovery, such as potency, selectivity and secondary mutations.

DNA damage repair is a kind of cellular self-protection mechanism in which some relevant proteins are activated when DNA damage response occurs in order to maintain the intracellular function stability and structure integrity. Post-translational modifications (PTMs) of proteins can rapidly confer to them more complicated structure and sophisticated function by covalently combining different small molecules with target proteins, which in turn plays an important regulatory role in DNA damage repair. It was reported that heterogeneous nuclear ribonucleoprotein K (hnRNP K) could be involved in DNA damage repair process under the regulation of its many post-translational modifications, including methylation, ubiquitination, sumoylation and phosphorylation. Here, we reviewed molecular mechanisms of hnRNP K protein post-translational modifications and their role in DNA damage repair, which will promote our understanding of how hnRNP K participating in the repair process to maintain the normal operation of biological activities in the cells.

The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small molecules displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead molecules have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivatives as modulators biological targets (viz. kinases, NAMPT, soluble epoxide hydrolases, mTOR, proteases, gyrB/parE, and epigenetic enzymes (such as HDAC, PRMT or DOT1L etc.). The findings of this review confirm the importance of urea moiety in medicinal chemistry and stimulate its use as a structural motif with rational decision making approach.