Current Medicinal Chemistry (v.23, #8)

Meet Our Editorial Board Member by Peter Chiba (747-747).

Targeting “Undruggable” Proteins: Design of Synthetic Cyclopeptides by Anna Russo, Carmela Aiello, Paolo Grieco, Daniela Marasco (748-762).
The development of synthetic macrocycles represents a powerful approach toward the identification of new protein binders or inhibitors of Protein-Protein Interactions (PPI) which are known to play key biological roles in cancer signaling as well as in the regulation of cell division cycle. Structural investigations led to identify “hot loops” sharing common motifs that are mainly involved in PPIs. Most PPIs occur through large and flat surfaces; currently these protein complexes are defined as “undruggable” by conventional drug-discovery approaches, since the identification of small molecules to inhibit these targets is often unreachable.
Typically macrocycles are 500-2000 Da in size, having 12-membered, or more, ring architecture: they do not obey the Lipinski's rule but, for them nature offers many examples as therapeutic agents such as erythromycin (antibiotic), cyclosporin (immunosuppressant) and somatostatin (hormone).
Peptide-based macrocycles offer the advantages of directly mimicking secondary structures involved in PPIs and their pharmacological application is related to the potential improvement of lead peptides in terms of potency, selectivity, stability and cell permeation.
The promising relevance of cyclopeptides prompted to develop new synthetic methods for cyclization: often biotechnological approaches as well as regioselective reactions have been employed to cyclize peptides rapidly and nearly quantitatively. Moreover, different synthetic strategies in peptidomimetics' macrocyclization are actually available based on surrogate peptide bonds or NCL (Native Chemical Ligation) methods.
In this review we focus on the most common methods for the preparation of cyclopeptides and interesting applications of the last decade.

An Overview of Non-Neural Sources of Calcitonin Gene-Related Peptide by Rong Hu, Yuan-Jian Li, Xiao-Hui Li (763-773).
Calcitonin gene-related peptide (CGRP) is extensively distributed throughout the central and peripheral nervous systems and has been shown to be a 37 amino acid multifunctional neuropeptide involved in a wide range of physiological and pathological processes. Recently, there is increasing evidence suggesting that CGRP also exists in non-nerve cells, such as epithelial cells, endothelial cells, endothelial progenitor cells (EPCs), T lymphocytes, B lymphocytes, peripheral blood mononuclear cells (PBMCs), and adipocytes. The existence of CGRP in non-neural tissue is of great importance to the regulation of multiple physiological and pathological processes via different pathways, especially through an autocrine/paracrine mode. This review integrates evidence from recent developments and aims to provide novel insights into non-neural sources of CGRP and its effects on physiological and pathological processes.

Morin: A Promising Natural Drug by Anna Caselli, Paolo Cirri, Alice Santi, Paolo Paoli (774-791).
Morin is a natural polyphenol, originally isolated from members of the Moraceae family that can be extracted from leaves, fruits, stems and branches of numerous plants. Several evidence have demonstrated that Morin could have a beneficial effect on several human diseases. In fact, Morin exerts antioxidant, antidiabetic, anti-inflammatory, antitumoral, antihypertensive, antibacterial, hypouricemic, and neuroprotective effects, by modulating the activity of many enzymes. In some cases, Morin shows a systemic protective action, reducing negative side effects of several drugs, without interfering with their functions. In addition, in vitro and in vivo studies demonstrated that Morin exhibits very low toxicity levels and its chronic administration is well tolerated. All these findings suggest that Morin could be used, either alone or in combination with other drugs, to prevent many human pathologies.

Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases by Marisa Cabeza, Araceli Sánchez-Márquez, Mariana Garrido, Aylín Silva, Eugene Bratoeff (792-815).
This article summarizes the importance of different targets such as 5?-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

Omega-3 Fatty Acids and their Role in Central Nervous System - A Review by Tomasz Wysocza|ski, Ewa Soko|a-Wysocza|ska, Jolanta P|kala, Stanis|aw Lochy|ski, Katarzyna Czy|, Robert Bodkowski, Grzegorz Herbinger, Bo|ena Patkowska-Soko|a, Tadeusz Librowski (816-831).
Polyunsaturated fatty acids (PUFAs) are crucial for our health and wellbeing; therefore, they have been widely investigated for their roles in maintaining human health and in disease treatment. Most Western diets include significant amount of saturated and omega-6 fatty acids and insufficient quantity of omega-3; however, the balance between omega-6 and omega-3 PUFA, in particular, is essential for the formation of pro- and anti-inflammatory lipids to promote health and prevent disease. As our daily diet affects our health, this paper draws attention to unique representatives of the omega-3 fatty acid group: alpha-linolenic acid and its derivatives. Recently, this has been shown to be effective in treating and preventing various diseases. It has been confirmed that omega-3 PUFAs may act as therapeutic agents as well and their significant role against inflammatory diseases, such as cardiovascular and neurodegenerative diseases, has been described. Some of nutritional factors have been described as a significant modifiers, which can influence brain elasticity and thus, effect on central nervous system functioning. Therefore, appropriate dietary management appears to be a non-invasive and effective approach to counteract neurological and cognitive disorders.

Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors by Yang Zhang, Zhao-Peng Liu (832-849).
Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.