Current Medicinal Chemistry - Volume 21, Issue 4, 2014

Since the discovery of penicillin, natural and synthetic β-lactams have aroused great interest not only as sources of effective antibacterial agents but also as specific inhibitors of proteases responsible for various non-bacterial pathological processes. This interest was reflected in our review published in Current Medicinal Chemistry in 2003. The present article summarises new data published during the last decade dedicated to the design, synthesis and biological exploration of new β-lactams with anti-inflammatory, antiviral, anticancer and other activities based on the inhibition of human leukocyte elastase, porcine pancreatic elastase, tryptase, chymase, human cytomegalovirus protease, fatty acid amide hydrolase, protein phosphatase methylesterase-1, serine protease responsible for tumor proliferation, cysteine proteases, matrix metalloproteinases, human 20s proteasome, human immunodeficiency virus, cholesterol absorption, human fatty acid synthase, bacterial RNase A and Leishmania D-mannosyl phosphate transferase. Antitumor effect was achieved also by new β-lactams activating apoptosis-specific poly(ADP-ribose) polymerase or participating in DNA intercalation.

Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user’s initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements.

Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson’s disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson’s disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, ‘pure’ compounds exclusively acting on the D2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

Malaria is one of the deadliest diseases on the planet affecting about 50% of the population worldwide. It is a leading cause of morbidity and mortality in the developing world. Plasmodium falciparum, a tiny parasite is the major cause of malaria and is possibly the most dangerous stow-away in history. Malaria has become a major economic concern to some of the tropical and sub-tropical countries. Though a number of antimalarials have been developed from plants as such or their semi-synthetic analogues, there is again an alarming situation of drug resistance against most of the antimalarial drugs. Plants have been an excellent source of antimalarial compounds. There are several plant leads exhibiting antimalarial activity better than the existing drugs. A systematic evaluation of these plant based leads is the need of the time to develop safe, effective and affordable new antimalarials. The present review is an update of plant based antimalarial agents.

Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells.GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.

Several medical conditions sharing similar signs and symptoms may be related to immune adjuvants. These conditions described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants), include a condition characterized by macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine derived-alum adjuvants into macrophages at sites of previous immunization. Despite increasing data describing clinical manifestations of ASIA have been reported, biological markers are particularly lacking for their characterization and follow up. We report an extensive cytokine screening performed in serum from 44 MMF patients compared both to sex and age matched healthy controls and to patients with various types of inflammatory neuromuscular diseases. Thirty cytokines were quantified using combination of Luminex® technology and ELISA. There was significant mean increase of serum levels of the monocytechemoattractant protein 1 (CCL2/MCP-1) in MMF patients compared to healthy subjects. MMF patients showed no elevation of other cytokines. This contrasted with inflammatory patients in whom CCL2/MCP-1 serum levels were unchanged, whereas several other inflammatory cytokines were elevated (IL1β, IL5 and CCL3/MIP1α). These results suggest that CCL2 may represent a biological marker relevant to the pathophysiology of MMF rather than a non specific inflammatory marker and that it should be checked in the other syndromes constitutive of ASIA.