Current Medicinal Chemistry - Volume 26, Issue 32, 2019

It is well-recognized that the majority of cancer-related deaths is attributed to metastasis, which can arise from virtually any type of tumor. Metastasis is a complex multistep process wherein cancer cells must break away from the primary tumor, intravasate into the circulatory or lymphatic systems, extravasate, proliferate and eventually colonize secondary sites. Since these molecular processes involve the coordinated actions of numerous proteins, targeted disruptions of key players along these pathways represent possible therapeutic interventions to impede metastasis formation and reduce cancer mortality. A diverse group of proteins with demonstrated ability to inhibit metastatic colonization have been identified and they are collectively known as metastasis suppressors. Given that the metastasis suppressors are often downregulated in tumors, drug-induced re-expression or upregulation of these proteins represents a promising approach to limit metastasis. Indeed, over 40 compounds are known to exhibit efficacy in upregulating the expression of metastasis suppressors via transcriptional or post-transcriptional mechanisms, and the most promising ones are being evaluated for their translational potentials. These small molecules range from natural products to drugs in clinical use and they apparently target different molecular pathways, reflecting the diverse nature of the metastasis suppressors. In this review, we provide an overview of the different classes of compounds known to possess the ability to upregulate one or more metastasis suppressors, with an emphasis on their mechanisms of action and therapeutic potentials.

DNA topoisomerases (Top) are a group of isomerase enzymes responsible for controlling the topological problems caused by DNA double helix in the cell during the processes of replication, transcription and recombination. Interestingly, these enzymes have been known since long to be key molecular machines in several cellular processes through overwinding or underwinding of DNA in all living organisms. Leishmania, a trypanosomatid parasite responsible for causing fatal diseases mostly in impoverished populations of low-income countries, has a set of six classes of Top enzymes. These are placed in the nucleus and the single mitochondrion and can be deadly targets of suitable drugs. Given the fact that there are clear differences in structure and expression between parasite and host enzymes, numerous studies have reported the therapeutic potential of Top inhibitors as antileishmanial drugs. In this regard, numerous compounds have been described as Top type IB and Top type II inhibitors in Leishmania parasites, such as camptothecin derivatives, indenoisoquinolines, indeno-1,5- naphthyridines, fluoroquinolones, anthracyclines and podophyllotoxins. The aim of this review is to highlight several facts about Top and Top inhibitors as potential antileishmanial drugs, which may represent a promising strategy for the control of this disease of public health importance.

Antimicrobial Peptides (AMPs) are one of the most common components of the innate immune system that protect multicellular organisms against microbial invasion. The vast majority of AMPs are isolated from the frog skin. Anuran (frogs and toads) skin contains abundant AMPs that can be developed therapeutically. Such peptides are a unique but diverse group of molecules. In general, more than 50% of the amino acid residues form the hydrophobic part of the molecule. Normally, there are no conserved structural motifs responsible for activity, although the vast majority of the AMPs are cationic due to the presence of multiple lysine residues; this cationicity has a close relationship with antibacterial activity. Notably, recent evidence suggests that synthesis of AMPs in frog skin may confer an advantage on a particular species, although they are not essential for survival. Frog skin AMPs exert potent activity against antibiotic-resistant bacteria, protozoa, yeasts, and fungi by permeating and destroying the plasma membrane and inactivating intracellular targets. Importantly, since they do not bind to a specific receptor, AMPs are less likely to induce resistance mechanisms. Currently, the best known amphibian AMPs are esculentins, brevinins, ranacyclins, ranatuerins, nigrocin-2, magainins, dermaseptins, bombinins, temporins, and japonicins-1 and -2, and palustrin-2. This review focuses on these frog skin AMPs and the mechanisms underlying their antimicrobial activity. We hope that this review will provide further information that will facilitate further study of AMPs and cast new light on novel and safer microbicides.

Background: As a new kind of green media and bioactive compounds with special structure, Ionic Liquids (ILs) are attracting much attention and applied widely in many fields. However, their roles and potential have not been fully recognized by many researchers of medicinal chemistry. Because of obvious differences from other traditional drugs and reagents, their uses and performance together with advantages and disadvantages need to be explored and reviewed in detail. Methods: For a systematic and explicit description of the relationship between ILs and medicinal chemistry, all of the contents were elucidated and summarized in a series of independent parts. In each part, it started from the research background or a conceptual framework and then specific examples were introduced to illustrate the theme. Finally, the important conclusions were drawn and its future was outlooked after the discussion about related key problems appearing in each mentioned research. Meanwhile, methodologies such as empirical analysis, comparison and induction were applied in different sections to exposit our subject. Results: The whole review was composed of five parts, and 148 papers were cited in total. Related basic information of ionic liquids was provided on the basis of representative references, including their concepts and important characters. Then 82 papers outlined ionic liquid-like active pharmaceutical ingredients, which unfolded with their major biological activities (antimicrobial activity, antibiofilm activity, antitumor activity, anticholinesterase activity and so on). Applications of ionic liquids in the synthesis of drugs and pharmaceutical intermediates were elaborated in 92 papers to illustrate the important roles of ILs and their extraordinary properties in this field. Moreover, new technologies (such as immobilization of IL, microwave reaction, solventfree synthesis, microreactor, etc) were introduced for further innovation. Finally, 26 papers were included to expound the status of the IL-assisted derivatization of various natural lead compounds. Conclusion: This review placed emphasis on chemical structures of ILs and their structureactivity relationships in a specific manner, leading to meaningful and valuable related information to some related fields and thus promotes further development and application of various ILs for medicinal chemistry. The deep exploration for key scientific problems is the driving force to propel their theoretical breakthrough and industrial production.

Background: Survival of multiple myeloma patients has considerably improved in the last decades thanks to the introduction of many new drugs, including immunomodulatory agents, proteasome inhibitors and, more recently, monoclonal antibodies. Methods: We analyzed the most recent literature focusing on the clinical and pharmacologic aspects of monoclonal antibody-based therapies in multiple myeloma, including monoclonal antibodies directed against plasma cell antigens, as well as checkpoint blockade therapy directed against immune inhibitory molecules, used as single agents or in combination therapy. Results: Anti-CD38 monoclonal antibodies including daratumumab, isatuximab and MOR202 have shown outstanding results in relapsed and/or refractory multiple myeloma patients. The addition of daratumumab to bortezomib-dexamethasone or lenalidomidedexamethasone substantially improved patients’ outcome in this patient population. The anti- SLAMF7 molecule elotuzumab in combination with lenalidomide-dexamethasone showed to be superior to lenalidomide-dexamethasone alone, without adding meaningful toxicity. Checkpoint blockade therapy in combination with immunomodulatory agents produced objective responses in more than 50% of treated patients. However, this combination was also associated with an increase in toxicity and a thorough safety evaluation is currently ongoing. Conclusion: Monoclonal antibodies are reshaping the standard of care for multiple myeloma and ongoing trials will help physicians to optimize their use in order to further improve patients’ outcome.

Background: Accumulating experimental data supports the capacity of natural compounds to intervene in complicated molecular pathways underlying the pathogenesis of certain human morbidities. Among them, diabetes is now a world’s epidemic associated with increased risk of death; thus, the detection of novel anti-diabetic agents and/or adjuvants is of vital importance. Alkaloids represent a diverse group of natural products with a range of therapeutic properties; during the last 20 years, published research on their anti-diabetic capacity has been tremendously increased. Purpose: To discuss current concepts on the anti-diabetic impact of certain alkaloids, with special reference to their molecular targets throughout the insulin-signaling pathway. Methodology: Upon in-depth search in the SCOPUS and PUBMED databases, the literature on alkaloids with insulin secretion/sensitization properties was critically reviewed. Results: In-vitro and in-vivo evidence supports the effect of berberine, trigonelline, piperine, oxymatrine, vindoneline, evodiamine and neferine on insulin-signaling and related cascades in beta-cells, myocytes, adipocytes, hepatocytes and other cells. Associated receptors, kinases, hormones and cytokines, are affected in terms of gene transcription, protein expression, activity and/or phosphorylation. Pathophysiological processes associated with insulin resistance, beta-cell failure, oxidative stress and inflammation, as well as clinical phenotype are also influenced. Discussion: Growing evidence suggests the ability of specific alkaloids to intervene in the insulin-signal transduction pathway, reverse molecular defects resulting in insulin resistance and glucose intolerance and improve disease complications, in-vitro and in-vivo. Future indepth molecular studies are expected to elucidate their exact mechanism of action, while large clinical trials are urgently needed to assess their potential as anti-diabetic agents.