Current Medicinal Chemistry - Volume 28, Issue 33, 2021

Several clinical studies have shown that exposure of skin to solar ultraviolet (UV) radiation causes adverse effects, such as inflammation, oxidative stress and DNA damage. As a result, different skin disorders can arise, among which are skin cancer, including non-melanoma skin cancer (NMSC) and melanoma (MM). Phenolic compounds are plant-derived secondary metabolites with a well-known antioxidant activity, able to counteract the negative effects of UV radiation. In this review, we discuss the effects of some selected phenols on NMSC and MM, demonstrating that they can be useful in the prevention and in the treatment of these types of tumors. Moreover, we report the mechanisms by which these phenols carry out their antitumor action. In vitro and in vivo studies have highlighted that many phenols are capable of inducing photoprotection, apoptosis and autophagy. They can also reduce DNA methylation, tumorigenesis, tumor incidence and proliferation. Moreover, we describe some examples of plant extracts, whose anticancer activity appears to be better than that of single phenols. A great concordance of results emerged, despite the differences in experimental methods. Therefore, the knowledge compiled here could provide the basis for conducting some well-organized clinical trials to validate the chemopreventive and the therapeutic potential of some phenolic compounds in patients with NMSC and MM.

Multiple myeloma (MM) is a common malignant hematological malignancy. Recently, interest has grown in the role of non-coding regions in disease pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs containing 19-25 bases that play a crucial role in messenger RNA silencing and post-transcriptional regulation of gene expression. Several miRNAs demonstrate markedly dysregulated expression in MM, suggesting that they may act as both tumor suppressors and oncogenes. microRNAs are also reportedly involved in the regulation of other epigenetic mechanisms of gene expression. Additionally, some miRNAs have been associated with drug resistance, and therefore a further exploration of their activity may lead to its reversal. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. This review describes the roles of miRNAs in MM and examines their potential to predict MM prognosis and play a role in novel therapeutic strategies.

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Objective: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure- activity relationships. Conclusion: Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-ΚB, mTOR, BRAF, and Wnt/β-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.

Cyclin-dependent kinases (CDKs) comprise a family of about 20 serine/threonine kinases whose catalytic activity requires a regulatory subunit known as cyclin; these enzymes play several roles in the cell cycle and transcription. PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions. Among these functions, we may highlight the following: modulation of cargo transport in membrane traffic, p53-responsive gene, regulation of genome integrity. According to different studies, PCTK3 dysfunction is related to a wide range of diseases, such as metabolic diseases, cerebral ischemia, depression, cancer, neurological disorders, and Alzheimer's disease. Although this protein participates in different biological events, we may say that PCTK3 has received far less attention than other CDKs. There are thousands of published articles about other CDKs and less than two hundred articles related to PCTK3. The main objective of this review is to present the selected published studies about this protein. Our focus is on PCTK3 particularities compared to other CDKs. Here we give an overview of the biological functions of PCTK3 and explore its potential as a target for drug design.

Background: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy have been almost the exclusive strategy for identifying the marketed compounds. However, the actual structural and functional information about the molecular targets of the anticonvulsant drugs and the increasing knowledge of the molecular alterations that generate epileptic seizures allow a more rational identification of active compounds. Objective: This review compiles target-based strategies used for the discovery of new anticonvulsant candidates and is divided in two main topics. The first one provides an overview of the computational approaches (docking-based virtual screening and molecular dynamics) to find anticonvulsant structures that interact with the voltage-gated ion channels and the enzyme carbonic anhydrase. The second one includes the analysis of active compounds synthesized to act simultaneously on different molecular targets by the combination of pharmacophores of anticonvulsant drugs. Conclusion: Current knowledge of the architectures of anticonvulsant targets makes computational simulations attractive methods for the discovery and optimization of active compounds. Combining the results achieved by virtual screening of different targets could lead to multitarget compounds, as an alternative to the design of structures that merge scaffolds of known drugs.

Ferroptosis plays a critical regulatory role as a new kind of cell death, initiating and developing an array of disorders like neurological diseases, acute injury of kidney, tumors, and ischemia, etc. Although selective deposition of iron is one of the pathogenic reasons for PD, it’s underlying mechanism is still unknown. In this review, the role of neuroinflammation in Parkinson’s disease (PD) leading to neurodegeneration has been discussed in detail. The accumulation of brain iron has been found in many chronic neurological disorders, including PD. We have also discussed the unique features of ferroptosis , and it links in aggravating the pathology of PD. Further, the concept of targeting ferroptosis for PD pathology and inducers and inhibitors, pharmacological drugs and clinical trials for PD candidates in phase IV stage in completed status are detailed in the respective sections.

Background: Lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, evokes intensive inflammatory responses in the human body. Naturally, inflammation is a part of the host immune response to an infection; nonetheless, an exaggerated response can lead to a series of pathophysiological consequences, collectively known as LPS toxicity or septic shock. Objective: This review will explore the cellular and experimental investigations that mainly focus on Curcumin's therapeutic effects on the LPS-mediated inflammatory responses. Method: A literature review of all relevant studies was performed. Conclusion: Curcumin has been reported to exert anti-inflammatory properties by interfering with LPS-induced inflammatory pathways, including binding to cell surface receptors of LPS, NF-kB activation pathway, and inflammasome activation. Further clinical studies on the effect of Curcumin in reducing the pathophysiological consequences of LPS toxicity would substantiate the use of this molecule for future therapeutic approaches.

End-stage liver diseases have long been a threat to human health, and so far, the treatment of these diseases lacks effective means. Allogenic organ transplantation has become the last straw for most of the patients with end-stage liver diseases. However, this technique has been greatly limited by the serious shortage of donors and other factors, such as immune rejection, drug syndrome, and high cost. Recently, the emergence of three-dimensional (3D) bioprinting technologies, together with the magnetic resonance imaging (MRI) and computed tomography (CT) techniques, has driven the rapid growth of this field toward liver therapies. There are several basic requirements for liver 3D bioprinting. From information collection of diseased livers, to 3D printing of liver substitutes (containing the major structural, material and functional characters), and to clinical applications, suitable ‘bioinks’ and ‘bioprinters’ have played essential roles. In this review, we highlight the advanced ‘bioinks’ and ‘bioprinters’ that have been used for vascularized and innervated liver tissue 3D bioprinting. Further studies for the incorporation of biliary networks in the bioartificial livers have been emphasized. It is expected that when all the bottle-neck problems for liver 3D bioprinting are solved, batch (i.e. mass) and personalized production of bioartificial livers will make it very easy to treat end-stage liver diseases.