Current Medicinal Chemistry - Volume 28, Issue 30, 2021

Mitotic kinases have integral roles in cell processes responsible for cancer development and progression in all tumor types and are common targets for therapeutics. However, a large subset of the human kinome remains unexplored with respect to functionality in cancer systems. Within the mitotic kinases, the never-in-mitosis kinase (NEK) family is emerging as novel kinase targets in various cancer types. NEK5 is an understudied member of the NEK family. While there are more recent studies describing the physiologic function of NEK5, its role in cancer biology remains widely understudied. However, emerging studies implicate that NEK5 has potentially crucial functions in various solid tumors. In this review, we discuss current knowledge regarding the role of NEK5 in cancer and the implications of NEK5 expression and activity in tumor development and metastasis. We summarize current studies that examine NEK5 activity in diverse cancer systems and cellular processes. As an understudied kinase, there are currently no selective NEK5-targeting agents to test the effects of pharmacologic inhibition on cancer, although there exist recent advancements in this area. Here we also include an update on efforts to develop selective pharmacologic inhibition of NEK5, and we discuss the current direction of NEK5-targeting therapeutic development. The generation of selective NEK5 inhibitors is promising new targeted therapies for cancer growth and metastasis.

Background: Cancer cells are characterized by metabolic heterogeneity. Although many research groups make efforts to analyze this heterogeneity, little attention has been paid to cancer cells utilizing otherwise unusable substrates as fuel for tumor development. Of the two stereoisomers of glucose, D-glucose but not L-glucose, the mirror image isomer of D-glucose is abundantly found in nature. D-glucose is the human body's key source of energy through aerobic respiration. However, data from in vitro and in vivo studies examining the ability of cancer cells to take up L-glucose are scarce. Objectives: The present mini-review aims to present current literature data on the role of L-glucose in cancer diagnosis based on in vitro and in vivo studies. Methods: The MEDLINE, EMBASE, and the Cochrane Library with restrictions to articles in English language databases were searched to retrieve available data. Results: There are limited data in the literature regarding in vitro and in vivo studies that examined the ability of cancer cells to take up L-glucose. Research work so far has shown that that the binding of a fluorescent detector to an L-glucose molecule produced a fluorescent probe that was specifically taken up by malignant cancer cells, thus providing a unique method for their detection. Conclusion: Given that L-glucose is taken up by cancer cells, L-glucose fluorescent probes can be a useful tool for visualization and characterization of cancer cells. More research on the potential biologic effects of L-glucose in cancer is necessary.

Nanomedicine is an arising field that exploits nanotechnology concepts for pioneered therapy and diagnostics. Colorimetric sensors for tumor markers have displayed interesting benefits compared to conventional systems in clinical laboratory diagnosis. Colorimetric immunoassay-based approaches show up-and-coming results since the goal cancer marker is determined with high sensitivity but without the utilization of advanced/- expensive techniques through an effortless optical color change. Also, colorimetric biosensor has the potential to detect proteins in biological fluids swiftly with high sensitivity, and they are anticipated to play a progressively serious role in tumor diagnosis. We reviewed (covering the period 2015-2020) various studies based on colorimetric sensing strategy using nanostructured materials (highly efficient enzyme mimics, artificial enzymes or nanozymes) to detect different tumor antigens in biological fluids. Specifically, we highlighted the recent progress and efforts in the construction of colorimetric immunosensors. Colorimetric immunosensors can be roughly divided into two main categories: transition metal nanozyme-based sensing and noble metal nanozyme-based sensing.

Multiple combinations of antiretroviral drugs have remarkably improved the treatment of HIV-1 infection. However, life-long treatments and drug resistance are still an open issue that requires continuous efforts for the identification of novel antiviral drugs. Background: The reverse transcriptase-associated ribonuclease H (RNase H) hydrolyzes the HIV genome to allow synthesizing viral DNA. Currently, no RNase H inhibitors (RHIs) have reached the clinical phase. Therefore, RNase H can be defined as an attractive target for drug design. Objective: Despite the wealth of information available for RNase H domain, the development of RHIs with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that reverse transcriptase is a highly versatile enzyme, undergoing major structural alterations to complete its catalysis, and that exists a close spatial and temporal interplay between reverse transcriptase polymerase and RNase H domains. This review sums up the present challenges in targeting RNase H encompassing the challenges in selectively inhibiting RNase H vs polymerase and/or HIV-1 integrase and the weak antiviral activity of active site inhibitors, probably for a substrate barrier that impedes small molecules to reach the targeted site. Moreover, the focus is given on the most recent progress in the field of medicinal chemistry that has led to the identification of several small molecules as RHIs in the last few years. Conclusion: RHIs could be a new class of drugs with a novel mechanism of action highly precious for the treatment of resistant HIV strains.

Background: To date, number of new and attractive materials have been applied in drug delivery systems (DDDs) to improve the efficiency of the treatment of cancers. Some problems like low stability, toxicity and weak ability of targeting have hampered most of materials for further applications in biomedicine. MIL(MIL = Materials of Institute Lavoisier), as a specific subclass of metal-organic frameworks (MOFs) owns more advantages than other subclass MOFs, such as better biodegradability and lower cytotoxicity. However, until now, systematic -s and analyses of Fe-based MIL on medical applications are rarely though the majority of documents discussed one research branch of the porous materials MOFs. Discussion: In this review, we have focussed mainly on the latest studies of applications, including bioimaging, biosensing, and antibacterial and drug delivery on Fe-based MIL. The existing shortcomings and future perspectives of the rapidly growing biomedical applications of Fe-based MIL materials addressing dosage and loading strategies issues are also discussed briefly, and further studies with the use of different therapies will be of great interest. Conclusion: This article reviews the Fe-based MOFs design and biomedical application, including biosensing, bioimaging, antibacterial agent, and drug delivery in recent years.

Background: Despite major advances in the fight against this parasitic disease, malaria remained a major cause of concern in 2021. This infection, mainly due to Plasmodium falciparum, causes more than 200 million cases every year and hundreds of thousands deaths in the developing regions, mostly in Africa. The last statistics show an increase in the cases for the third consecutive year; from 211 million in 2015, it has reached 229 million in 2019. This trend could be partially explained by the appearance of resistance to all the used antimalarials, including artemisinin. Thus, the design of new anti- Plasmodium compounds is an urgent need. For thousands of years, nature has offered humans medicines to cure their diseases or the inspiration for the development of new active principles. It then seems logical to explore the natural sources to find new molecules to treat this parasitosis. Methods: Therefore, this review reports and analyzes the extracts (plants, bacteria, sponges, fungi) and the corresponding isolated compounds, showing antiplasmodial properties between 2013 and 2019. Results and Conclusion: Nature remains a major source of active compounds. Indeed, 648 molecules from various origins, mostly plants, have been reported for their inhibitory effect on Plasmodium falciparum. Among them, 188 scaffolds were defined as highly active with IC50 ≤ 5 μM, and have been reported here in detail. Moreover, the most active compounds showed a large variety of structures, such as flavonoids, triterpenes, and alkaloids. Therefore, these compounds could be an interesting source of inspiration for medicinal chemists; several of these molecules could become the next leads for malaria treatment.

Pain is a symptom of ninety percent of human diseases, and pain management is a very important medicinal problem. Various modulators of the pain response have been detected, and analgesic effects are obtained by increasing inhibition or decreasing excitation in the nervous system. Various known analgesic drugs are commonly used to relieve the pain; however, this problem is still not fully resolved by currently available treatments. Available analgesic drugs (non-steroidal anti-inflammatory drugs, opioids and analgesic adjuvants) are not too effective and are severely limited by adverse effects, for example, opioid addiction. Therefore, developing effective pain management is a difficult but necessary task. Thus, there is an urgent need for further development of the design and synthesis of new analgesic agents. The aim of this review is to present recent progress in search of new small molecule analgesics. The structures and effects of new perspective analgesic agents (anti-inflammatory agents, opioid analgesics, adjuvant agents for pain management, and natural compounds) are presented and discussed. The review covers the literature published in 2015-2020 years and includes 173 references.

Background: Drug delivery systems such as hydrogels have become relevant in cardiovascular and metabolic therapies due to their sustained and controlled release properties of drugs, versatile polymer structures, safety, and biodegradability. Results: The literature presented demonstrates that a hydrogel-based controlled release system increases the therapeutic efficacy in different components of the metabolic syndrome. Hypertension has been the most explored component with advances in in vitro and murine models. However, clinical evidence in humans is scarce, and more translational studies are needed. Hydrogel-based systems for diabetes, obesity, and dyslipidemia have been little explored. Observations mainly demonstrated an increase in therapeutic efficacy, in vitro and in vivo, for the use of insulin, leptin, and natural components, such as epigallocatechin gallate. In all cases, the hydrogel systems achieve better plasma levels of the loaded compound, higher bioavailability, and low cytotoxicity compared to conventional systems. Also, the evidence existing suggests that the development of an injectable hydrogel system for controlled release of drugs or therapeutic compounds is presented as an attractive option for MeS treatment, and due to the possibility of sustained pharmacological release, there is no need for repeated doses and a safe administration route. Conclusion: The following review aims to evaluate the use of the hydrogel systems in the therapy of diabetes, obesity, hypertension, and dyslipidemia, which are the main components of metabolic syndrome.

Background: Vascular remodeling processes induced by acute and chronic injuries are characterized by inflammation and oxidative stress. In arteriosclerosis, atherosclerosis, and restenosis, the progression of neointimal hyperplasia is a key event of vascular damage. Objective: Our study was aimed to investigate the inflammation and oxidative stress development during vascular impairment and the potential efficacy of treatment of new micro composite N-palmitoylethanolamine/Rutin at a ratio of 1:1 (PEA/RUT). The anti-inflammatory effects of Palmitoylethanolamide (PEA) are well known. Rutin has important pharmacological actions, including antioxidant and vasoprotective. Methods: As a model of vascular injury, we used the complete ligature of the left carotid artery for fourteen days and administered PEA/RUT at the dose of 10 mg/Kg. Results: This study demonstrated that after fourteen days of carotid ligation, there is a substantial structural change in the vessel morphology, with inflammatory cell infiltration and reactive oxygen species production. PEA/RUT administration reduced change in vascular morphology, cytokines like monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules expression like intercellular adhesion molecules-1 (ICAM-1), proinflammatory cytokines production (IL-1 β, IL-6 and TNF- α), oxidative and nitrosative stress (nitrotyrosine and PARP expression and NRF2 pathway). Conclusion: Our data clearly demonstrate the beneficial effect of PEA/RUT administration in reducing inflammation, oxidative stress, and vascular damage.