Current Medicinal Chemistry - Volume 28, Issue 21, 2021

Nucleotide metabolism has been targeted for many years and in various clinical settings, including cancer. The increased knowledge of certain enzymes involved in this metabolism and associated cellular processes accumulated over the last few years, gives important information related to the druggability of certain proteins and the use of inhibitors for others. Here, we review recent data on such enzymes with a major interest in drug development, i.e. SAMHD1 and the proteins of the NUDIX family. These include information on their roles in cancer progression, correlations with clinical outcomes in cancer patients, and the development and study of enzymatic inhibitors.

Nuclear Factor-Κappa B (NF-ΚB) is a family of critical transcription factors of the inflammatory pathway and plays an imperative role in the progression of various cancers such as breast, lung, liver, pancreatic, prostate and multiple types of lymphoma. NF- ΚB develops an inherent relationship between inflammation and cancer. It is a crucial factor that controls the ability of malignant and pre-neoplastic cells to prevent programmed cell death-based tumor-surveillance channels. Due to its high significance in the onset and progression of various cancers, it has become an excellent target for cancer therapy. The emerging targeted therapies provide a lot of hope, whereby a single protein or generally the target enzyme is completely blocked. Several natural compounds have shown anticancer and anti-inflammatory activities by inhibiting the NF-ΚB pathway in various cancer types. About 750 natural and synthetic inhibitors of the NF-ΚB have been reported. These inhibitors include microbial and viral proteins, small RNA/DNA, antioxidants, small molecules, peptides, and engineered constitutively active polypeptides, all of which may inhibit canonical and alternative NF-ΚB pathways. Thus, blocking or targeting the NF-ΚB-signaling pathways using natural and synthetic compounds could be a potential mechanism to cure the NF-ΚB induced tumors.

As an important post-transcription modification, histone deacetylation plays significant roles in chromatin remodeling and gene expression. The aberrant modification of histone deacetylation leads to various diseases. As a critical member of histone deacetylase (HDAC), HDAC6 serves as a key modulator in many physiological processes. Abnormal expression of HDAC6 gives rise to cancer, neurodegeneration and other diseases. Here, we have reviewed recent advances in physiological, protein structure and development of HDAC6 selective inhibitors.

Disorders of the central nervous system (CNS) and tumors of the brain are challenging to treat, and they rank amongst the most common causes of death worldwide. The delivery of drugs to the brain is problematic because the blood-brain barrier (BBB) effectively arrests the transport of large molecules (including drugs) from the blood to the CNS. Nanoparticle (NP)-mediated drug delivery has received much interest as a technique to overcome this difficulty. In particular, liposome NPs are promising candidates to carry and deliver drugs across the BBB and into the CNS. Liposomes are easy to prepare, highly biodegradable, and biocompatible. Liposomes can be easily modified with various ligands to enable efficient and targeted drug delivery. Liposomes can promote increased cellular uptake of drugs and can reduce the extent to which efflux transporters can remove drugs. Liposomes can be loaded with a wide range of drugs and biologically active substances. In this review, we will summarize recent advances in research relating to liposome-based strategies to enable drug delivery across the BBB.

Sigma-2 receptor plays key roles in promoting tumor cell apoptosis, enhancing efficacy of anti-tumor drugs, blocking signal transduction controlled by Aβ oligomers, regulating Ca²⁺ homeostasis and protecting nerve cells. Studies indicated that sigma-2 receptor may be closely coupled with ROS, LDL, mTOR, RAS, PLC/PKC, lysosomal autophagy and mitochondrial super oxidative stress. In addition, the high expression of this receptor in proliferating cells and nerve cells indicates that sigma-2 receptor is an ideal molecular target for imaging and therapeutic development for cancer, Alzheimer's disease, schizophrenia and traumatic brain injury. Various sigma-2 agonists have shown promising anticancer activities, while sigma-2 antagonists have displayed neuroprotection and inhibition of Aβ oligomers in the brain of Alzheimer's disease patients. Thus, both sigma-2 agonists and antagonists are potentially useful therapeutics for the management of cancer and neurodegenerative disorders.

Mitochondria are a potent source of cellular reactive oxygen species (ROS) and are vulnerable to oxidative damage. Mitochondria dysfunction could result in adenosine triphosphate (ATP) decrease and cell death. The kidney is an ATP-consuming organ, and the relationship between mitochondrial dysfunction and renal disease has been long noted. Mitochondrial targeting is a novel strategy for kidney diseases. At present, there are several ways to target mitochondria, such as the addition of a triphenylphosphonium cation, mitochondria-targeted peptides, and nanocarrier. There are also a variety of choices for the payload, such as nitroxides, quinone derivates, vitamins and so on. This review summarized the chemical and also clinical characteristics of various mitochondria- targeted antioxidants and focused on their application and perspectives in kidney diseases.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has been a global challenge. The complicated forms of the Coronavirus Disease 2019 (COVID- 19) can evolve to multiple-organ failure, including several coagulopathies related to a sudden worsening of respiratory status. This article aimed to review studies about hematological and hemostatic laboratory disorders directly related to COVID-19 and to discuss how SARS-CoV- 2 causes these abnormalities. The coagulation cascade model is associated with both COVID- 19 and pulmonary involvement. Laboratory changes are relevant to evaluate the coagulation state - D-dimer, prothrombin time (PT), Activated Partial Thromboplastin Time (APTT), platelet count and fibrinogen. Pregnant women and patients in Extracorporeal Membrane Oxygenation (ECMO) need special attention. Prophylactic interventions for COVID-19 coagulopathy should consider patients at risk for thrombotic events and potential contraindications. The mechanisms exerted by SARS-CoV-2 that impairs hemostatic balance include endothelial injury, inflammation, and activation of the immune and complement systems. For diagnosis of coagulopathy, mainly D-dimer, but also PT, APTT and FDP, should be evaluated in COVID-19 patients. Intervention possibilities vary between low-molecular-weight heparin (LMWH) and Unfractionated Heparin (UFH). Until now, there is sufficient evidence that acutely-ill patients with risk factors for coagulopathies will benefit from thrombophylaxis during hospitalization and post-discharge, but not all patients.

Background: Leishmaniasis, a still important public health problem, exhibits environmental risk factors such as massive migrations, urbanization, and deforestation. WHO research for Leishmaniasis is mainly focused on the development of new tools, such as diagnostic tests, drugs, and vaccines. During the drug development strategy, only a few compounds were promising and call for further study after the in vitro and in vivo preclinical tests. Objective: In this review, our group aimed to highlight the utmost research done during 2014 to 2019 in the fields of natural and synthetic compounds, as well as repurposed drugs and new formulations tested in vivo for Leishmania spp. Method: Based on the literature search, we used the databases MEDLINE, PUBMED, CAPES PERIODIC and ELSEVIER to delineate an interval of the last 5 years of research on each field. Results: Among the natural compounds tested, allicin and a fraction of potato tuber extract showed the most promising antileishmanial activity. Concerning synthetic compounds, quinolines, bornyl ester, thymol, benzoxaborole and nitroimidazole derivatives exhibited encouraging results. Moreover, repositioned alternatives involved combinations with known drugs and monotherapy protocols as well. In these years, new formulations were widely assessed as drug delivery systems, such as nanoparticles, micelles and liposomes in polymer conjugations. Conclusion: Drug repurposing and new formulations of already-known drugs are worthwhile approaches to promptly introduce new treatment schemes to Leishmaniasis. Nevertheless, the interest in new synthetic compounds and new formulations brings light to new treatment proposals and are notable lines of research.

Background: Alzheimer's disease (AD) involves an irreversible and progressive neurodegeneration, with multifactorial pathophysiology, including the cholinergic deficit, amyloid plaques, neurofibrillary tangles, oxidative stress, and neurodegeneration. Despite the severity of the disease, the therapeutic arsenal is limited, arousing the interest of researchers to search for substances that can act on these markers. Objective: In this review, we highlight some relevant points, such as the ability of chalcones to act on different targets related to the pathophysiology of Alzheimer's disease; cholinesterases, amyloid peptide, beta-secretase and other biomarkers. Method: This mini-review covered the literature concerning chalcones bioactivity from 2010 until now. In addition to the theoretical review, we included the prediction of physicochemical properties using SwissADME software. Results: We found that the majority of the chalcones have been tested against cholinesterases, with moderate to good potencies, but in recent years, the number of publications related to targets of the amyloid hypothesis has been growing. Regarding the physicochemical properties, chalcones have a good profile, except for the water solubility, which is not favorable. Conclusion: The most important characteristic of these molecules is that many of the examples mentioned here act on more than one target, characterizing them as multi-target compounds. Regarding predicted properties, solubility stands out as the most problematic one; however, these structures can incorporate functional groups that circumvent this problem of solubility without interfering in the biological activity.

Background: We report herein the synthesis of a novel dicationic boron dipyrromethene derivative (compound 3) which is symmetrically substituted with two trimethylammonium styryl groups. Methods: The antibacterial photodynamic activity of compound 3 was determined against sixteen methicillin-resistant Staphylococcus aureus (MRSA) strains, including four ATCC type strains (ATCC 43300, ATCC BAA-42, ATCC BAA-43, and ATCC BAA-44), two mutant strains [AAC(6’)-APH(2”) and RN4220/pUL5054], and ten nonduplicate clinical strains of hospital- and community-associated MRSA. Upon light irradiation, the minimum bactericidal concentrations of compound 3 were in the range of 1.56-50 μM against all the sixteen MRSA strains. Interestingly, compound 3 was not only more active than an analogue in which the ammonium groups are not directly connected to the n-conjugated system (compound 4), but also showed significantly higher (p < 0.05) antibacterial potency than the clinically approved photosensitizer methylene blue. The skin irritation of compound 3 during topical application was tested on human 3-D skin constructs and proven to be non-irritant in vivo at concentrations below 1.250 mM. In the murine MRSA infected wound study, the colony forming unit reduction of compound 3 + PDT group showed significantly (p < 0.05) higher value (>2.5 log10) compared to other test groups except for the positive control. Conclusion: In conclusion, the present study provides a scientific basis for future development of compound 3 as a potent photosensitizer for photodynamic therapy for MRSA wound infection.