Current Medicinal Chemistry - Volume 29, Issue 2, 2022

Gastrointestinal stromal tumors (GISTs) are unusual cancers, which are developed in specialized cells in the gastrointestinal tract wall. Various strategies involving single-agents, combinations, and rapid complementary inhibitor cycling are now being used to control such tumors. Based on promising early clinical trial experience, certain novel KIT and PDGFRA tyrosine kinase inhibitors have shown advanced clinical development. Resistance to tyrosine kinase inhibitors has brought immense difficulties, with patients now requiring additional therapeutic options. This review describes and discusses the last five years (2016-2020) in developing novel c-KIT kinase inhibitors using virtual screening and docking approaches. Computational techniques can be used to complement experimental studies to identify new candidate molecules for therapeutic use. Molecular modeling strategies allow the analysis of the required characteristics that compounds must have to effectively bind c-KIT. Through such analyses, it is possible to both discover and design novel inhibitors against cancer-related proteins that play a critical role in tumor development (including mutant strains). Docking showed potential in the detection of the key residues responsible for ligand recognition and is very helpful to understand the interactions in the active site that can be used to develop new compounds/classes of anticancer drugs and help millions of cancer patients.

Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological treatment. These cancers’ types are found in one of the three categories, leukemias (also named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated with three genetic mutations, where could emerge from oncogenes, tumor suppressor genes, and/or genes responsible for regulating DNA replication. The term “undruggable” is frequently related to the difficulty to design drugs to specific targets, such as MYC, MYB, NF-ΚB, and RAS family of proteins. This last comprises more than 140 proteins, and these are responsible for 30% of mutations in human cancers. Also, there are three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes) perform essential steps in post-translational modification of eukaryotes cells, such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation of the new C-terminal prenylated cysteine. Thus, the inhibition of this undruggable RAS family of proteins has been considered a promising alternative to design new anticancer agents since they are responsible for many types of human cancers. Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs (epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones core) have been described as promising FTase inhibitors, which have demonstrated their benefits against several types of cancer. In this review, a complete introduction about cancer and its relation with RAS proteins is provided, as well as, the prenylation mechanism of the cysteine residue is discussed in detail. Posteriorly, studies involving manumycin-related compounds are described, showing some synthetic routes for obtaining them and utilizing these natural products in monotherapies or combined therapies with other anticancer drugs.

The molecular mechanisms of mitotic cell cycle progression involve very tightly restricted types of machinery which are highly regulated by a fine balance between the positive and negative accelerators (or regulators). These regulators include several checkpoints that have proteins acting as enzymes and their activating partners. These checkpoints incessantly monitor the external as well as internal environments such as growth signals, favorable conditions for growth, cell size, DNA integrity of the cell and hence function to maintain the highly ordered cell cycle progression by sustaining cell homeostasis and promoting error-free DNA replication and cell cycle division. To progress through the mitotic cell cycle, the cell has to successfully drive past the cell cycle checkpoints. Due to the abnormal behavior of some cell cycle proteins, the cells tend to divide continuously overcoming the tight regulation of cell cycle checkpoints. Such anomalies may lead to unwanted cell division, and this deregulation of cell cycle events is considered as one of the main reasons behind tumor development, and thus, cancer progression. So the understanding of the molecular mechanisms in cancer progression might be insightful for designing several cancer treatment strategies. The deregulation in the checkpoints is caused due to the changes in the tyrosine residues of TPKs via PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways. Therefore, the inhibitors of PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways could be potential anticancer agents. The resistance and toxicity in the existing synthetic anticancer chemotherapeutics may decrease the life span of a patient. For long, natural products have played an essential alternative source of therapeutic agents due to having least or no side effect and toxicity. The present study is an attempt to promote natural anticancer drug development focusing on the updated structural information of PDGFR, EGFR, FGFR, and VEGFR inhibitors isolated from the plant sources. The data used in this review has been collected from internet resources, viz. GOOGLE Web, GOOGLE SCHOLAR, and PubMed Central. The citation of each report was first checked, after which the articles were selected as an authentic reference for the present study. Around 200 journal articles were initially selected, of which around 142 were finally chosen for presenting the study on the natural sourced inhibitors of EGFR, PDGFR, FGFR, and VEGFR-mediated signaling pathways which may help to enhance the potential cancer treatment.

Acetylation on lysine residues is considered one of the most potent protein post-translational modifications, owing to its crucial role in cellular metabolism and regulatory processes. Recent advances in experimental techniques have unraveled several lysine acetylation substrates and sites. However, owing to its cost-ineffectiveness, cumbersome process, time-consumption, and labor-intensiveness, several efforts have been geared towards the development of computational tools. In particular, machine learning (ML)-based approaches hold great promise in the rapid discovery of lysine acetylation modification sites, which could be witnessed by the growing number of prediction tools. Recently, several ML methods have been developed for the prediction of lysine acetylation sites, owing to their time- and cost-effectiveness. In this review, we present a complete survey of the state-of-the-art ML predictors for lysine acetylation. We discuss a variety of key aspects for developing a successful predictor, including operating ML algorithms, feature selection methods, validation techniques, and software utility. Initially, we review lysine acetylation site databases, current ML approaches, working principles, and their performances. Lastly, we discuss the shortcomings and future directions of ML approaches in the prediction of lysine acetylation sites. This review may act as a useful guide for the experimentalists in choosing the right ML tool for their research. Moreover, it may help bioinformaticians in the development of more accurate and advanced MLbased predictors in protein research.

Proprotein convertase subtilisin/Kexin 9 (PCSK 9) is revealed to be a key player in lipid metabolism and, therefore, in the development and progression of atherosclerosis. PCSK 9 binds to the low-density lipoprotein (LDL) receptor, induces its degradation, and increases circulating blood LDL. As a result, PCSK 9 inhibitors represent an essential pillar in cardiovascular risk reduction therapies due to their highly sufficient LDL decreasing properties. While the influence of PCSK 9 on lipid metabolism has been widely investigated, the full pathophysiological spectrum of PCSK 9 is yet to be determined. Statins have already been demonstrated to have beneficial anti-inflammatory effects. In this context, evidence suggests that PCSK 9 also interferes with inflammatory processes, thereby contributing to the development of atherosclerosis. As lipid metabolism on its own affects inflammatory processes, it is difficult to distinguish between lipid-dependent and -independent inflammatory properties of PCSK 9. A body of evidence has revealed that PCSK9 LDL-independently regulates the secretion of pro-inflammatory cytokines and inflammation-underlying pathways in vascular walls, whereas recent observations suggest that PCSK9 also interacts with lectin-like oxidized LDL receptor-1 (LOX-1) and dampens inflammatory responses through LDL reduction. In conclusion, this review provides mounting evidence indicating how PCSK9 promotes vascular inflammation and subsequent atherosclerosis to shed light on the anti-inflammatory effects of PCSK9 inhibitors in the prevention of atherosclerosis.

Cancer is one of the leading social problems of the modern world. Today prostate cancer is the second leading cause of cancer deaths among men. Targeted drug delivery is widely used to treat and diagnose prostate cancer. Conjugates selectively binding to prostatespecific membrane antigen-based on urea ligands are being actively developed against this disease. The linker has a significant influence on the biological activity of such conjugates. The linker performs a large number of functions, and its modification is one of the key methods for creating the best pharmacological profile. This review aims to discuss and analyze the main approaches to the method of introduction and synthesis of linkers for this type of conjugates without a description of the influence of biologically active molecules, as well as to establish the key modification methods that have a significant role on the structure-activity relationship. For this purpose, a review of the current scientific literature was performed, both for the conjugates under development and those already undergoing clinical trials. It was found that the optimal structure is a linker containing an aliphatic fragment near the vector- molecule (n(CH2) = 3-6), followed by a polypeptide chain consisting of 2 to 4 amino acid residues. The presence of a Phe-Phe dipeptide chain or the introduction of negatively charged groups also has a positive effect. Ongoing research in this field helps to establish the accurate effect of each linker fragment, and the development of solid-phase synthesis methods makes it much easier to achieve this goal.

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accretion of triacylglycerides in the absence of alcohol intake that may progress to steatohepatitis, fibrosis and cirrhosis, becoming the main cause of chronic liver disease. This article discusses recent data concerning the use of dietary polyphenols in the prevention and treatment of NAFLD in vitro, in vivo, and in clinical trials. Methods: Study searches were performed using the PubMed database from the National Library of Medicine-National Institutes of Health. Results: Polyphenols exert beneficial effects in NAFLD, with positive outcomes being related to body weight gain, insulin resistance, liver fat accumulation, oxidative stress, proinflammatory status, mitochondrial dysfunction and ER stress. Data reported for hydroxytyrosol suggest that the activation of the hepatic PPAR-α-FGF21-AMPK-PGC-1α signaling cascade is associated with fatty acid oxidation enhancement, de novo lipogenesis diminution and recovery of mitochondrial function, a contention that is supported by the actions of several polyphenols on specific components of this signaling pathway. Besides, polyphenols downregulate NF-ΚB, suppressing the pro-inflammatory state developed in NAFLD and upregulate liver Nrf2, increasing the cellular antioxidant potential. The latter feature of polyphenols is contributed by chelation of pro-oxidant trace elements, reduction of free radicals to stable forms and inhibition of free radical generating systems. Conclusion: Polyphenols are relevant bioactive compounds in terms of prevention and treatment of NAFLD, which exhibit low bioavailability and instability in biological systems that could limit their health effects. These drawbacks reinforce the necessity of further studies to improve the efficacy of polyphenol formulations for human interventions.

Conducting polymers are an outstanding class of materials characterized by electroconductive properties that make them good candidates for applications in several sectors. Among them, polyaniline (PANI) is unique for its extraordinary ability to conduct electricity, biocompatibility, and low toxicity. In spite of its surprising features, to date, PANI has not found application in practical uses due to its low solubility and processability. In order to overcome these limitations, different approaches have been developed, such as polymer grafting processes, PANI-based composites, and blends preparation. The present review describes the most recent advances on PANI applications in biomedical fields, such as antioxidant, antimicrobial and antivirus activity, drug delivery, cancer therapy, etc. In this article, synthetic procedures are also reported which are crucial for the realization of more innovative materials in the future.

Compared to the classical chemicals, nanoparticles (NPs) exhibit unique properties, which lead to challenges in sample preparation and analysis. Fractionation techniques and, in particular, hollow fiber flow field flow fractionation (HF5) have recently become popular in the characterization and quantification of nanomaterials, because of their fine fractionation capability in the nanoscale-range. When dealing with NPs, a great drawback during fractionation is the loss of particles in the fractionation devices, tubing and connectors. There is a need for studies to systematically explore and assess the quality of the fractionation process. A combination of two complementary mass-based setups was used to determine particle loss in HF5. Inductively coupled plasma mass spectrometry (ICP-MS) enabled the estimation of recovery rates for NPs after HF5 separation. Reciprocally, laser ablation ICP-MS (LA-ICP-MS) permitted the evaluation of particles retained on the hollow fiber. 15 nm Au-NPs in different concentrations were evaluated in this study and showed a recovery level for Au-NPs of 50 – 65% based on the applied concentrations after a complete HF5 separation run. Detection of sample deposition on the hollow fiber by LA-ICP-MS indicated a sample loss of about 8%. These findings are important for experiments relying on fractionation of low concentrated nanoparticulate samples.

Background: 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. Objectives: We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computerassisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. Methods: The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4- triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. Results: The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity, and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (μM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. Conclusion: These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin- 4(1H)-ones as seed compounds.