Current Medicinal Chemistry - Volume 27, Issue 33, 2020

Prion pathologies are fatal neurodegenerative diseases caused by the misfolding of the physiological Prion Protein (PrP^C) into a β-structure-rich isoform called PrP^Sc. To date, there is no available cure for prion diseases and just a few clinical trials have been carried out. The initial approach in the search of anti-prion agents had PrP^Sc as a target, but the existence of different prion strains arising from alternative conformations of PrP^Sc, limited the efficacy of the ligands to a straindependent ability. That has shifted research to PrP^C ligands, which either act as chaperones, by stabilizing the native conformation, or inhibit its interaction with PrP^Sc. The role of transition-metal mediated oxidation processes in prion misfolding has also been investigated. Another promising approach is the indirect action via other cellular targets, like membrane domains or the Protein- Folding Activity of Ribosomes (PFAR). Also, new prion-specific high throughput screening techniques have been developed. However, so far no substance has been found to be able to extend satisfactorily survival time in animal models of prion diseases. This review describes the main features of the Structure-Activity Relationship (SAR) of the various chemical classes of anti-prion agents.

Background: Over the past decade, there has been a surge in the number of mitochondrialactive therapeutics for conditions ranging from cancer to aging. Subcellular targeting interventions can modulate adverse intracellular processes unique to the compartments within the cell. However, there is a dearth of reviews focusing on mitochondrial nano-delivery, and this review seeks to fill this gap with regards to nanotherapeutics of the mitochondria. Methods: Besides its potential for a higher therapeutic index than targeting at the tissue and cell levels, subcellular targeting takes into account the limitations of systemic drug administration and significantly improves pharmacokinetics. Hence, an extensive literature review was undertaken and salient information was compiled in this review. Results: From literature, it was evident that nanoparticles with their tunable physicochemical properties have shown potential for efficient therapeutic delivery, with several nanomedicines already approved by the FDA and others in clinical trials. However, strategies for the development of nanomedicines for subcellular targeting are still emerging, with an increased understanding of dysfunctional molecular processes advancing the development of treatment modules. For optimal delivery, the design of an ideal carrier for subcellular delivery must consider the features of the diseased microenvironment. The functional and structural features of the mitochondria in the diseased state are highlighted and potential nano-delivery interventions for treatment and diagnosis are discussed. Conclusion: This review provides an insight into recent advances in subcellular targeting, with a focus on en route barriers to subcellular targeting. The impact of mitochondrial dysfunction in the aetiology of certain diseases is highlighted, and potential therapeutic sites are identified.

Background: Multidrug Resistance (MDR) is defined as a cross-resistance of cancer cells to various chemotherapeutics and has been demonstrated to correlate with drug efflux pumps. Visualization of drug efflux pumps is useful to pre-select patients who may be insensitive to chemotherapy, thus preventing patients from unnecessary treatment. Near-Infrared (NIR) imaging is an attractive approach to monitoring MDR due to its low tissue autofluorescence and deep tissue penetration. Molecular NIR imaging of MDR cancers requires stable probes targeting biomarkers with high specificity and affinity. Objective: This article aims to provide a concise review of novel NIR probes and their applications in MDR cancer treatment. Results: Recently, extensive research has been performed to develop novel NIR probes and several strategies display great promise. These strategies include chemical conjugation between NIR dyes and ligands targeting MDR-associated biomarkers, native NIR dyes with inherent targeting ability, activatable NIR probes as well as NIR dyes loaded nanoparticles. Moreover, NIR probes have been widely employed for photothermal and photodynamic therapy in cancer treatment, which combine with other modalities to overcome MDR. With the rapid advancing of nanotechnology, various nanoparticles are incorporated with NIR dyes to provide multifunctional platforms for controlled drug delivery and combined therapy to combat MDR. The construction of these probes for MDR cancers targeted NIR imaging and phototherapy will be discussed. Multimodal nanoscale platform which integrates MDR monitoring and combined therapy will also be encompassed. Conclusion: We believe these NIR probes project a promising approach for diagnosis and therapy of MDR cancers, thus holding great potential to reach clinical settings in cancer treatment.

Mixed Lineage Leukemia 1 (MLL1), an important member of Histone Methyltransferases (HMT) family, is capable of catalyzing mono-, di-, and trimethylation of Histone 3 lysine 4 (H3K4). The optimal catalytic activity of MLL1 requires the formation of a core complex consisting of MLL1, WDR5, RbBP5, and ASH2L. The Protein-Protein Interaction (PPI) between WDR5 and MLL1 plays an important role in abnormal gene expression during tumorigenesis, and disturbing this interaction may have a potential for the treatment of leukemia harboring MLL1 fusion proteins. In this review, we will summarize recent progress in the development of inhibitors targeting MLL1- WDR5 interaction.

Metastasis is the main cause of death in cancer patients; there is currently no effective treatment for cancer metastasis. This is primarily due to our insufficient understanding of the metastatic mechanisms in cancer. An increasing number of studies have shown that the C-X-C motif chemokine Ligand 12 (CXCL12) is overexpressed in various tissues and organs. It is a key niche factor that nurtures the pre-metastatic niches (tumorigenic soil) and recruits tumor cells (oncogenic “seeds”) to these niches, thereby fostering cancer cell aggression and metastatic capabilities. However, the C-X-C motif chemokine Receptor 4 (CXCR4) is aberrantly overexpressed in various cancer stem/progenitor cells and functions as a CXCL12 receptor. CXCL12 activates CXCR4 as well as multiple downstream multiple tumorigenic signaling pathways, promoting the expression of various oncogenes. Activation of the CXCL12-CXCR4 signaling axis promotes Epithelial-Mesenchymal Transition (EMT) and mobilization of cancer stem/progenitor cells to pre-metastatic niches. It also nurtures cancer cells with high motility, invasion, and dissemination phenotypes, thereby escalating multiple proximal or distal cancer metastasis; this results in poor patient prognosis. Based on this evidence, recent studies have explored either CXCL12- or CXCR4-targeted anti-cancer therapeutics and have achieved promising results in the preclinical trials. Further exploration of this new strategy and its potent therapeutics effect against metastatic cancer through the targeting of the CXCL12- CXCR4 signaling axis may lead to a novel therapy that can clean up the tumor microenvironment (“soil”) and kill the cancer cells, particularly the cancer stem/progenitor cells (“seeds”), in cancer patients. Ultimately, this approach has the potential to effectively treat metastatic cancer.

Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by sequential phosphorylation carried out by deoxycytidine kinase to mono-, di-, and triphosphate nucleotides with the last one as the active form. But the instability, drug resistance and toxicity severely limited its utilization in clinics. In the field of medicinal chemistry, prodrugs have proven to be a very effective means for elevating drug stability and decrease undesirable side effects including the nucleoside anticancer drug such as gemcitabine. Many works have been accomplished in design and synthesis of gemcitabine prodrugs, majority of which were summarized in this review.

CBP and p300 are two closely related Histone Acetyltransferases (HATs) that interact with numerous transcription factors and act to increase the expression of their target genes. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important in binding of CBP/p300 to chromatin, which offers an opportunity to develop protein-protein interaction inhibitors. Since their discovery in 2006, CBP/p300 bromodomains have attracted much interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, autoimmune disorders, and cardiovascular disease. Herein, we present a comprehensive review of the structure, function, and inhibitors of CBP/p300 bromodomains developed in the last several years, which is expected to be beneficial to relevant studies.

Studies on fluorinated inhalation anesthetics, including synthesis, physical chemistry and pharmacology, have been summarized in this review. Retrospecting the history of inhalation anesthetics revealed their increasing reliance on fluorine and ether structures. Halothane causes a rare but severe immune-based hepatotoxicity, which was replaced by enflurane in the 1970s. Isoflurane replaced enflurane in the 1980s, showing modest advantages (e.g. lower solubility, better metabolic stability, and without convulsive predisposition). Desflurane and sevoflurane came into use in the 1990s, which are better anesthetics than isoflurane (less hepatotoxicity, lower solubility, and/or markedly decreased pungency). However, they are still less than perfect. To gain more ideal inhalation anesthetics, a large number of fluorinated halocarbons, polyfluorocycloalkanes, polyfluorocycloalkenes, fluoroarenes, and polyfluorooxetanes, were prepared and their potency and toxicity were evaluated. Although the pharmacology studies suggested that some of these agents produced anesthesia, no further studies were continued on these compounds because they showed obvious lacking as anesthetics. Moreover, the anesthetic activity cannot be simply predicted from the molecular structures but has to be inferred from the experiments. Several regularities were found by experimental studies: 1) the potency and toxicity of the saturated linear chain halogenated ether are enhanced when its molecular weight is increased; 2) the margin of safety decreases and the recovery time is prolonged when the boiling point of the candidate increases; and 3) compounds with an asymmetric carbon terminal exhibit good anesthesia. Nevertheless, the development of new inhalation anesthetics, better than desflurane and sevoflurane, is still challenging not only because of the poor structure/activity relationship known so far but also due to synthetic issues.