MedChemComm最新文献

Building on previous investigations, structural modifications to the neuronal calcium ion channel blocker MONIRO-1 and related compounds were conducted that included replacement of the amide linker with an aniline and isosteric sulfonamide moiety, and the previously used strategy of substitution of the guanidinium group with less hydrophilic amine functionalities. A comprehensive SAR study revealed a number of phenoxyaniline and sulfonamide compounds that were more potent or had similar potency for the Ca_V2.2 and Ca_V3.2 channel compared to MONIRO-1 when evaluated in a FLIPR-based intracellular calcium response assay. Cytotoxicity investigations indicated that the sulfonamide analogues were well tolerated by Cos-7 cells at dosages required to inhibit both calcium ion channels. The sulfonamide derivatives were the most promising Ca_V2.2 inhibitors developed by us to date due, possessing high stability in plasma, low toxicity (estimated therapeutic index > 10), favourable CNS MPO scores (4.0–4.4) and high potency and selectivity, thereby, making this class of compounds suitable candidates for future in vivo studies.

Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. In the absence of H₂O₂ (trigger T1), e.g. in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H₂O₂), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both in vitro and in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.

DNA polymerase β (Polβ) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polβ inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polβ was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polβ interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Indole is a prestigious heterocyclic skeleton widely found in both naturally-occurring and biologically-active compounds. Pharmaceutical agents containing an indole skeleton in their framework possess a wide range of pharmacological properties, including antiviral, antitumor, analgesic, and other therapeutic activities, and many indole-containing drugs have been proven to have excellent pharmacokinetic and pharmacological effects. Over the past few decades, the FDA has approved over 40 indole-containing drugs for the treatment of various clinical conditions, and the development of indole-related drugs has attracted significant attention from medicinal chemists. This review aims to provide an overview of all the approved drugs that contain an indole nucleus, focusing on their targets, pharmacological activities, and SAR studies.

Correction for ‘A high-throughput effector screen identifies a novel small molecule scaffold for inhibition of ten-eleven translocation dioxygenase 2’ by Shubhendu Palei et al., RSC Med. Chem., 2022, 13, 1540–1548, https://doi.org/10.1039/D2MD00186A.

ATP-binding cassette (ABC) transporters are a large family of proteins involved in membrane transport of a wide variety of substrates. Among them, ABCB1, also known as MDR-1 or P-glycoprotein (P-gp), is the most characterized. By exporting xenobiotics out of the cell, P-gp activity can affect the ADME properties of several drugs. Moreover, P-gp has been found to mediate multidrug resistance in cancer cells. Thus, the inhibition of P-gp activity may lead to increased absorption and/or intracellular accumulation of co-administered drugs, enhancing their effectiveness. Using the human-mouse chimeric cryoEM 3D structure of the P-gp in the inhibitor-bound intermediate form (PDBID: 6qee), approximately 200 000 commercially available natural compounds from the ZINC database were virtually screened. To build a model able to discriminate between substrate and inhibitors, two datasets of compounds with known activity, including P-gp inhibitors, substrates, and inactive molecules were also docked. The best docking pose of selected substrates and inhibitors were used to generate 3D common feature pharmacophoric models that were combined with the Autodock Vina binding energy values to prioritize compounds for visual inspection. With this consensus approach, 13 potential candidates were identified and then tested for their ability to inhibit P-gp, using zosuquidar, a third generation P-gp inhibitor, as a reference drug. Eight compounds were found to be active with 6 of them having an IC₅₀ lower than 5 μM in a membrane-based ATPase activity assay. Moreover, the P-gp inhibitory activity was also confirmed by two different cell-based in vitro methods. Both retrospective and prospective results demonstrate the ability of the combined structure-based pharmacophore modeling and docking-based virtual screening approach to predict novel hit compounds with inhibitory activity toward P-gp. The resulting chemical scaffolds could serve as inspiration for the optimization of novel and more potent P-gp inhibitors.

A diverse range of 9-substituted 1,8-dioxohexahydroxanthenes was conceptualized and synthesized through a TFA-mediated approach in near quantitative yields without the use of column chromatography. From a series of 25 compounds, we found that compounds 14c and 14r exhibited promising anti-tuberculosis potential against avirulent and virulent strains of Mycobacterium tuberculosis with a Minimal Inhibitory Concentration (MIC) of 8 μg ml⁻¹, achieving 99% bactericidal activity at the same concentration. This series of compounds was found to be inactive against common Gram-positive and Gram-negative pathogens, indicating that the activity is mycobacteria-specific. Since the strategies for treating tuberculosis employ a combinatorial therapy, we tested and observed that the two lead compounds displayed synergistic behavior with known anti-TB drugs (ATDs) and a significant (16–32 fold) decrease in MIC values of both leads was observed in combination with either RIF or INH. Interestingly the lead molecule 14c displayed only time-dependent kill kinetics and sterilized the whole culture of Mycobacterium tuberculosis H37Rv in just 48 hours.

In eukaryotic cells, RNA splicing is crucial for gene expression. Dysregulation of this process can result in incorrect mRNA processing, leading to aberrant gene expression patterns. Such abnormalities are implicated in many inherited diseases and cancers. Historically, antisense oligonucleotides, which bind to specific RNA targets, have been used to correct these splicing abnormalities. Despite their high specificity of action, these oligonucleotides have drawbacks, such as lack of oral bioavailability and the need for chemical modifications to enhance cellular uptake and stability. As a result, recent efforts focused on the development of small organic molecules that can correct abnormal RNA splicing event under disease conditions. This review discusses known and potential targets of these molecules, including RNA structures, trans-acting splicing factors, and the spliceosome – the macromolecular complex responsible for RNA splicing. We also rely on recent advances to discuss therapeutic applications of RNA-targeting small molecules in splicing correction. Overall, this review presents an update on strategies for RNA splicing modulation, emphasizing the therapeutic promise of small molecules.

A series of novel dehydroabietic acid derivatives containing both 1,2,3-triazole and oxazolidinone 4a–4t have been synthesized and their antiproliferative activity in vitro against HeLa, HepG2, MGC-803 and T-24 cell lines evaluated. Most of them displayed cell proliferation inhibition on four tested human malignant tumour cell lines to some degree. Among them, compound 4p exhibited promising cytotoxicity with IC₅₀ values ranging from 3.18 to 25.31 μM and weak cytotoxicity toward normal cells. The mechanism of action of 4p was then studied using flow cytometry, Hoechst 33258 staining, ROS generation assay, and JC-1 mitochondrial membrane potential staining, which illustrated that compound 4p induced apoptosis, arrested mitotic process at the G1 phase of the cell cycle, reduced the mitochondrial membrane potential, and increased intracellular ROS levels. In summary, the introduction of an oxazolidinone group via a “1,2,3-triazole” linker significantly improved the antitumor activity of dehydroabietic acid, and deserves to be further investigated.

Alkaline phosphatase (ALP) is known as one of the most crucial members of the phosphatase family and encompasses the enormous ability to hydrolyze the phosphate group in various biomolecules; by this, it regulates several events in the pool of biological medium. Owing to its overexpression in various cancer cells, recently, its potential has evolved as a prominent biomarker in cancer research. In this article, we have underlined the recent advances (2019 onwards) of alkaline phosphatase in the arena of emerging cancer theranostics. Herein, we mainly focused on phosphate-locked molecular systems such as peptides, prodrugs, and aggregation-induced emission (AIE)-based molecules. When these theranostics encounter cancer cell-overexpressed ALP, it results in the hydrolysis of the phosphate group, which leads to the release of highly cytotoxic agents along with turn-on fluorophore/pre-existing fluorophore.