Category Archives: ChemMedChem

Design, Synthesis of (±)‐Millpuline A, and Biological Evaluation for the Lung Cell Protective Effects through SRC

Posted on 27 September 2023 by

We report a visible-light-induced intermolecular [2+2] photocycloaddition reaction based on flavonoids to synthesize (±)-millpuline A and 20 derivatives (B1–B20), which could be constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of complex natural products.

Abstract

In this study, a visible-light-induced intermolecular [2+2] photocycloaddition reaction based on flavonoids was constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of (±)-millpuline A whose bioactivity remains unknown. As a result, 20 derivatives were synthesized for bioactivity evaluation. Consequently, lung cell protective effects of (±)-millpuline A and compound B13 a were revealed for the first time and the crucial role of stereoconfiguration of the cyclobutane moiety in their protective effects against NNK in normal lung cells was demonstrated. Moreover, through target prediction and experimental verification in MLE-12 cells, SRC was determined to be the target of (±)-millpuline A regarding its protective effect in NNK-induced lung cell injury. Results from RT-Q-PCR and HTRF experiments verified that (±)-millpuline A could repress SRC activity through a transcriptional mechanism but not acting as an inhibitor to directly bind to and thereby inhibit SRC protein. The results in this paper are informative for the further development of visible light-catalyzed cycloaddition of flavonoids and lay a scientific foundation for understanding the bioactivity and underlying mechanism of (±)-millpuline A and other structurally similar natural skeletons.

Virus‐Bionic Mesoporous Silica Nanoplatform for Malignant Tumor Inhibition via Effective Cellular Uptake and Precise Drug Delivery

Posted on 26 September 2023 by nXiyang Yang, nYilin Xie, nXiaoli Liao, nTingting Zhengn

Virus-bionic mesoporous-silica-based nanocarriers can be successfully prepared for precise programmed drug delivery. These unique viral mimic nanovesicles not only present virus bionic counterparts and nanostructures, but also have infectious virus-like properties toward tumor cells and tumor tissues, showing rapid cell uptake.

Abstract

Over the past few decades, sophisticated nanomaterials have been used as carries for the targeted delivery of therapeutics to solid tumors. However, the low efficiency of intracellular internalization of nanocarriers in current use restricts their biomedical application. In this work, we demonstrate that novel virus-bionic mesoporous-silica-based nanocarriers can be successfully prepared for programmed precise drug delivery. These unique viral mimic nanovesicles not only present virus bionic counterparts and nanostructures, but also have infectious virus-like properties toward tumor cells and tumor tissues. Encouragingly, their large surface area (322.1 m²/g) endows them with high loading capacity for therapeutic agents, especially, they have more effective gene transfection properties than the commercially available LipoGene^TM transfection reagent. Thanks to their virus-inspired morphology, they exhibit outstanding cellular uptake efficiency with living tumor cells and the ability to invade cells in large quantities with incubation times as short as 5 min, which is much faster than traditional mesoporous silica nanoparticles (mSN) with smooth appearance. Importantly, after doxorubicin (DOX) loading and surface modification of tumor recognition motifs, RGD (Arg-Gly-Asp, vMN@DOX-RGD), the bionic drug-loaded viral mimics elicit potent tumor cell elimination both in vitro and in vivo, greatly exceeding the mSN-based group. Our work paves the way toward virus bionic nanocarrier design for malignant tumor suppression in the clinic.

Structural Modification of the Natural Product Valerenic Acid Tunes RXR Homodimer Agonism

Posted on 25 September 2023 by

Valerenic acid is an RXR agonist with unique subtype and homodimer preference. We have studied the impact of structural modification of the natural product on RXR modulation and identified an analogue exhibiting enhanced and selective RXR homodimer activation.

Abstract

Retinoid X receptors (RXR) are ligand-sensing transcription factors with a unique role in nuclear receptor signaling as universal heterodimer partners. RXR modulation holds potential in cancer, neurodegeneration and metabolic diseases but adverse effects of RXR activation and lack of selective modulators prevent further exploration as therapeutic target. The natural product valerenic acid has been discovered as RXR agonist with unprecedented preference for RXR subtype and homodimer activation. To capture structural determinants of this activity profile and identify potential for optimization, we have studied effects of structural modification of the natural product on RXR modulation and identified an analogue with enhanced RXR homodimer agonism.

Screening and Synthesis of Tetrazole Derivatives that Inhibit the Growth of Cryptococcus Species

Posted on 25 September 2023 by

The compounds 8-fluoro-7-methyl-5-(pyridin-2-yl)tetrazolo[1,5-c]pyrimidine and 5-(pyridin-2-yl)-8,9-dihydro-7H-cyclopenta[e]tetrazolo[1,5-c]pyrimidine belong to a novel class of antifungals. Both compounds with tetrazole backbone exhibit inhibitory activity that is equivalent or superior to those of conventional drugs on a weight-per-volume basis, with IC₅₀ equalling 0.05 μM (0.012 μg mL⁻¹) against each Cryptococcus species. Thus, tetrazole-backbone-containing compounds may be novel antifungal drugs with distinct mechanisms against cryptococcosis.antifungal agentsCandidaCryptococcushigh-throughput screeningtetrazoles

Abstract

Cryptococcosis has become a major health problem worldwide and caused morbidity and mortality in immunocompromised patients, especially those infected with human immunodeficiency virus (HIV). Despite the global distribution of cryptococcosis, the number and types of the available antifungals are limited, and the treatment outcomes in HIV patients are generally poor. In this study, we screened a compound library and identified one tetrazole derivative as an efficient inhibitor of Cryptococcus neoformans and Cryptococcus gattii. We further designed and synthesized a series of tetrazole derivatives and determined their structure-activity relationship, demonstrating that tetrazole backbone-containing compounds could be developed as novel antifungal drugs with distinct mechanisms against Cryptococcus spp. Our findings provide a starting point for novel target identification and structural optimization to develop a distinct class of therapeutics for patients with cryptococcosis.

Structure−Activity Relationship and Solubility Studies of N1‐Substituted Quinoxaline‐2,3‐diones as Kainate Receptor Antagonists

Posted on 25 September 2023 by

This study presents the synthesis and structure-activity analysis of 21 new quinoxaline-2,3-dione derivatives as glutamate receptor ligands. Solubility studies focused on strategic structural modifications and resulted in increased solubility in water and alkaline conditions. These findings provide the potential for the development of active compounds with improved solubility.

Abstract

Kainate receptors are a class of ionotropic glutamate receptors that respond to the excitatory neurotransmitter glutamate in the central nervous system and play an important role in the development of neurodegenerative disorders and the regulation of synaptic function. In the current study, we investigated the structure- activity relationship of the series of quinoxaline-2,3-diones substituted at N1, 6, and 7 positions, as ligands of kainate homomeric receptors GluK1-3 and GluK5. Pharmacological characterization showed that all derivatives obtained exhibited micromolar affinity at GluK3 receptors with K _i values in the range 0.1–4.4 μM range. The antagonistic properties of the selected analogues: N-(7-fluoro-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide, N-(7-(1H-imidazol-1-yl)-6-iodo-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide and N-(7-(1H-imidazol-1-yl)-2,3-dioxo-6-(phenylethynyl)-3,4-dihydroquinoxalin-1(2H)-yl)-3-sulfamoylbenzamide at GluK3 receptors, were confirmed by an intracellular calcium imaging assay. To correlate in vitro affinity data with structural features of the synthesized compounds and to understand the impact of the substituent in N1 position on ability to form additional protein-ligand interactions, molecular modeling and docking studies were carried out. Experimental solubility studies using UV spectroscopy detection have shown that 7-imidazolyl-6-iodo analogues with a sulfamoylbenzamide moiety at the N1 position are the best soluble compounds in the series, with molar solubility in TRISS buffer at pH 9 more than 3-fold higher compared to NBQX, a known AMPA/kainate antagonist.

Metabolism of (R)‐Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Posted on 25 September 2023 by

Praziquantel is an anthelmintic drug activating schistosome worms’ Transient Receptor Potential Melastatin ion channel for which the cyclohexyl moiety is a key pharmacophore and also the main site of CYP-mediated oxidative metabolism. While attempting to limit metabolism, the contribution to the overall activity of both the parent and the main metabolite of praziquantel in humans is discussed.

Abstract

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPM_PZQ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPM_PZQ, as well as serving as the primary site of oxidative metabolism which results in PZQ being a short-lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPM_PZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

E‐64c‐Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1’‐S2’ Area

Posted on 25 September 2023 by

With an optimized S1’-S2’ ligand, the E-64c-hydrazide derived compound efficiently inhibits the cysteine protease cathepsin C and thus suppresses the proteolytic activation of neutrophil elastase in the neutrophil precursor cell line U937.

Abstract

The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro-inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E-64c-hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n-butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1’-S2’ area was now investigated by a combinatorial approach, showing that Nle-tryptamide is a ligand superior to the initially used Leu-isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.

Total Synthesis and Biological Investigation of Mindapyrroles A and B

Posted on 25 September 2023 by nRyan A. Allen, nWilliam M. Wuestn

Antibiotics with novel and polypharmacological mechanisms of action are urgently needed. To this end, the total synthesis of mindapyrroles A and B was completed via a Friedel-Crafts alkylation. The antibacterial activity of these compounds was investigated against a panel of gram-positive and gram-negative pathogens, and their mechanism of action was determined to be different from their monomer pyoluteorin.

Abstract

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.

Synthesis and Biological Activity of 2‐Benzo[b]thienyl and 2‐Bithienyl Amidino‐Substituted Benzothiazole and Benzimidazole Derivatives

Posted on 25 September 2023 by

Novel benzo[b]thienyl and 2-bithienyl amidino-substituted benzothiazoles and benzimidazoles were shown to have antitumor and antitrypanosomal activities in vitro. Benzothiazoles were found to be more active than benzimidazole analogs as both antiproliferative and antitrypanosomal agents. Benzothiazoles were selective against lung carcinoma cells, and the benzimidazoles were selective against cervical carcinoma cells. The benzimidazoles target DNA, the benzothiazoles have a different cellular target.

Abstract

Novel benzo[b]thienyl- and 2,2′-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2′-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2′-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2′-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA.

Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging

Posted on 25 September 2023 by

Over the past two decades, lysyl oxidases have been recognised as key enzymes in tumour invasion and metastasis, which has spurred efforts to develop inhibitors and molecular probes for therapeutic and imaging purposes, respectively. This review summarises the structural and functional aspects of these unique enzymes in relation to tumour progression and highlights recent developments in inhibitors and imaging probes.

Abstract

The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.