ChemMedChem最新文献

Multiple drug resistance, which leads to tumor recurrence and contributes to high mortality rates in ovarian cancer, is a significant issue that must be overcome for successful treatment. Within this study, we explored the efficacy of lipid-chitosan hybrid nanoparticles with NTD as an ABCB1 inhibitor and PTX as a chemotherapeutic agent in ABCB1 overexpressed ovarian cancer cells. Sensitive ovarian cancer cells acquired resistance by continuous paclitaxel treatment and confirmed by the resistance index and ABCB1 expression by qRT-PCR. PTX-NTD-loaded lipid-chitosan hybrid nanoparticles (N-PTX-LPHNPs) were synthesized via ionic gelation and characterized by the DLS method, in vitro release, encapsulation and loading efficiency, FT-IR and SEM. XTT, Rho-123 accumulation assay, and DCFH-DA staining were conducted to examine the drug resistance inhibition and anti-cancer activity of NTD and N-PTX-LPHNPs. Bioinformatics analyzes were performed to evaluate the ADME/T properties of NTD and the interaction between the PTX-NTD combination and ABCB1. NTD showed high binding affinity to ABCB1 and had cytotoxicity against ovarian cancer cells. Moreover, the PTX-NTD drug combination loaded nanoparticles increased PTX accumulation and intracellular ROS levels, enhanced anti-cancer activity, and overcame resistance to ovarian cancer. Our results highlight the NTD-PTX-loaded lipid-chitosan hybrid nanoparticles as a potential therapeutic for ABCB1 overexpressed ovarian cancer.

InhA, an NAD-dependent enoyl-acyl carrier protein reductase, is involved in the biosynthesis of mycolic acids, specific lipids to mycobacteria. InhA is the target of isoniazid, a first-line anti-tuberculosis drug used since the 1950s. Isoniazid is a prodrug that needs to be activated by the catalase-peroxidase KatG. Due to resistance problems, a substantial amount of work has been carried out to identify or design direct inhibitors of InhA, demonstrating that this enzyme is still considered a relevant target for the discovery of new anti-tuberculosis drugs. Much of this work included the resolution of crystallographic structures. Indeed, over a hundred structures have been deposited in the Protein Data Bank for different forms of the enzyme (apo, holo, and complexes), demonstrating a real crystalline polymorphism. Taken together, these structures constitute a valuable dataset. However, the complete decoding of the enzyme's properties and its inhibition literally comes up agaisnt its molecular plasticity at the level of a motif essential to the definition of the active site: the substrate-binding loop. In this article, we propose a detailed analysis of this structural dataset, describing in particular the different families of inhibitors, and attempt to establish structural links of causality.

Kallikrein-related peptidases are a family of serine proteases which loss of activity regulation has been particularly linked to neurodegenerative diseases. Moreover, iron overload is also a key process in some of these leading pathological conditions, particularly Alzheimer's disease. We identified for the first time Deferasirox, a well-known FDA-approved iron chelator (DFX) as an initial hit for kallikrein's (KLK) inhibition and propose here the design and synthesis of a small library of molecules using DFX as chemical scaffold. Resulting sub-series of compounds were evaluated against lead central nervous system KLK's, namely KLK1, KLK6 and KLK8 using targeted pharmacomodulations on DFX. Beyond DFX, several reversible micromolar inhibitors of these KLKs have been identified as hits and were shown to be devoid of any noticeable cytotoxicity towards neural cell lines commonly used in the field of neurodegenerative diseases. Their ability to chelate iron was also assessed in comparison to DFX and preformed iron-compound complexes displayed slightly improved inhibition potency for some derivatives with a KLK-dependent manner. Hence, we identified several DFX derivatives as promising starting points for the development of dual therapeutic agents in the context of neurodegenerative diseases where both deregulated KLK's proteolysis and iron dysregulation are involved.

EP2 is a G-protein coupled receptor that is activated by Prostaglandin E2 (PGE2). Signaling through the EP2 receptor has been shown to play a key role in various processes involved in diseases such as immune disorders or cancer. We have identified a new class of selective EP2 antagonists with an attractive in vitro and in vivo profile. The amide bond in the original screening hit was replaced by various alternatives. Introduction of an aminopyrimidine scaffold resulted in excellent potency. Improvement of physicochemical and ADME properties was achieved by incorporation of a carboxylic acid moiety, resulting in lead compound 29 exhibiting drug-like properties.

Neuraminidase enzymes (NEU) play a crucial role in many physiological and pathological conditions. Humans have four isoenzymes of NEU and their specific roles continue to be investigated. Isoenzyme-selective inhibitors are needed as research tools and may lead to future therapeutics. We tested a series of new candidate inhibitors by replacing the C5-amide of 2-deoxy-2,3-dididehydro-N-acetyl neuraminic acid (DANA) with amide bioisosteres. Design of candidate inhibitors was accomplished using substituents that were components of previously identified NEU inhibitors combined with alternative amide bioisosteres. Compounds were tested for inhibition of the four human NEU, and inhibitory activities were compared to reference amide compounds. We observed that 1,4-disubstituted-1,2,3-triazole was the best bioisostere for inhibitors of NEU1. Inhibitor 542 showed high potency for NEU1 (K-i = 0.4 ± 0.1 μM) and gave significant improvement in selectivity compared to the reference amide compound 502. Additionally, compound 542 had improved lipophilic characteristics which could provide improved pharmacokinetic properties. Screening of these inhibitors also identified a selective NEU2 inhibitor 543 (Ki = 2.6 ± 0.6 μM), illustrating that amide bioisostere replacement can identify improved inhibitors for multiple NEU isoenzymes.

The O'nyong-nyong virus (ONNV) is a member of the Alphavirus genus isolated for the first time in 1959 in Gulu (Uganda). The main symptoms of O'nyong-nyong fever are nonspecific and flu-like; a proper diagnosis at the early stage is challenging. Until today, the first ONNV epidemic in 1959-1962 remains one of the largest arbovirus outbreaks ever recorded (over 2 million cases). No specific therapy is available thus far. Capsid protease (CP) is a chymotrypsin-like serine protease that catalyzes the autoproteolytic maturation of the structural polyprotein and undergoes self-inactivation upon the release of the mature capsid (C) protein. Despite the discovery of this virus more than 60 years ago, many aspects of CP remain understudied, including substrate specificity. Here we present the structures of the first phosphonic-type inhibitors and activity-based probes specific to the ONNV CP.

Dengue virus (DENV) serotypes 1-4 are mosquito-borne flaviviruses that are responsible for significant morbidity and mortality worldwide, particularly in tropical and subtropical regions. Although two vaccines have been approved, their unbalanced efficacy across serotypes poses potential risks for specific populations. There are currently no approved antiviral treatments for DENV, resulting in a clear medical need, especially in endemic countries. In this study, a medicinal chemistry optimization of the pyridobenzothiazolone (PBTZ) derivative 2 was conducted, which resulted in the synthesis of a new series of PBTZ analogues. Compounds 15 and 19 exhibited nanomolar EC50 values against all four DENV serotypes. While new PBTZ analogues did not inhibit DENV polymerase as the first series of PBTZ analogues did, they displayed anti-DENV activity across all time points during time-of-addition assays and demonstrated the capacity to influence the infectivity of newly produced virions without affecting viral RNA synthesis. Compound 19 exhibited an EC50 of 50 nM against DENV-2 and a selectivity index of >2074, representing the most potent PBTZ analogue reported to date, with a significant improvement of over 30-fold compared to the initial hit 2. In vitro pharmacokinetic studies conducted on compound 19 disclosed a promising profile, but with still some suboptimal values.

Prostaglandin E2 (PGE2) signalling via receptors EP2 and EP4 is involved in various aspects of cancer and has been shown to promote tumor progression, metastasis, and immune evasion. Inhibition of PGE2 signaling by blockade of the EP2 and EP4 receptors has the potential to counteract the tumor-promoting effects of PGE2. We herein present the discovery of compound 30 (ACT-1002-4271), a dual EP2/EP4 antagonist with single digit nanomolar potency on both receptors. Our medicinal chemistry strategy is based on fine-tuning of the substitution pattern on an EP2 selective starting point to achieve dual EP2/EP4 antagonism. ACT-1002-4271 demonstrated significant anti-tumor efficacy in an EMT-6 mouse model when administered subcutaneously.

The development of nanosystems with enhanced photothermal and photoacoustic properties is crucial for advancing theranostic applications in cancer therapy. This study explores polymeric nanoparticles constituted by a biocompatible poly(ethylene glycol)-block-poly(benzyl malate) copolymer and loaded with metal-bis(dithiolene) complexes (M = Ni, Pd, Pt). These nanoparticles, prepared via a robust nanoprecipitation method, demonstrate uniform morphology, efficient encapsulation (~70%), and tailored near-infrared (NIR) optical absorption properties. Photothermal and photoacoustic evaluations revealed superior performance of Palladium-loaded nanoparticles, offering high contrast for imaging and significant temperature increases under NIR laser irradiation. Cytotoxicity assays confirmed their non-toxicity without laser exposure, while effective cancer cell eradication was achieved upon irradiation at power densities ≥2 W/cm2. In vivo experiments on zebrafish embryos bearing human cancer xenografts showed significant tumor size reduction (20%) post-treatment with Palladium-loaded nanoparticles under 880 nm laser irradiation. These findings underscore that metal-bis(dithiolene)-loaded nanoparticles can be versatile agents for combined diagnostics and photothermal therapy, paving the way for further optimization and clinical translation.

Total synthesis of potent antiausterity agent callistrilone O was accomplished. The cover art illustrates that callistrilone O helped the legendary Heracles crushed a giant crab under his mighty foot to preferentially attack cancer that has adapted to nutrient deprivation, with the plant Callistemon citrinus from which it was isolated in the background. More details can be found in article 10.1002/cmdc.202400818 by Kensuke Okuda and co-workers. The cover art was designed and created by Prof. Kensuke Okuda with assistance by graphic designer Takashi Tsujino.