ChemMedChem最新文献

Low cure rate and high death rate of cancers have seriously threatened human health. The combining multiple therapies is a promising strategy for cancer treatment. In this study, we construct a novel multinucleated nanocomplex loaded with carbon dots (CDs-SA@TAMn) that responds to tumor microenvironment for combined photothermal/chemodynamic cancer therapy. Fluorescence imaging results show that CDs-SA@TAMn can effectively accumulated in tumor sites. In acidic tumor microenvironment, CDs-SA@TAMn will release Mn²⁺, activating chemodynamic therapy and producing substantial reactive oxygen species (ROS) to kill tumor. Additionally, when irradiated by an 808 nm laser, CDs-SA@TAMn will exert the photothermal effect to realize high performance of cancer hyperthermia treatment. The nanocomplexes feather simple preparation, low toxicity, controlled release and imaging-guided therapy, showcasing the potential of precise and high-performance anti-tumor combination therapy in biomedical applications.

Cofactors are non-protein entities necessary for proteins to operate. They provide "functional groups" beyond those of the 20 canonical amino acids and enable proteins to carry out more diverse functions. Such a viewpoint is rarely mentioned, if at all, when it comes to natural products and is the theme of this Concept. Even though the mechanisms of action (MOA) of only a few natural products are known to require cofactors, we believe that cofactor mediated MOA in natural products are far more prevalent than what we currently know. Bleomycin is a case in point. It binds iron cation to form a pseudoenzyme that generates reactive oxygen species. As another example, calcium cations induce laspartomycin to "fold" into the active conformation. Iron and calcium are bona fide cofactors for bleomycin and laspartomycin, respectively, as these natural products do not display their characteristic anticancer and antibacterial activities without Fe(II) and Ca(II). These types of cofactor mediated MOA in natural products were discovered mostly serendipitously, and being conscious of such a possibility is the first step toward identifying more novel chemistry that nature performs.

Quaternary ammonium compounds (QACs) play crucial disinfectant roles in healthcare, industry, and domestic settings. Most commercially utilized QACs like benzalkonium chloride have a common architectural theme, leading to a rise in bacterial resistance and urgent need for novel structural classes. Some potent QACs such as chlorhexidine (CHX) and octenidine (OCT) feature a bolaamphiphilic architecture, comprised of two cationic centers at the molecular periphery and a non-polar region connecting them; these compounds show promise to elude bacterial resistance mechanisms. Inspired by such structures, we synthesized a series of 43 biscationic amphiphilic compounds focused on a resorcinol core, featuring flexibility of linker lengths, alkyl tails, and relative substituent positioning, to study their structure activity relationships (SARs). Antibacterial activity evaluation against a panel of gram-positive and gram-negative strains, including ESKAPE pathogens (A. baumannii, P. aeruginosa), were encouraging, with minimum inhibitory concentrations (MICs) of 0.5-4 μM against all tested strains for select compounds. Ten prepared compounds bearing either 17 or 18 total side chain carbons demonstrated uniformly strong antibacterial activity against P. aeruginosa (MIC 4-16 μM) and 6 other strains (MIC ≤4 μM), irrespective of cationic spacing. These findings promise to further extend the application of bolaamphiphilic QACs as a novel class of disinfectants.

For decades quaternary ammonium compounds (QACs) have served as main component of a top antiseptic and disinfectant compositions. Among them, bis-QACs are the most prominent and effective class of biocides. Although mono-QACs still dominate the antiseptic market, their activity against Gram-negative bacteria is largely inferior to bis-QACs. Moreover, the new wave of bacterial resistance during the COVID-19 pandemic is threatening the efficiency of popular antiseptics. Therefore, the requirement for novel biocides is urgent. Reported here is a unified and simple two-step synthesis to achieve novel biocide's architectures with aromatic linkers. Thus, a series of 14 bis-QACs have been prepared using an Ullman-type reaction following by N-alkylation. The most prominent compounds showed strong bioactivity against a panel of nineteen microbial pathogens, multi-resistant bacterial ESKAPEE strains, fungi and biofilms, including strains, which acquired resistance during COVID-19 in 2021. Moreover, significant improvements in antibiofilm action were observed, where bis-QACs 5 c and 6 a outperformed gold standard pyridinium antiseptic octenidine. These findings will serve as a good basis for further studies of bis-QACs architectures as highly effective biocides.

The antiausterity strategy in anticancer drug discovery has attracted much attention as a way to exterminate cancer cells under nutrient deprived conditions which are commonly found in solid tumors. These tumors under low nutrient stress are known to be malignant and often resist conventional drug therapy. As a potential drug candidate, we focused on the meroterpenoid natural product callistrilone O which has demonstrated extremely potent antiausterity properties toward PANC-1 pancreatic carcinoma in vitro. Here, we report for the first time the total synthesis of callistrilone O in seven steps from phloroglucinol. A Friedel-Crafts-type Michael addition and an oxidative [3+2] cycloaddition with Fetizon's reagent were used to construct the molecular skeleton. The preferential cytotoxicity of callistrilone O was also evaluated with multiple starvation-resistant cancer cell lines under low nutrient conditions. Furthermore, callistrilone O was found to strongly suppress B16 melanoma tumor growth without critical toxicity in vivo. Overall, this study presents a novel anticancer agent candidate from natural products with a concise synthetic route which can be readily applied to the synthesis of derivatives.

Tumor-associated human carbonic anhydrases (hCAs), particularly isoforms hCA IX and hCA XII, are overexpressed in hypoxic regions of solid tumors and play a crucial role in regulating pH homeostasis, promoting cancer cell survival and enhancing invasiveness. These enzymes have emerged as promising therapeutic targets in cancer treatment, including photothermal therapy (PTT). PTT is a minimally invasive technique that uses light-absorbing agents to convert near-infrared (NIR) light into heat, effectively inducing localized hyperthermia and promoting cancer cell apoptosis. Recent advances in the design of hCA-targeted photothermal agents have shown promise in selectively targeting and ablating cancer cells while sparing healthy tissues. We explore here recent advancements in developing combination therapies that integrate hCA-targeted strategies with PTT for tumor treatment. By focusing on tumor-associated isoforms hCA IX and hCA XII, we underscore the potential of hCA inhibition to enhance both the efficacy and specificity of PTT in cancer therapy. We also address critical challenges and outline future directions, emphasizing the need to improve the biocompatibility, stability, and clinical translation of hCA-targeted photothermal agents. This mini review highlights the promise of combining hCA inhibition with PTT as an innovative therapeutic approach, aiming to advance more precise and effective cancer treatments.

The vibrant illustration depicts two figures dancing gracefully within a round-bottom flask, symbolizing the fusion of skills in medicinal chemistry education. One figure embodies soft skills—communication, teamwork, and critical thinking—while the other represents hard skills like synthetic expertise, knowledge in chemical biology and drug design. Their synchronized dance reflects the seamless integration of these competencies, essential for meeting stakeholder demands and preparing students for a future as drug designers and medicinal chemists. The flask′s enclosing form signifies the dynamic yet contained environment of academic and professional growth. More details can be found in article 10.1002/cmdc.202400791 by Philipp Klahn.

As a newly emerging technology, conformational engineering (CE) has been gradually displaying the power of producing protein-like nanoparticles (NPs) by tuning flexible protein fragments into their original native conformation on NPs. But apparently, not all types of NPs can serve as scaffolds for CE. To expedite the CE technology on a broader variety of NPs, the essential characteristic of NPs as scaffolds for CE needs to be identified. Herein, we investigate the potential of two distinct types of NPs as scaffolds for CE: CdSe/ZnS quantum dots (QDs), an ionic compound NP, and palladium NPs (PdNPs), a metal NP. The results demonstrate that while QDs cannot support the restoration of the native conformation and function of the complementary-determining region (CDR) fragments of antibodies, PdNPs can. The notably disparate outcomes unequivocally show that the mobility of the surface atoms/adatoms of the NPs or the mobility of the conjugating bonds to the NPs is essential for CE, which allows the conjugated peptides to undergo a conformational change from their initial random conformation to their most stable native conformation under the constraints mimicking the native long-range interactions in the original proteins. This discovery opens the door for CE on more NPs in the future.

The front cover picture shows the critical role of arginine residues in G-quadruplex (G4) mediated liquid-liquid phase separation (LLPS). A visual representation shows an RGG peptide interacting with G4-DNA, forming LLPS droplets. The art highlights the importance of arginine′s specific interactions for LLPS, reflecting the study's insights into the molecular mechanisms driving G4-LLPS. More details can be found in article 10.1002/cmdc.202400460 by Daisuke Miyoshi and co-workers.

Antibody-based pharmaceuticals are the leading biologic drug platform (> $75B/year).^[1] Despite a wealth of information collected on them, there is still a lack of knowledge on their inter-domain structural distributions, which impedes innovation and development. To address this measurement gap, we have developed a new methodology to derive biomolecular structure ensembles from distance distribution measurements via a library of tagged proteins bound to an unlabeled and otherwise unmodified target biologic. We have employed the NIST monoclonal antibody (NISTmAb) reference material as our development platform for use with spin-labeled affinity protein (SLAP) reagents. Using double electron-electron resonance (DEER) spectroscopy, we have determined inter-spin distance distributions in SLAP complexes of both the isolated Fc domain and the intact NISTmAb. Our SLAP reagents offer a general and extendable technology, compatible with any non-isotopically labeled immunoglobulin G class mAb. Integrating molecular simulations with the DEER and solution X-ray scattering measurements, we enable simultaneous determination of structural distributions and dynamics of mAb-based biologics.