ChemMedChem最新文献

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.

In the recent two decades, the multidisciplinary field of medicinal chemistry has undergone several conceptual and technology-driven paradigm changes with significant impact on the skill set medicinal chemists need to acquire during their education. Considering the need for academic medicinal chemistry teaching, this article aims at identifying important skills, competences, and basic knowledge as general learning outcomes based on an analysis of the relevant stakeholders and concludes effective teaching strategies preparing students for a future career as medicinal chemists and drug designers.

Obesity is a critical risk factor for the development of metabolic diseases and is often associated with dysfunctional adipocytes. Prevalent treatments such as lifestyle intervention, pharmacotherapy, and bariatric surgery are often accompanied by adverse side effects and poor patient compliance. Nanotechnology and cell-based therapy offer innovative approaches for targeted obesity treatments, as they can directly target adipocytes, regulate lipid metabolism, and minimize off-target effects. Here, we provide an overview of the intricate relationship between adipocytes and obesity, highlighting the potential of nanotechnology and cell-based therapy in obesity treatment. Additionally, we discuss the advancements of adipose-derived mesenchymal stem cells (ADMSCs) in obesity progression, including the latest challenges and considerations for developing adipose-targeted treatments for obesity. The objective is to provide a perspective on the design and development of nanotechnology and cell-based therapy for treating obesity and related comorbidities.

In recent years, selenocompounds have gained increasing attention as potential anticancer and antibacterial agents. Several selenoderivatives have been confirmed to act as MDR efflux pump inhibitors, based on their in vitro results against the bacterial AcrAB-TolC system and the cancer MDR efflux pump P-glycoprotein. Efflux pumps can contribute directly or indirectly to the virulence of bacteria, as they can reduce the intracellular concentration of antibacterial substances by expelling them out of the cell. The present work aims to study the antibacterial and efflux pump inhibiting properties of four families of selenoesters, namely aspirin-selenoesters, phenone-selenoesters, hydroxy-selenoesters, and benzyl-selenoesters. The real-time ethidium bromide accumulation assay confirmed that these derivatives inhibited the efflux systems of methicillin-resistant Staphylococcus aureus (MRSA) without exerting any antibacterial effect. The relative expression of efflux pump gene of NorA transporter was also monitored in the presence of the most potent derivatives on reference S. aureus, finding that these derivatives could change the expression of the tested efflux pump gene. Regarding the anti-biofilm activity, aspirin-selenoesters, benzyl-selenoesters, and hydroxy-selenoesters could efficiently inhibit the biofilm production of the MRSA strain. It can be concluded that selenocompounds could act as efflux pump inhibitors, thus reducing the virulence of biofilm-producing bacteria.

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 X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20 c. The ability of compound 20 c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

With the advent of antibiotic resistant organisms, development of alternate classes of molecules other than antibiotics to combat microbial infections, have become extremely important. In this context, antimicrobial peptides have taken center stage of antimicrobial therapeutic research. In this work, we have reported two cationic antimicrobial octapeptides WRL and LWRF, with broad spectrum antimicrobial activities against several strains of ESKAPE pathogens. Both the peptides were membrane associative and induced microbial cell death through membranolysis, being selective towards microbial membranes over mammalian membranes. The AMPs were unstructured in water, adopting partial helical conformation in the presence of microbial membrane mimics. Electrostatic interaction formed the primary basis of peptide-membrane interactions. WRL was more potent, salt tolerant and faster acting of the two AMPs, owing to the presence of two tryptophan residues against that of one in LWRF. Increased tryptophan number in WRL enhanced its membrane association ability, resulting in higher antimicrobial potency but lower selectivity. This experimental and computational work, established that an optimum number of tryptophan residues and their position was critical for obtaining high antimicrobial potency and selectivity simultaneously in the designed cationic AMPs. Understanding the peptide membrane interactions in atomistic details can lead to development of better antimicrobial therapeutics in future.

A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) was synthesized via a one-pot reaction of 5-amino-[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4 e demonstrated superior efficacy against the Salinivibrio proteolyticus strain of Gram-negative bacteria compared to ciprofloxacin. Compound 4 d exhibited the highest potency against the fungal strain Candida albicans, surpassing amphotericin B. The physicochemical characteristics of 4 d and 4 e were assessed. According to docking analysis, DHTDAPy 4 e shows a higher binding affinity of -7.2 kcal/mol in the binding cavity of the receptor. These findings illustrate the safety, tolerability, and potency of the newly synthesized DHTDAPy compounds against fungal and bacterial infections.