ChemMedChem最新文献

Intrinsically disordered proteins (IDPs) lack stable structure and classical binding pockets, making them remarkably difficult to drug. However, upon interacting with partner proteins, IDPs can form transient yet specific and defined interfaces, which, if discovered, can become exploitable footholds for therapeutic intervention. Here, AlphaFold-Multimer is used to shine light on the underexplored oncogenic protein–protein interaction between MYC and Miz-1. Notably, AlphaFold-Multimer predicts that Miz-1 binds at a site overlapping with the MYC/MAX dimerization domain, which is MYC's best-characterized oncogenic interface. Guided by this prediction, stapled peptidomimetics are designed and synthesized, targeting the MYC/Miz-1 and MYC/MAX interface. The best variant, Mizmetic 2, binds MYC and alanine scanning identifies key binding hotspots and promising sites for beneficial substitutions. The optimized variants disrupt MYC/MAX complex formation and prevents MYC from binding its canonical E-box DNA elements in vitro, with submicromolar potency. MAX/MAX DNA complex formation is also reduced, likely indicating some degree of unspecific binding. While still at a proof-of-concept stage, the findings showcase how AI-based structure prediction can illuminate disordered protein interactions and reveal new targetable sites on MYC.

Acetaminophen (ApAP) toxicity arises from the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI), a degradation product known to cause significant liver damage and kidney injury. This toxicity is a major concern associated with the widespread use of ApAP, a commonly used nonsteroidal anti-inflammatory drug. To address this important issue, a series of novel nonopioid analgesic candidates with reduced toxicity have been recently reported. However, the molecular and atomic-level mechanisms underlying their decreased toxicity remain largely unexplored. In this study, computational analyses is performed to investigate the dynamic behavior, physicochemical properties, and ligand-receptor interactions of these new chemical entities (NCEs). The findings provide a rational explanation for their differing toxicity profiles and contribute to a deeper understanding of their metabolic pathways. Based on these insights, compound 6 has emerged as a promising ApAP alternative and is currently under development. These investigations pave the way for designing novel hepatotoxicity-free NCE analgesics with improved drug metabolism and pharmacokinetic properties.

A method based on micellar liquid chromatography has been developed to quantify edoxaban in oral solid dosage forms. Samples are dissolved in methanol and diluted in mobile phase up to nearly 5 mg L⁻¹ and directly injected. The drug is resolved in less than 8 min using a C18 column and an isocratic mobile phase of 0.10 M sodium dodecyl sulfate −4%, v/v 1-butanol buffered at pH = 3 with a phosphate salt, running at 1 mL min⁻¹. The detection wavelength is 290 nm. The procedure is successfully validated by the guidelines of the International Conference on Harmonization. The calibration curve is linear (r² > 0.999) over the interval 1–10 mg L⁻¹. Trueness is 100.4–103.0% and precision < 1.7% and is finally applied to commercial tablets. The method is found to be quite sustainable by several quantitative assessed tools. The surfactant is found to be the primary contributor to the elution strength of the mobile phase and the partition constants of the equilibria involved in retention are determined. The method uses a low quantity of hazardous chemicals; is easy to conduct, safe, eco-friendly, and cost-effective, and offers a high sample throughput, thus suitable for routine analysis.

Targeting C1 domains is a promising strategy for modulating the activity of signaling proteins driving tumor growth and progression. While most small molecules developed to date have focused on typical C1 domains, the development of regulators targeting atypical C1 domains remains under-explored. Herein, we describe the design and synthesis of novel cationic diacylglycerol DAG-lactones to efficiently interact with the negatively charged residues present in the atypical C1 domain of Vav1, a guanine nucleotide exchange factor playing a critical role in tumor development, including pancreatic cancer. We evaluated the therapeutic potential of this new family of compounds using models from this dismal condition where Vav1 is aberrantly expressed. Treatment of cultured pancreatic tumor cells with sn-1 cationic DAG-lactones inhibited proliferation of Vav1-expressing cells while Vav1-negative cells showed no response. Additionally, we demonstrated that these compounds inhibited growth of patient-derived organoids models of pancreatic cancer. These findings underscore the translational value of these cationic DAG-lactones for pancreatic cancer patients expressing Vav1 and serve as foundation for future approaches targeting atypical C1 domain-containing signaling proteins.

The cornea is a crucial refractive medium in the visual system, characterized by its avascular and transparent nature under physiological conditions. Pathological factors such as ocular trauma and inflammation can induce the formation of new capillaries from the limbal vascular network, leading to corneal neovascularization (CNV). With an associated blindness rate as high as 12%, CNV has become a significant challenge in ophthalmology. Current treatment strategies for CNV primarily include drug therapy such as anti-inflammatory and antiangiogenic agents, as well as surgical procedures like laser photocoagulation. These approaches are often limited by invasive procedures, suboptimal efficacy, and other constraints. Therefore, developing effective, safe, and convenient therapeutic options has become a critical research focus. Due to structural barriers of the ocular surface, the bioavailability of conventional eye drops is limited to ≈1%–5%, significantly restricting therapeutic efficacy. In recent years, researchers have been actively optimizing drug delivery systems using nanotechnology, hydrogels, and other advanced techniques to prolong ocular surface retention time, improve corneal penetration, and enhance drug release properties. This review summarizes recent advances in topical drug therapy for CNV, focusing on its pathogenesis, therapeutic agents, and delivery strategies, as well as approaches to enhance the bioavailability of topical treatments.

The growing threat of multidrug-resistant tuberculosis highlights the need for new agents with alternative mechanisms of action. Herein, a series of pyrazole-sulfonamide derivatives are synthesized and evaluated for inhibition of Mycobacterium tuberculosis β-carbonic anhydrases (MtCA 1 and MtCA 3). N-substituted analogues (6a–6i) are inactive, while compounds bearing a free sulfonamide group (SO₂NH₂) (5a–5s) exhibit potent inhibitory activity, with K_i values of 0.2154–0.7542 µM for MtCA 1 and 0.0548–0.3241 µM for MtCA 3. Molecular docking studies support their binding interactions and selectivity. Antitubercular screening of all synthesized compounds reveals minimum inhibitory concentration (MIC) values in the range of 4–128 µg mL⁻¹. Among them, compound 5p emerges as the most potent derivative, with a K_i of 0.07 µM against MtCA 3 and an MIC of 8 µg mL⁻¹, outperforming the reference inhibitor acetazolamide. It exhibits no cytotoxicity in THP-1 cells, showing no toxicity against human cell lines, and demonstrates a favorable selectivity index. Furthermore, compound 5p retains activity against rifampicin-resistant M. tuberculosis. In silico ADMET predictions indicate acceptable pharmacokinetic and safety profiles. These findings suggest that compound 5p is a promising lead for the development of novel antitubercular agents, potentially acting through MtCA inhibition.

In recent years, developing effective theranostic agents for precise cancer treatment has been one of the most prevalent strategies. Herein, three staurosporine derivatives, MCY-STS, ECY-STS, and ICY-STS, synthesized through minor modifications of natural staurosporine, are reported. These derivatives not only exhibit attractive fluorescence properties, including solvatochromism and dual-state (solution and solid) emission, but also demonstrate potent protein kinase C inhibitory activity and anticancer effects against NCI-N87, MCF-7, and SK-OV-3 cell lines. Theoretical calculation analyses, including density functional theory calculations, molecular docking, and molecular dynamics simulations, are employed to elucidate their protein–ligand interactions and luminescence mechanisms. Further investigations reveal that ECY-STS significantly inhibits tumor growth while illuminating tumor tissues for therapy visualization. Collectively, these modified fluorescent staurosporine derivatives, particularly ECY-STS, represent promising theranostic agents that provide a novel strategy for cancer imaging and treatment in humans.

Aptamer is a promising therapeutic modality, offering strong target affinity and target versatility. In the previous studies, DNA aptamers with potent thrombin inhibitory activity, M08s-1 and its bivalent derivatives, have been developed as novel anticoagulant agents. Among them, the heterobivalent aptamer Pse08-29 exhibits the most potent ex vivo anticoagulant activity, surpassing the approved drug argatroban. However, its long oligonucleotide chains composed of 106 nucleotides may hinder its drug development due to limited chemical synthetic efficiency. Here, a segmented form of Pse08-29 composed of two DNA strands, assembled via a sticky end-type strategy, is developed. The cleavage positions and optimal linker lengths are studied based on the anticoagulant activity and structural stability, revealing that a few cleavage sites within the duplex linker region are acceptable without losing the activity. Surprisingly, one of such aptamers, Stick08-29(19-B), shows the significantly enhanced serum stability compared to Pse08-29, despite the two nick-like sites existing. Finally, selected bivalent aptamers, consisting of two split DNA strands (<65 mer), exhibit the high anticoagulant activity as well as Pse08-29. This highlights not only efficient nucleobase reduction with preserved function but also a new design strategy for bivalent aptamers.

The proteasome is a central component of the cellular machinery responsible for degrading misfolded or damaged proteins, thereby maintaining protein homeostasis. Dysregulation of proteasome activity has been implicated in various diseases, including neurodegenerative disorders and cancer. In this article, a new β-cyclodextrin conjugate of suxibuzone (SB-CD) is designed and its proteasome activity on purified human 20S core particle and in differentiated human neuroblastoma SH-SY5Y cells (dSHSY5Y) is investigated. This conjugate enhances the proteolytic activity of the 20S proteasome in a dose-dependent manner, with an increase observed at concentrations as low as 5 µM. The EC50 values for SB-CD are determined to be 0.6 ± 0.1 µM for chymotrypsin-like activity and 1.1 ± 0.3 µM for trypsin-like activity, indicating higher efficacy compared to suxibuzone alone. In dSH-SY5Y cells, a decrease in the accumulation of ubiquitinated proteins is observed, consistent with the activation of the proteasome. High-resolution electrospray ionization mass spectrometry investigations confirmed the internalization of SB-CD in cells and verified the stability of the conjugate in response to cellular protease effects, after incubation for up to 24 h. These promising results suggest that the new conjugate is an effective enhancer of proteasome activity, holding significant promise for therapeutic applications targeting proteasome-related pathologies.

Zinc complexes have promising possibilities as medicines since they have better efficacy and lower toxicity. Herein, two ligands are synthesized based on hydrazine-1-carbothioamide with substituents having different electronic nature {nitro (HNPhHCT) and methoxy (HMoPhHCT)} and their respective Zn(II) complexes {[Zn(NPhHCT)₂] and [Zn(MoPhHCT)₂]}. They have been fully characterized via several spectroscopic techniques (IR, NMR, HRMS, UV–Vis studies) and DFT studies. In addition, ligands and their respective complexes are screened for their antiproliferative activity against three different cancer cell lines, namely HuT-78 (T-cell lymphoma), DL (Dalton's lymphoma), and MCF-7 (Breast cancer) cell lines. Among the two complexes, [Zn(MoPhHCT)₂] is found to be most cytotoxic on all three cancer cell lines. In HuT-78 cells, [Zn(MoPhHCT)₂] exhibited IC₅₀ value at ≈4 µM. Further, glucose and ROS estimation assays suggested that [Zn(MoPhHCT)₂] shows antiproliferative activity against T lymphoma cells by inhibiting their glycolytic activity and apoptosis induction by increasing ROS production. A molecular docking study is performed against an antiapoptotic protein, BCL2 (PDB: 2O2F), that confirms its inhibitory response with a binding score of −8.34 kcal mol⁻¹. Further, the expression of BCL2 at the protein level is found to be significantly inhibited in response to treatment with [Zn(MoPhHCT)₂], as evident by the Western blot analysis results.