Notes

Ginkgolic acid solution induces apoptosis as well as autophagy of endometrial carcinoma cells by way of suppressing PI3K/Akt/mTOR pathway within vivo and in vitro.
After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. see more Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro-in vivo correlations and pharmacokinetic-pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles, and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK-PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.Since 1977, the World Health Organization publishes a list of essential medicines, i.e., those that satisfy the priority health care needs of the population and are selected with regard to disease prevalence and public health relevance, evidence of clinical efficacy, and safety, as well as comparative costs and cost-effectiveness. The Essential Medicines List (EML) is an invaluable tool for all countries to select those medicines that have an excellent risk/benefit ratio and that are reputed to be of pivotal importance to health. In the present perspective, we describe the chemical composition and the main features of the small molecules that are included in the EML, spanning from their origin, to their stereochemistry and measure of drug-likeness. Most and foremost, we wish to disseminate the importance of the EML, which can be both a helpful teaching tool in an ever-expanding world of medicines and an inspiration for those involved in pharmaceutical R&D.Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.The discovery and development of targeted protein degraders has become an important area of research in the field of medicinal chemistry. Inducing degradation of a target protein presents several advantages relative to simple inhibition including a potential for extended duration of action and more profound pharmacology. Whilst engineered heterodimeric molecules have recently been a major focus within industry and academia, this perspective highlights examples of targeted protein degradation observed for smaller, monomeric molecules. Methods and tools for evaluating protein degradation as well as a discussion of physical properties of monomeric vs. engineered heterodimeric degraders are presented.Difluoromethylene-containing compounds have attracted substantial research interest over the past decades for their ability to mimic biological functions of traditional functional groups while providing a wide variety of pharmacological benefits bestowed by the C-F bond. We report a novel strategy to access RCF2Br-containing heterocycles by regio- and enantioselective bromocyclization of difluoroalkenes enabled by chiral anion phase-transfer catalysis. The utility of this methodology was highlighted through a synthesis of an analogue of efavirenz, a drug used for treating HIV. Additionally, the synthetic versatility of the CF2Br intermediates was showcased through functionalization to a variety of enantioenriched α,α-difluoromethylene-containing products.Ternary systems consisting of polymers, lithium salts, and ionic liquids (ILs) are promising materials for the development of next-generation lithium batteries. The ternary systems combine the advantages of polymer-salt and IL-salt systems, thus providing media with high ionic conductivity and solid-like mechanical properties. In this work, we apply nuclear magnetic resonance 1H microimaging [magnetic resonance imaging (MRI)] techniques and molecular dynamics (MD) simulations to study the translational and rotational dynamics of the N-butyl-N-methylpyrrolidinium (PYR14) cation in poly(ethylene oxide) (PEO) matrices containing the lithium bis(trifluoromethanesulfonyl) imide salt (LiTFSI) and the PYR14TFSI IL. The analysis of diffusion-weighted images in PEO/LiTFSI/PYR14TFSI samples with varying mole ratios (101x, with x = 1, 2, 3, and 4) shows, in a wide range of temperatures, a spatially heterogeneous distribution of PYR14 diffusion coefficients. Their weight-averaged values increase with IL content but remain well below the values estimated for the neat IL. The analysis of T2 (spin-spin relaxation) parametric images shows that the PEO matrix significantly hinders PYR14 rotational freedom, which is only partially restored by increasing the IL content. The MD simulations, performed on IL-filled cavities within the PEO matrix, reveal that PYR14 diffusion is mainly affected by Li/TFSI coordination within the IL phase. In agreement with MRI experiments, increasing the IL content increases the PYR14 diffusion coefficients. Finally, the analysis of MD trajectories suggests that Li diffusion mostly develops within the IL phase, although a fraction of Li cations is strongly coordinated by PEO oxygen atoms.
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