Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.     

蛋白质-多糖复合体系在活性物质传递中的应用

蛋白质-多糖复合体系作为生物活性物质传递系统的壁材,有着人工合成聚合物或无机物等其他材料不可比拟的多重优势。本文就蛋白质和多糖之间的连接方式及蛋白质-多糖复合体系形成传递系统的多种形式进行了综述,以及对此领域的发展趋势进行了展望。结合蛋白质和多糖的结构特点,二者之间的链接方式分为非共价结合的物理共聚,和共价结合的美拉德偶联、化学交联、酶催化交联等方式,文中分别对各种连接方式的原理和机理,以及其影响因素做了深入阐述。以蛋白质-多糖复合体系为壁材对活性物质的传递形式大体上分成乳化系统、胶束、纳米凝胶、分子复合物以及壳核结构等系统。不同的活性物质的特征和传递需求,可针对性地选择合适结构的蛋白质和多糖种类以及二者的连接方式和传递系统的形式。并且,随着研究的逐步发展和推进,此领域的发展趋势朝着智能化和靶向性的方向进行。目前活性物质的蛋白质-多糖复合体系的传递系统,还依然面临着系统设计、评价和应用等多方面的挑战,这就要求我们在更全面更深入了解认识其对活性物质影响和功效的基础上,安全合理地设计和深入细致地评价活性成分的传递系统。     

Doxorubicin Encapsulation in Carbon Nanotubes Having Haeckelite or Stone–Wales Defects as Drug Carriers: A Molecular Dynamics Approach

Doxorubicin (DOX), a recognized anticancer drug, forms stable associations with carbon nanotubes (CNTs). CNTs when properly functionalized have the ability to anchor directly in cancerous tumors where the release of the drug occurs thanks to the tumor slightly acidic pH. Herein, we study the armchair and zigzag CNTs with Stone–Wales (SW) defects to rank their ability to encapsulate DOX by determining the DOX-CNT binding free energies using the MM/PBSA and MM/GBSA methods implemented in AMBER16. We investigate also the chiral CNTs with haeckelite defects. Each haeckelite defect consists of a pair of square and octagonal rings. The armchair and zigzag CNT with SW defects and chiral nanotubes with haeckelite defects predict DOX-CNT interactions that depend on the length of the nanotube, the number of present defects and nitrogen doping. Chiral nanotubes having two haeckelite defects reveal a clear dependence on the nitrogen content with DOX-CNT interaction forces decreasing in the order 0N > 4N > 8N. These results contribute to a further understanding of drug-nanotube interactions and to the design of new drug delivery systems based on CNTs.     

Unlocking the Drug Potential of the Bryostatin Family: Recent Advances in Product Synthesis and Biomedical Applications

Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014–present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1 , the most-studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development.     

Capillary Electrophoresis Chiral Separation for Enantiomeric Purity Determination of a Basic Drug in Pharmaceutical Formulations

Capillary electrophoresis using a running buffer composed of β-cyclodextrin as the chiral selector and ethanolamine mesylate at pH 9.6 is being used to monitor the stereochemical stability of a hydrophobic drug, containing two chiral centers, in two different formulated self-emulsifying drug delivery system (SEDDS) products. The separation takes place in less than 25 min. Strategies for enhancing the method reproducibility and detection sensitivity in the lower potency formulation are presented. The results demonstrating the specificity, assay precision, recovery, linearity and range achieved during the method validation experiments are presented in this paper.Presented at: CE in the Biotechnology and Pharmaceutical Industries: 7th Symposium on the Practical Applications for the Analysis of Proteins, Nucleotides and Small Molecules, Montreal, Canada, August 12–16, 2005.     

Synthesis and characterization of oxidized cellulose

Samples of oxidized cellulose (OC) with various carboxyl contents and degrees of crystallinity were obtained by the oxidation of native and mercerized cellulose with a solution of nitrogen(IV) oxide in CCl₄. A detailed characterization of these OC samples was performed. The effect of oxidation conditions (concentration of N₂O₄ in the solution and oxidation time) and starting cellulose material on OC characteristics (carboxyl, carbonyl and nitrogen content, degree of crystallinity and polymerization, surface area and swelling, and acidic properties) was investigated. Reactivity in the oxidation process was higher in mercerized cellulose than in native cellulose. The action of dilute solutions (10–15%) of N₂O₄ did not affect the degree of crystallinity of cellulose samples. Under these conditions, the oxidation took place mainly in amorphous regions and on the surface of crystallites. Oxidation in a concentrated (40%) N₂O₄ solution led to the destruction of crystallites, which increased the surface area and swelling of cellulose in water. The surface area and the swelling of OC samples increased with a decrease in the index of crystallinity. The acidic properties of OC were shown to increase with an increase of swelling in water. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4785–4791, 2004     

Thermal decomposition of a generation 4.5 PAMAM dendrimer platinum drug conjugate

A nanoscale multivalent platinum drug based on a poly(amidoamine) [PAMAM] dendrimer (generation 4.5, carboxylate surface) has been synthesized and fully characterized using a variety of spectroscopic, chromatographic and thermal methods. Treatment of the dendrimer with an aqueous solution containing an excess diaquo(cis-1,2-diaminocyclohexane)platinum(II) produces a conjugate containing approximately forty (diaminocyclohexane)platinum(II) moieties at the surface of the dendrimer. This material undergoes smooth two-stage thermal decomposition to provide residual platinum oxide reflecting the platinum loading in the drug.