Identification and further development of thiazolidinones spiro-fused to indolin-2-ones as potent and selective inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B

Tuberculosis continues to be a major cause of morbidity and mortality throughout the world. Protein tyrosine phosphatases from Mycobacterium tuberculosis are attractive targets for developing novel strategies in battling tuberculosis due to their role in the intracellular survival of M. tuberculosis in various infection models. Here, we report on the identification and further development of thiazolidinones spiro-fused to indolin-2-ones as a new class of potent and selective inhibitors of M. tuberculosis protein tyrosine phosphatase B. Detailed structure-activity relationship (SAR) studies revealed that a nitro-substituted 2-oxoindole core together with a dihalogenated anilide and a halogenated N-benzyl moiety are essential for strong inhibitory activity against MptpB (M. tuberculosis protein tyrosine phosphatase B). Small structural modification of the identified compounds led to significant improvement of compound solubility and cell permeability retaining inhibitory activity in the micromolar range. The configuration of the spiro-center was found to be crucial for the inhibitory activity and the separation of the racemate revealed the R-(−)-enantiomers as the biologically active component. The reported MptpB inhibitors show excellent selectivity against a selected panel of protein tyrosine phosphatases, including MptpA (M. tuberculosis protein tyrosine phosphatase A), PTP1B (protein tyrosine phosphatase 1B), SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase), PTPN2, h-PTPβ (human protein tyrosine phosphatase β), and VHR (Vaccinia virus VH1-related dual-specific protein phosphatase) and further highlight the identified thiazolidinones spiro-fused to indolin-2-ones as a promising class of new compounds that might prove useful for chemical biology research to dissect MptpB function and eventually foster the development of next generation antibiotics.     

微量元素在人体内的化学行为

从配位化学的角度，论述了微量元素在人体生命过程中的化学行为。     

Reprogramming the chemical reactivity of iron in cancer stem cells

Cancer stem cells (CSCs) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. Salinomycin can selectively kill CSCs. We have shown that salinomycin derivatives accumulate in lysosomes and sequester iron in this organelle. As a result, accumulation of iron leads to the production of reactive oxygen species and lysosomal membrane permeabilization, which in turn promotes cell death by ferroptosis. These findings have revealed the prevalence of iron homeostasis in CSCs and paved the way toward the development of next-generation therapeutics.     

Chemical Ecology—A Chapter of Modern Natural Products Chemistry

The chemical reaction of arthropods to their environment, i.e. their chemical ecology, can be studied particularly well with water beetles. Stenus comma, an aquatic beetle weighing only 2.5 mg, saves itself from drowning with the aid of an alkaloid, and the water beetle Ilybius fenestratus defends itself against small mammalian predators with a compound belonging to the same class. The water beetle Platambus maculatus employs a diterpene for precisely the same purpose and the whirligig beetle a norsesquiterpene, which also offers protection against troublesome microorganisms. As chemical artists, the ants can hardly be surpassed. In particular, the myrmecine ants guarantee their food supplies with plant growth substances. Since these compounds, depending upon concentration, can also act as inhibitors, we are confronted with an excellent example of an ecological equilibrium being established with the aid of organic chemicals. Even the little parasitic bombardier beetle Paussus favieri is tolerated, on account of its defensive chemistry, in the nest of the myrmecine ant Pheidole. In contrast, inorganic compounds are largely responsible for the stability of spiders' webs.     

Coupling of thioamides with 4-bromocrotonate esters and subsequent conjugate addition for the rapid one-pot synthesis of functionalized thiazolines

An efficient one-pot synthesis of functionalized thiazolines via the coupling of thioamides with 4-bromocrotonate esters is described. A range of aryl- and alkyl-thioamides with various substitutions are well-tolerated. Additionally, the presence of the exocyclic ester functionality provides a convenient handle for the synthesis of more complex thiazoline-containing natural products and biologically-relevant compounds.     

In silico identification of natural products with anticancer activity using a chemo-structural database of Brazilian biodiversity

Cancer is one of the leading causes of death worldwide, and the number of patients has only increased each year, despite the considerable efforts and investments in scientific research. Since natural products (NPs) may serve as suitable sources for drug development, the cytotoxicity against cancer cells of 2221 compounds from the Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBE_DB) was predicted using CDRUG algorithm. Molecular modeling, chemoinformatics, and chemometric tools were then used to analyze the structural and physicochemical properties of these compounds. We compared the positive NPs with FDA-approved anticancer drugs and predicted the molecular targets involved in the anticancer activity. In the present study, 46 families comprising potential anticancer compounds and at least 19 molecular targets involved in oncogenesis. To the best of our knowledge, this is the first large-scale study conducted to evaluate the potentiality of NPs sourced from Brazilian biodiversity as anticancer agents, using in silico approaches. Our results provided interesting insights about the mechanism of action of these compounds, and also suggested that their structural diversity may aid structure-based optimization strategies for developing novel drugs for cancer therapy.     

Concise Synthesis and X-Ray Crystal Structure of N-Benzyl-2-(pyrimidin-4′-ylamino)-thiazole-4-carboxamide (Thiazovivin), a Small-Molecule Tool for Stem Cell Research

Stem cell research is one of the most promising fields of modern biomedical research and regenerative medicine. Limited availability and ethical concerns suggest the renouncement of embryonic stem cells (ESCs), thus raising the need for more efficient procedures for the generation of stem cells, ideally through reprogramming of mammalian cells. The small molecule N-benzyl-2-(pyrimidin-4′-ylamino)-thiazole-4-carboxamide (thiazovivin) is known to improve the generation of human induced pluripotent stem cells (iPSCs) from human fibroblasts. We herein describe a highly efficient procedure for the synthesis of thiazovivin over just five steps, which should be suitable for a large-scale application, and the first x-ray crystal structure of the target compound.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]     

Chemistry and Biology of Taxol

One can view plants as a reference library of compounds waiting to be searched by a chemist who is looking for a particular property. Taxol, a complex polyoxygenated diterpene isolated from the Pacific Yew, Taxus brevifolia, was discovered during extensive screening of plant materials for antineoplastic agents during the late 1960s. Over the last two decades, interest in and research related to taxol has slowly grown to the point that the popular press now seems poised to scoop each new development. What was once an obscure compound, of interest only to the most masochistic of synthetic chemists and an equally small number of cellular biologists, has become one of the few organic compounds, which, like benzene and aspirin, is recognizable by name to the average citizen. In parallel, the scientific study of taxol has blossomed. Physicians are currently studying its effects on nearly every known neoplasm. Biologists are using taxol to study the mechanisms of cell function by observing the effects of its interactions with the cellular skeletal systems. Synthetic chemists, absorbed by the molecule's unique and sensitive structure and functionality, are exploring seemingly every available pathway for its synthesis. Indeed, the demand for taxol has risen so in the last five years that alternative sources to the extraction of T. brevifolia are being vigorously pursued. Because of the rapidly expanding scope of research in the multifaceted study of taxol, those who are interested in the field may find acquisition of a reasonable base of knowledge an arduous task. For this reason, this account attempts to bring together, for the first time, in a cogent overview the chemistry and biology of this unique molecule.     

Discovery of 2,4-dimethoxypyridines as novel autophagy inhibitors

Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen for autophagy inhibitors, which led to the discovery of a dimethoxypyridine-based class of autophagy inhibitors, which derive from previously reported, natural product-inspired MAP4K4 inhibitors. Comprehensive structure-activity relationship studies led to a potent compound, and biological validation experiments indicated that the mode of action was upstream or independent of mTOR.     

Probing the biology of natural products: molecular editing by diverted total synthesis

The systematic modification of natural products through diverted total synthesis is a powerful concept for the systematic modification of natural products with the aim of studying mechanistic aspects of their biological activity. This concept offers far-reaching opportunities for discovery at the interface of biology and chemistry. It is underpinned by the power of chemical synthesis, which manifests itself in the ability to modify structure at will. Its implementation, when combined with innovative design, enables the preparation of unique mechanistic probes that can be decisive in differentiating and validating biological hypotheses at the molecular level. This Review assembles a collection of classic and current cases that illustrate and underscore the scientific possibilities for practitioners of chemical synthesis.     

Synthesis, biology, and modeling of a C-4 carbonyl C,D-seco-taxoid

A C,D-seco-paclitaxel derivative 26 was prepared from taxine and tested for biological activity. Chemical reactivity of the seco-compounds proved to be substantially modified, with respects to taxoids. The corresponding C,D-seco-taxoid does not show tubulin stabilizing activity or cytotoxicity. Explanation of these observations based on molecular modeling is provided.