An azonia cation has been explored for the first time as an acceptor unit in charged π-donor π-acceptor chromophores. Initial experimental and theoretical data show that quinolizinium, the simplest ...heteroaromatic azonia cation, behaved as a good acceptor unit and conferred promising nonlinear optical properties to simple push–pull cationic chromophores.
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Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our ...society, such as human health and environment.
For the 2nd PSL Chemical Biology Symposium, the state of the art in chemical biology has been presented by world leaders to feature the latest innovation and future perspectives in this dynamic and innovative field.
Chemical biology of salinomycin Versini, Antoine; Saier, Lou; Sindikubwabo, Fabien ...
Tetrahedron,
09/2018, Letnik:
74, Številka:
39
Journal Article
Recenzirano
Cancer stem cells (CSC) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. The natural product Salinomycin has been ...identified by means of high throughput phenotypic screening as a selective killer of CSC in vitro and in vivo. In this article we comprehensively review the chemistry of Salinomycin, documenting early total syntheses, along with strategies that have been developed over the years to effectively modify this natural product at key positions with the view to establish a robust structure-activity-relationship and to delineate the complex mechanism of action of this fascinating molecule in the context of cancer research. Then, we document the biology of Salinomycin, putting forward phenotypic alterations that have been observed in the relevant biological models and highlighting how chemistry has been instrumental in discovering unprecedented physiological features of cancer stem cells that can be exploited for therapeutic benefits.
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Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via ...similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications.
Salinomycin, a natural carboxylic polyether ionophore, shows a very interesting spectrum of biological activities, including selective toxicity toward cancer stem cells (CSCs). Recently, we have ...developed a C20-propargylamine derivative of salinomycin (ironomycin) that exhibits more potent activity in vivo and greater selectivity against breast CSCs compared to the parent natural product. Since ironomycin contains a terminal alkyne motif, it stands out as being an ideal candidate for further functionalization. Using copper-catalyzed azide–alkyne cycloaddition (CuAAC), we synthesized a series of 1,2,3-triazole analogs of ironomycin in good overall yields. The in vitro screening of these derivatives against a well-established model of breast CSCs (HMLER CD24low/CD44high) and its corresponding epithelial counterpart (HMLER CD24high/CD44low) revealed four new products characterized by higher potency and improved selectivity toward CSCs compared to the reference compound ironomycin. The present study highlights the therapeutic potential of a new class of semisynthetic salinomycin derivatives for targeting selectively the CSC niche and highlights ironomycin as a promising starting material for the development of new anticancer drug candidates.
An efficient palladium-catalyzed cross-coupling reaction on heteroaromatic cations is described. A comparative study of the Stille and Suzuki reactions shows that only the Stille reaction is able to ...produce an efficient C−C bond formation between any of the four isomeric bromoquinolizinium bromides and a variety of stannanes. In the presence of the catalysts Pd(PPh3)4 or Pd2(dba)3P(o-Tol)3, vinyl, ethynyl, aryl, and heteroaryl groups are successfully incorporated into the quinolizinium system in satisfactory yields under mild reaction conditions. This procedure represents a marked improvement on the functionalization of this class of heteroaromatic cation.
A variety of alkynylazinium cationic (D‐π‐A+) chromophores were prepared in good yields by the reaction of bromoazinium (pyridinium, quinolinium, and isoquinolinium iodides) with alkynes under ...Sonogashira conditions. The analysis of the experimentally recorded spectra is supported by quantum chemical calculations using restricted configuration interaction and density functional methods. First‐order hyperpolarizabilities of (D‐π‐A+) azinium‐based cations as a new class of second‐order nonlinear optical (NLO) chromophores were also studied by hyper‐Rayleigh scattering experiments and computational procedures.
A variety azinium cations (D‐π‐A+) were synthesized by the Sonogashira reaction in good yields. The hyperpolarizabilities (β) of the chromophores (D‐π‐A+) were determined by hyper‐Rayleigh scattering experiments and ab initio quantum chemicalmethods.
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