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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Iminosugars exhibit great importance in the treatment of multiple diseases (Horne and Wilson, 2011; Horne et al., 2011); for instance, inhibition of intestinal glycosidases, integrated into the cell membranes of the brush border region in the small intestine, is used as a therapy for T2DM, as a result of the interference over the oligosaccharides-to-monosaccharides hydrolysis, and the concomitant regulation of carbohydrate absorption leading to a lower blood glucose levels (Mitrakou et al., 1998; Derosa and Maffioli, 2012; Campo et al., 2013). Naturally occurring iminocyclitols can be divided into five classes depending on their structures: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines, or nortropanes (Fig. 11.39). Five types of naturally occurring iminocyclitols.
Reactor and microreactor performance and kinetics of the aldol addition of dihydroxyacetone to benzyloxycarbonyl-N-3-aminopropanal catalyzed by D-fructose-6-phosphate aldolase variant A129G
Published in Chemical Engineering Communications, 2019
Martina Sudar, Zvjezdana Findrik, Anna Szekrenyi, Pere Clapés, Đurđa Vasić-Rački
C–C bond formation is one of the crucial reactions in organic synthesis (Clapés et al., 2010; Windle et al., 2014). Among the methods available for performing this reaction, aldol addition is a privileged methodology for the bottom up synthesis of polyfunctionalized molecules such as carbohydrates and amino acids (Mahrwald, 2004a, 2004b, 2013). Aldolases catalyze this reaction in nature typically involving a ketone, as nucleophile, and an aldehyde, as electrophile (Schürmann and Sprenger, 2001; Clapés and Garrabou, 2011; Oroz-Guinea and García-Junceda, 2013; Roldán et al., 2017). Aldolases are gaining a great interest in the synthesis of bioactive chiral carbohydrates, amino acids, etc. (Clapés and Joglar, 2013; Guérard-Hélaine et al., 2014; Soler et al., 2014; 2015; Hernández et al., 2015; Szekrenyi et al., 2015; Roldán et al., 2017; Saravanan et al., 2017; Hernández et al., 2018). This is due to their high efficiency, selectivity, and control over the configurations of the formed stereogenic centers. Furthermore, they can operate under mild conditions and in aqueous solutions (Müller, 2012; Müller et al., 2013; Schmidt et al., 2016; Clapés, 2016a, 2016b). Another great advantage of using enzymes for C–C bond formation is their ability to form new C–C bonds with structurally different substrates as opposed to their natural substrates (Garrabou et al., 2009; Brovetto et al., 2011; Hernández et al., 2015; Szekrenyi et al., 2015; Güclü et al., 2016; Hernández et al., 2017; Roldán et al., 2017; Saravanan et al., 2017; Hernández et al., 2018). D-Fructose-6-phosphate aldolase from E. coli (FSA), first reported by Schürmann and Sprenger (2001), catalyzes the equilibrium reaction between dihydroxyacetone (2) and aldehyde. In this paper a novel FSA aldolase variant, FSA A129G (Szekrenyi et al., 2014), was investigated in the reaction of aldol addition of 2 to Cbz-N-3-aminopropanal (1) to furnish a precursor of the iminosugar D-fagomine (Scheme 1). D-Fagomine is an iminosugar found in nature with the ability to lower blood glucose peak after meal by inhibiting intestinal disaccharidases and to reduce low-grade inflammation mediated fat-induced weight gain and insulin resistance probably by maintaining the adequate proportions of intestinal microbiota (Gómez et al., 2012; Amézqueta et al., 2013; Ramos-Romero et al., 2014). In preliminary experiments, FSA A129G showed a superior performance in the aforementioned reaction as compared to the previously reported variants FSA A129S and A129S/A165G (Sudar et al., 2013b).
Binuclear ruthenium(II) complexes of 4,4′-azopyridine bridging ligand as anticancer agents: synthesis, characterization, and in vitro cytotoxicity studies
Published in Journal of Coordination Chemistry, 2019
Priyanka Khanvilkar, Ramadevi Pulipaka, Kavita Shirsath, Ranjitsinh Devkar, Debjani Chakraborty
Ferrocene, one of the members of the well-known organometallic family “metallocenes”, shows properties appropriate for the design of potential pharmaceutical agents. Its lipophilicity (logP = 2.66) facilitates its derivatives for membrane penetration and bioavailability [10–12]. The rotation of the aromatic cyclopentadienyl ring confers conformational diversity on ferrocene (staggered or eclipsed conformation), which is of advantage for orientating ferrocene-derived ligands into their receptor pockets [13]. An exclusive review [14] focuses on ferrocene’s basic properties, ferrocene-containing ligands, the ferrocene/ferricinium redox couple, the ferricinium/ferrocene redox shuttle in catalysis, ligand-exchange reactions, ferrocene-containing polymers, ferrocenes in supramolecular ensembles, liquid crystals, and nonlinear optical materials, ferrocene-containing dendrons, dendrimers, and nanoparticles (NPs) and their application in redox sensing and catalysis. The review also focuses on the use of ferrocenes in nanomedicine; a few have been exemplified here. The ferrocene/ferricinium redox couple is currently used as a redox mediator for the amperometric detection of glucose in blood [15, 16]. The most used ferrocene-based drug in medicine is the antimalarial drug ferroquine [17]. This organoiron drug has also recently been found to inhibit infection by the hepatitis C virus [18]. Antitumor activities of ferrocenes were first reported in 1978 by Brynes’ group, with derivatives bearing an amine or amido group that were active against lymphocytic leukemia P-388 [19]. Ferrocenyl compounds based on selective estrogen modulators, including ferrocifens, ferrociphenols, and ferrocenophanes [20], as well as ferrocenyl raloxifen, show promising results for breast cancer [21]. Ferrocene-derived ligands coordinated to transition-metal ions including those of Ru, Rh, Ir, Pd, Pt, and Au have also shown excellent anticancer activites [22, 23]. Most recently, ferrocene-related anticancer research is also focusing on ferrocene–chalcogeno-triazole–sugar conjugates [24], membrane interactions of nitroaryl ferrocenes [25], PEGylated ferrocene radiosensitizers of cancer cells [26], tubulin-binding ferrocene-substituted 3,3′-diindolylmethane [27], ferrocene-modified phospholipids [28], ferrocene–iminosugar hybrids [29], ferrocene–N-heterocyclic carbene–gold(I) complexes targeting antioxidant pathways [30] and dendrimer-related strategies [31]. In terms of drug delivery, an elegant approach was reported by Wang’s group with pH-responsive supramolecular vesicles based on water-soluble pillar[6]arene and ferrocene derivatives [32]. Thus, design and development of ferrocene derivatives and their metal complexes could be regarded as an effective approach to discover potential novel pharmaceutical agents.