The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Abnormal activation of the Hh signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. The modification was started from the HTS hit thieno[3,2-c]quinoline-4-one derivative 1a, and focused on the enhancement of Gli reporter inhibitory activity and the improvement metabolic stability. Following optimization for the improvement of solubility was led to discover compound 3h (TAK-441) which was selected as a clinical candidate. The further SAR acquisition of TAK-441 brought to discover the several novel cores with potent Gli reporter inhibitory activity which was equal to that of TAK-441.
This report describes the details of the discovery of TAK-441 and the potent Hh signaling inhibitor with novel core skeletons.
Fluorous solvents are generally immiscible with common organic solvents. Using to this unique property, “fluorous technique” has spread across various fields, including those of synthetic, catalytic, and analytical chemistry. In synthetic chemistry, a fluorous chemistry is suitable as a strategic alternative to solid-phase synthesis, because it does not inevitably resort to chromatography. In this paper, the efficient synthesis of monosaccharide units and oligosaccharide by the use of fluorous methods is reported. Further, the synthesis of a monosaccharide unit using the combination of fluorous chemistry and a microreactor as a single system is described. Additionally, oligosaccharide library synthesis by fluorous mixture method is reported.
Catalysts that can promote acyl transfer processes are important for enantioselective synthesis and their development has received significant attention in recent years. Very recently, we developed a method for the synthesis of chiral DMAP derivatives starting from an α-amino acid as a chiral source using a diastereoselective Ugi multicomponent reaction, and the protocol allowed us to access a variety of chiral catalysts in a one-step and one-pot manner. Such catalysts could be applied to various enantioselective acyl transfer reactions. In addition, we also reported a conceptually new type of kinetic resolution of secondary alcohols with a chiral phosphoric acid for the first time. Finally, we developed a binaphthyl-based chiral DMAP derivatives utilizing H-bonding interactions for enantioselective intra- and intermolecular acyl transfer reactions with high enantioselectivity. tert-Alcohol units of the catalyst play important roles in the acceleration of the rate of the reaction and achieving high enantioselectivity.
This article describes the recent developments in C3-symmetric tris-urea low molecular weight gelators and their applications. The supramolecular organogel of the C3-symmetric tris-urea molecule exhibited a chemical stimuli responsive reversible gel-sol phase transition. Supramolecular hydrogels are constructed from self-assemblies of amphiphilic C3-symmetric tris-urea derivatives. Sugar-connected amphiphilic C3-symmetric tris-urea was found to form a gel with water, and the hydrogels showed chemical stimuli responsive gel-sol phase transitions. Another amphiphilic C3-symmetric tris-urea formed gels with various aqueous solutions, such as buffers, saturated NaCl, 8 M HCl, and 7 M KOH solutions, and these gels showed thixotropic nature. Supramolecular hydrogels obtained from amphiphilic C3-symmetric tris-ureas were used in the electrophoresis of proteins. These electrophoreses showed several unique characteristics compared to typical electrophoreses using polyacrylamide matrices. A mixture of a hexa-carboxylated amphiphilic C3-symmetric tris-urea and an alkaline solution gave a viscous solution composed of fibrous aggregates. This viscous solution transformed into supramolecular hydrogels, which are capable of hierarchically organizing into higher-order aggregates, in response to several cationic triggers.
Sumanene (C21H12) is a bowl-shaped π-conjugated molecule, which is a minimum C3v symmetric fragment of the structural motif of the fullerene or endcap of the carbon nanotube. The presence of three sp3 hybridized benzyl moieties is one of the most distinctive structural features in sumanene, enabling a unique chemistry. I have engaged in the study of sumanene since 2004. In this article, our researches such as structure, dynamics, derivatization, complex formation with transition and alkali metals, charge carrier mobility, and laser-induced conversion to nitrogen-doped graphitic carbon are summarized.
The indole flamework is one of the ubiquitous heterocycles in natural products and pharmaceuticals. Thus, various methods have been developed to afford functionalized indoles. Recently, direct functionalization of indoles at the C7 position has been emerged. Introduction of directing groups such as hydrosilyl, phosphinoyl, and pivaloyl group at the N1 position enables site-selective functionalization via coordination to metal catalysts. In these cases, bulkiness of the directing group is found to be crucial for high reactivity and C7-selectivity.
Oxocarbenium ions are key intermediates in a wide variety of important synthetic transformations. Since they have generally high reactivities and lack of basic sites suitable for interaction with chiral Lewis acids or hydrogen-bond donors, the development of catalytic enantioselective reactions involving oxocarbenium intermediates is a great challenge for chemical synthesis. This review highlights recent progress in developing catalytic enantioselective oxa-Pictet-Spengler reaction.