Third Generation Photo-Cross-Linked Small-Molecule Affinity Matrix: A Photoactivatable and Photocleavable System Enabling Quantitative Analysis of the Photo-Cross-Linked Small Molecules and Their Target Purification

The third generation of photoactivatable beads designed to capture bioactive small molecules in a chemo- and site-nonselective manner upon irradiation at 365 nm of UV light and release them as coumarin conjugates after exposure to UV light of 302 nm is described. These photoactivatable and photocleavable beads enable quantification of the amount and distribution of immobilized small molecules prior to the pull-down experiments to identify target protein(s) for the immobilized small molecules. The newly developed system was then used to analyze the functional group compatibility of the photo-cross-linking technology as well as the preferable nature of small molecules to be immobilized. As a result, compounds having a hydroxyl group, carboxylic acid, or aromatic ring were shown to give multiple conjugates, indicating that these compounds are well compatible with the photoactivatable beads system

Stereocontrolled Construction of ABCD Tetracyclic Ring System with Vicinal All-Carbon Quaternary Stereogenic Centers of Calyciphylline A Type Alkaloids

A unique approach to the synthesis of an ABCD tetracyclic core bearing the vicinal all-carbon quaternary stereogenic centers of the calyciphylline A type alkaloids is reported. The synthesis features two C–C bond formations at a sterically congested position: one is an intramolecular pinacol coupling to construct the central A ring; the other is a semipinacol rearrangement to construct a quaternary stereogenic center adjacent to another quaternary center

Dual Structure–Activity Relationship of Osteoclastogenesis Inhibitor Methyl Gerfelin Based on TEG Scanning

Methyl gerfelin derivatives, each having an amine-terminated tri­(ethylene glycol) linker at the peripheral position, were designed and systematically synthesized. These “TEGylated” derivatives were then subjected to a structure–activity relationship (SAR) study to examine their glyoxalase 1-inhibition activity and binding affinity toward the three binding proteins identified. Among the derivatives synthesized, that with a NH₂-TEG linker at the C6-methyl group showed the most potent glyoxalase 1-inhibiting activity and glyoxalase 1 selectivity. These results indicated that derivatization at the C6-methyl group would be suitable for the further development of selective glyoxalase 1 inhibitors

Eu(OTf)₃‑Catalyzed Highly Regioselective Nucleophilic Ring Opening of 2,3-Epoxy Alcohols: An Efficient Entry to 3‑Substituted 1,2-Diol Derivatives

In our study of the total synthesis of (+)-irciniastatin A, we found a need to develop a method that enables a C3-selective nucleophilic ring opening of 2,3-epoxy alcohol by MeOH, by which we found that the use of combined catalytic amounts of Eu­(OTf)₃ and 2,6-di-<i>tert</i>-butyl-4-methylpyridine (DTBMP) enables the intended transformation to obtain 3-methoxy-1,2-diol efficiently. Promising features of a protocol that effects a highly regioselective nucleophilic ring opening of 2,3- and 3,4-epoxy alcohols using various nucleophiles including alcohols, thiols, and unprotected amines are described

A Concise and Unified Strategy for Synthesis of the C1–C18 Macrolactone Fragments of FD-891, FD-892 and Their Analogues: Formal Total Synthesis of FD-891

A concise and unified strategy for the synthesis of C1–C18 macrolactone fragments of FD-891 and FD-892 as well as their analogues is reported. The strategy includes a stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using chiral silyl ketene <i>N,O</i>-acetal to construct C6–C7 stereocenters, an <i>E</i>-selective ring closing metathesis to construct a C12–C13 olefin, and stereodivergent construction of a C8–C9 epoxide

Nazarov Cyclization Entry to Chiral Bicyclo­[5.3.0]­decanoid Building Blocks and Its Application to Formal Synthesis of (−)-Englerin A

A divergent entry to the chiral bicyclo[5.3.0]­decane skeletons relevant to sesqui- and higher terpenoids has been achieved. Its usefulness was demonstrated by formal synthesis of a guaiane sesquiterpenoid (−)-englerin A. The key reactions are (i) diastereoselective Nazarov cyclization for stereoselective construction of the bicyclo[5.3.0]­decane skeleton, (ii) intramolecular C–H amination for tuning an oxidation state, and (iii) introduction of an alkyl group to a β-alkoxy ketone with a zinc­(II) ate complex

Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B

Irciniastatin A (a.k.a. psymberin) and irciniastatin B are members of the pederin natural product family, which have potent antitumor activity and structural complexity. Herein, we describe a full account of our total synthesis of (+)-irciniastatin A and (−)-irciniastatin B. Our synthesis features the highly regioselective Eu­(OTf)₃-catalyzed, DTBMP-assisted epoxide ring opening reaction with MeOH, which enabled a concise synthesis of the C1–C6 fragment, extensive use of AZADO (2-azaadamantane <i>N</i>-oxyl) and its related nitroxyl radical/oxoammonium salt-catalyzed alcohol oxidation throughout the synthesis, and a late-stage assembly of C1–C6, C8–C16, and C17–C25 fragments. In addition, for the synthesis of (−)-irciniastatin B, we achieved the C11-selective control of the oxidation stage via regioselective deprotection and AZADO-catalyzed alcohol oxidation. The synthetic irciniastatins showed high levels of cytotoxic activity against mammalian cells. Furthermore, chemical footprinting experiments using synthetic compounds revealed that the binding site of irciniastatins is the E-site of the ribosome

Vicenistatin induces early endosome-derived vacuole formation in mammalian cells

<p>Homotypic fusion of early endosomes is important for efficient protein trafficking and sorting. The key controller of this process is Rab5 which regulates several effectors and PtdInsPs levels, but whose mechanisms are largely unknown. Here, we report that vicenistatin, a natural product, enhanced homotypic fusion of early endosomes and induced the formation of large vacuole-like structures in mammalian cells. Unlike YM201636, another early endosome vacuolating compound, vicenistatin did not inhibit PIKfyve activity <i>in vitro</i> but activated Rab5-PAS pathway in cells. Furthermore, vicenistatin increased the membrane surface fluidity of cholesterol-containing liposomes <i>in vitro</i>, and cholesterol deprivation from the plasma membrane stimulated vicenistatin-induced vacuolation in cells. These results suggest that vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity.</p> <p>Vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity.</p