Takahiro Soeta

Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.

Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines.

A strategy for exo and enantioselective 1,3-dipolar cycloaddition of azomethine imines to 2-acryloyl-3-pyrazolidinone is described. The corresponding cycloadducts are isolated with high diastereoselectivities (up to >96:4 exo/endo) and enantioselectivities (up to 98% ee).

Structure-Based Design, Synthesis, and Characterization of Dual Hotspot Small-Molecule HIV-1 Entry Inhibitors.

Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4-negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction.

Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening.

The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity.

O-silylative Passerini reaction: a new one-pot synthesis of α-siloxyamides.

A new method for the highly effective synthesis of α-siloxyamides is described. The addition of isocyanide to aldehyde proceeded smoothly in the presence of silanol to give the corresponding α-siloxyamides in high yields. A wide range of aldehydes and isocyanides are applicable in this reaction.

Nitrile Ylides: Diastereoselective Cycloadditions using Chiral Oxzolidinones Without Lewis Acid

Lewis acid complexation is generally required for chiral-auxiliary-controlled stereoselectivity, and chiral Lewis acid catalysis is frequently optimal for introducing asymmetry. In this work, we show that nitrile ylide cycloadditions to electron-poor acceptors attached to chiral auxiliaries proceed in high yield and stereoselectivity in the absence of Lewis acids. In contrast, chiral Lewis acids are inferior in these cycloadditions.

A One‐Pot O‐Phosphinative Passerini/Pudovik Reaction: Efficient Synthesis of Highly Functionalized α‐(Phosphinyloxy)amide Derivatives

A one-pot O-phosphinative Passerini/Pudovik reaction has been developed, based on reacting aldehydes, isocyanides, and phosphinic acids followed by the addition of second aldehydes to form the corresponding α-(phosphinyloxy)amide derivatives. This is the first reported instance of a Passerini-type, isocyanide-based multicomponent reaction using a phosphinic acid instead of a carboxylic acid. The nucleophilicity of the phosphinate group allows a subsequent catalytic Pudovik-type reaction, affording the highly functionalized α-(phosphinyloxy)amide derivative in high yield. A wide range of aldehydes and isocyanides are applicable to this reaction.

One‐Pot Stereoselective Synthesis of 2‐Acylaziridines and 2‐Acylpyrrolidines from N‐(Propargylic)hydroxylamines

The stereoselective direct transformation of N-(propargylic)hydroxylamines into cis-2-acylaziridines was achieved by the combined use of AgBF4 and CuCl. Copper salts were found to promote the transformation of the intermediary 4-isoxazolines into 2-acylaziridines and both 3-aryl- and 3-alkyl-substituted 2-acylaziridines could be prepared by using this method. Furthermore, subsequent 1,3-dipolar cycloaddition of azomethine ylides that were generated in situ from the intermediary 2-acylaziridines with maleimides was achieved in a stereoselective one-pot procedure to afford the corresponding 2-acylpyrrolidines, which consisted of an octahydropyrrolo[3,4-c]pyrrole skeleton.

Chlorosilane-promoted addition reaction of isocyanides to 3,4-dihydroisoquinoline N-oxides.

The addition reaction of isocyanides to 3,4-dihydroisoquinoline N-oxides in the presence of TMSCl has been demonstrated, with the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxylamides being obtained in moderate to high yields. A wide range of 3,4-dihydroisoquinoline N-oxides and isocyanides were applicable to this reaction.

A one-pot O-sulfinative Passerini/oxidation reaction: synthesis of α-(sulfonyloxy)amide derivatives.

We have developed a one-pot O-sulfinative Passerini/oxidation reaction, in which a combination of an aldehyde, an isocyanide, and a sulfinic acid react, followed by the addition of mCPBA as an oxidant to give the corresponding α-(sulfonyloxy)amides in high yields. This reaction is the first reported demonstration of an isocyanide-based multicomponent reaction using a sulfinic acid in place of a carboxylic acid. A wide range of aldehydes and isocyanides are applicable to this reaction.