Young Taek Han

Design, Synthesis, and Biological Evaluation of Novel Deguelin-Based Heat Shock Protein 90 (HSP90) Inhibitors Targeting Proliferation and Angiogenesis

Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).

Ligand-Based Design, Synthesis, and Biological Evaluation of 2-Aminopyrimidines, a Novel Series of Receptor for Advanced Glycation End Products (RAGE) Inhibitors

Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis(4-chlorophenyl)pyrimidine analogs, 59, significantly lowered the concentration of toxic soluble Aβ in the brain and improved cognitive function. SPR analysis confirmed the direct binding of 59 with RAGE, which should contribute to its biological activities via inhibition of the RAGE-Aβ interaction. We also predicted the binding mode of the 4,6-bis(4-chlorophenyl)pyrimidine analogs to the RAGE V-domain through flexible docking study.

Asymmetric syntheses of 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine.

Asymmetric syntheses of both 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate.

Diastereoselective Total Synthesis of (−)-Galiellalactone

An enantioselective total synthesis of (-)-galiellalactone has been accomplished. The key features of the synthesis involve the highly stereoselective construction of the cis-trisubstituted cyclopentane intermediate by a Pd(0)-catalyzed cyclization, the stereospecific introduction of an angular hydroxyl group by Riley oxidation, and the efficient construction of the tricyclic system of (-)-galiellalactone via a combination of diastereoselective Hosomi-Sakurai crotylation and ring-closing metathesis (RCM).

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis.

Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review specifically examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of α-amino acid templates in natural product synthesis research and related areas.

Synthesis of the Proposed Structure of Damaurone D and Evaluation of Its Anti-inflammatory Activity

Concise and efficient synthesis of the proposed structure of damaurone D is accomplished in five steps without protection-deprotection operations. The key feature of our synthesis includes a versatile aldol reaction of the benzofuranone, provided by selective α-halogenation and intramolecular O-alkylation. However, the H- and C-NMR spectral data of the synthesized damaurone D did not agree with previous reports. The structure of the synthesized damaurone D was confirmed using combined two dimensional (2D)-NMR analysis, including heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC), and nuclear Overhauser effect spectroscopy (NOESY). The synthesized damaurone D was found to exhibit potent anti-inflammatory activity in murine macrophage RAW264.7 cells, which was demonstrated by the findings that damaurone D treatment in cells resulted in the inhibition of lipopolysaccharide (LPS)-stimulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and nitrite production.

A versatile synthetic approach to grandisol monoterpene pheromone

A versatile and efficient synthetic procedure for the grandisol pheromone library has been established. The key feature of our synthesis involves a versatile and highly regioselective Pd(0)-catalyzed intramolecular allylic alkylation for the key cyclobutane skeleton of grandisol. In this connection, the concise synthesis of (±)-grandisol as well as mechanism study of Pd(0)-catalyzed regioselective cyclization as a key reaction have also been accomplished.

Studies on the Synthesis of Indothiazinone and Its Derivatives via Direct 3-Acylation of Indole

Abstract Indothiazinone is a natural 3-acylindole alkaloid, isolated from a culture of myxobacterial strain. It was found to possess antibacterial activity against yeast and filamentous fungi. Indothiazinone is also structurally related with a mammalian endogenous aryl hydrocarbon receptor ligand, (2-(1′H-indole-3′-carbonyl)thiazol-4-carboxylic acid methyl ester (ITE). In this article, the synthesis of indothiazinone has been disclosed for the first time. Key feature includes direct and selective 3-acylation of indole in the presence of Lewis acid. In addition, an efficient preparation of N-substituted indothiazinone derivatives has been demonstrated. GRAPHICAL ABSTRACT

Stereoselective synthesis of 7-epi-incarvilline.

The enantioselective synthesis of 7-epi-incarvilline for formal syntheses of (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine is described. The key features of our synthesis involve (1) stereoselective construction of the optically active bicyclic lactone utilizing Pd(0)-catalyzed allylic alkylation, (2) efficient transformation of the bridged bicyclic lactone to the key bicyclic lactam skeleton, and (3) stereoselective elaborations of two stereocenters via a substrate-controlled catalytic hydrogenation and a 1,4-addition.

Heterocycle‐linked Phenylbenzyl Amides as Novel TRPV1 Antagonists and Their TRPV1 Binding Modes: Constraint‐Induced Enhancement of In Vitro and In Vivo Activities

A series of heterocycle-linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan-linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model.