Jae-Kyung Jung

Total Synthesis of (+)-Brefeldin A

(+)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol via tandem Li-I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with SmI2, and (4) a 2-methyl-6-nitrobenzoic anhydride-mediated (Shiina) lactonization.

Synthesis and evaluation of antitumor activity of novel 1,4-Naphthoquinone derivatives (IV)

Abstract1,4-Naphthoquinones are widely distributed in nature and many clinically important antitumor drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and saintopin, show excellent anticancer activity. In this study, 2- or 6-substituted 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) and 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) derivatives were synthesized, and their cytotoxic activity against L 1210 and P388 cancer cells was examined. Their antitumor activity was also assessed in mice bearing S-180 cells in the peritoneal cavity. In comparison with the DMNQ derivatives, the DHNQ derivatives exhibited more potent bioactivities than the DMNQ derivatives against both L 1210 and P388 cellsin vitro and S-180 cellsin vivo. The ED50 values of the DHNQ derivatives against P388 cells were in the range of 0.18–1.81 μg/mL whereas those of the DMNQ derivatives were in the range of 0.26–40.41 μg/mL. The T/C (%) values of the DHNQ derivatives,8, 17, 18, 19, and20, were found to be comparable to or even better than that of adriamycin. It was also observed that the 2-substituted derivatives (8, 19, 20) showed better antitumor activity than the 6-substituted derivatives (7, 17, 18) in the mice bearing S-180 cells in the peritoneal cavity.

Nuclear factor-kappa B inhibitors; a patent review (2006 – 2010)

Introduction: Nuclear factor (NF)-κB, as transcription factor, is linked to the expression of various genes and plays an essential role in immune and inflammatory responses. Abnormal NF-κB signaling results in human diseases, such as immune disorders, inflammation and various cancers. Therefore, regulation of NF-κB may treat or improve the symptoms in human disorders. Areas covered: This review provides information on recent NF-κB inhibitor-related patents from 2006 to 2010. The patents are explained and categorized by mechanism. The reader will gain an understanding of NF-κB function and the structure and biological activity of recently developed NF-κB inhibitors that may be new drug candidates. Expert opinion: NF-κB plays an essential role in the human body and thus regulation of NF-κB is very important for the treatment of diseases. Furthermore, patented compounds and peptides are available as lead compounds in drug development studies.

Asymmetric Total Synthesis of Fluvirucinine A1

Diastereoselective vinyl addition to an amide carbonyl group and amide enolate induced aza-Claisen rearrangement are the key steps in the first asymmetric total synthesis of fluvirucinine A(1) (1), the aglycon of fluvirucin A(1). Fluvirucins are a class of macrolactam antibiotics produced by actinomycete strains that show promising biological properties.

Myeloid differentiation 2 as a therapeutic target of inflammatory disorders.

Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, activates the innate immunity system through a receptor complex of myeloid differentiation 2 (MD-2) and toll-like receptor 4 (TLR4). MD-2 directly recognizes the lipid A domain of LPS, which triggers MD-2/TLR4-mediated cellular response aimed at eliminating the invaded pathogen. However, excess production of inflammatory mediators is harmful to host tissue and this can cause septic death in extreme cases. MD-2 represents an attractive therapeutic target of inflammatory and immune diseases in human. In particular, eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site, and it ameliorates various inflammatory conditions due to infection or sterile organ injury. In this review, we outline the recent advances in the structure biology of ligand interaction with MD-2/TLR4, and highlight the MD-2-directed LPS antagonists, which are natural and synthetic chemicals, under development to treat inflammatory diseases.

The versatile conversion of lactams to the α-alkylated azacycles via cyclic N,O-acetal TMS ether

The efficient preparation of the cyclic N,O-acetals from lactams by DIBAL reduction followed by direct trapping of the resulting N,O-hemiacetals using TMSOTf/pyridine system is described. In addition, the facile nucleophilic addition of various carbon nucleophiles at the carbonyl carbons of the lactams through the corresponding N,O-acetals is also reported.

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)-tetrabenazine (1), a drug for the treatment of chorea associated with Huntingtons disease, and of (+)-α-dihydrotetrabenazine (2), an active metabolite of 1, have been accomplished. Our synthetic route features a trans-selective enol etherification, followed by an unprecedented cation-dependent aza-Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)-2 and eight steps (22 % overall yield) for (+)-1.

Synthesis of xanthone derivatives based on α-mangostin and their biological evaluation for anti-cancer agents.

A xanthone-derived natural product, α-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on α-mangostin were synthesized and evaluated as anti-cancer agents by cytotoxicity activity screening using 5 human cancer cell lines. Some of these analogs had potent to moderate inhibitory activities. The structure-activity relationship studies revealed that phenol groups on C3 and C6 are critical to anti-proliferative activity and C4 modification is capable to improve both anti-cancer activity and drug-like properties. Our findings provide new possibilities for further explorations to improve potency.

Pimarane cyclooxygenase 2 (COX-2) inhibitor and its structure-activity relationship.

The structure-activity relationship and molecular modelings of a novel pimarane COX-2 inhibitor are reported. Particularly, a series of linker extended analogues designed on the basis of these studies exhibited significantly enhanced COX-2 inhibitory activities and selectivities.

First total synthesis and structural confirmation of fluvirucinine A2 via an iterative ring expansion strategy.

The first asymmetric total synthesis of fluvirucinine A(2) has been accomplished. A key feature of the synthesis is an iterative lactam ring expansion to provide rapid access to the 14-membered lactam skeleton and three stereogenic centers. The excellent remote control of the three stereogenic centers relied on stereoselective amidoalkylation followed by an amide-enolate-induced aza-Claisen rearrangement. In addition, the structure of fluvirucinine A(2) has been completely elucidated by our total synthesis.