Jae-Hwan Kwak

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.

Synthesis of 7-hydroxy-4-oxo-4H-chromene-and 7-hydroxychroman-2-carboxylic acidN-alkyl amides and their antioxidant activities

A series of 7-hydroxy-4-oxo-4H-chromene- (3a - h) and 7-hydroxychroman-2-carboxylic acid N-alkyl amides (4a - g) were synthesized and their antioxidant activities were evaluated. While compounds 3a - h were less active, compounds 4a - g exhibited more potent inhibition of lipid peroxidation initiated by Fe2+ and ascorbic acid in rat brain homogenates. Among them, 7-hydroxychroman-2-carboxylic acid N-alkylamides (4e - g) bearing nonyl, decyl, and undecyl side chain exhibited 3 times more potent inhibition than trolox (1).

Structure-activity relationship of indoline-2-carboxylic acid N-(substituted)phenylamide derivatives

Chroman derivatives exhibited potent inhibitory activity of NF-kappaB. For SAR, the chroman scaffold was modified with an indoline moiety. A series of indoline-2-carboxylic acid N-(substituted)phenylamide derivatives were synthesized to explore their inhibitory activities of NF-kappaB and they were also evaluated for cytotoxicity against various cancer cell lines. Since intermediates with Boc showed outstanding results, various substituents in place of the Boc group were introduced additionally and these compounds were also evaluated for SAR.

Design and synthesis of 4-O-methylhonokiol analogs as inhibitors of cyclooxygenase-2 (COX-2) and PGF1 production

A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure-activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was oriented towards modification of the potential metabolic soft spots (e.g., phenol and olefin) or by altering the polar surface area via incorporating heterocycles such as isoxazole and triazole. Most of all exhibited the inhibitory effects on COX-2 and PGF(1) production but not macrophage NO production. Especially, aryl carbamates 10 and 11 exhibited more potent inhibitory activity against COX-2 and PGF(1) production.

Concise synthesis of Obovatol: Chemoselective ortho-bromination of phenol and survey of Cu-catalyzed diaryl ether couplings

Concise total synthesis of obovatol (1) was achieved from the commercially available eugenol (5) via linear 4 steps in 40% overall yield. The key features of the synthesis involve the chemoselective orthobromination of phenol in the presence of isolated double bond and the efficient Cu-catalyzed Ullmann coupling of two aromatic moieties for the diaryl ether skeleton.

A novel synthetic compound MCAP suppresses LPS-induced murine microglial activation in vitro via inhibiting NF-kB and p38 MAPK pathways

Aim:To investigate the anti-neuroinflammatory activity of a novel synthetic compound, 7-methylchroman-2-carboxylic acid N-(2-trifluoromethyl) phenylamide (MCAP) against LPS-induced microglial activation in vitro.Methods:Primary mouse microglia and BV2 microglia cells were exposed to LPS (50 or 100 ng/mL). The expression of iNOS and COX-2, proinflammatory cytokines, NF-κB and p38 MAPK signaling molecules were analyzed by RT-PCR, Western blot and ELISA. The morphological changes of microglia and nuclear translocation of NF-ĸB were visualized using phase contrast and fluorescence microscopy, respectively.Results:Pretreatment with MCAP (0.1, 1, 10 μmol/L) dose-dependently inhibited LPS-induced expression of iNOS and COX-2 in BV2 microglia cells. Similar results were obtained in primary microglia pretreated with MCAP (0.1, 0.5 μmol/L). MCAP dose-dependently abated LPS-induced release of TNF-α, IL-6 and IL-1β, and mitigated LPS-induced activation of NF-κB by reducing the phosphorylation of IκBα in BV2 microglia cells. Moreover, MCAP attenuated LPS-induced phosphorylation of p38 MAPK, whereas SB203580, a p38 MAPK inhibitor, significantly potentiated MCAP-caused inhibition on the expression of MEF-2 (a transcription factor downstream of p38 MAPK).Conclusion:MCAP exerts anti-inflammatory effects in murine microglia in vitro by inhibiting the p38 MAPK and NF-κB signaling pathways and proinflammatory responses. MCAP may be developed as a novel agent for treating diseases involving activated microglial cells.

Development of Novel 1,2,3,4-Tetrahydroquinoline Scaffolds as Potent NF-κB Inhibitors and Cytotoxic Agents.

1,2,3,4-Tetrahydroquinolines have been identified as the most potent inhibitors of LPS-induced NF-κB transcriptional activity. To discover new molecules of this class with excellent activities, we designed and synthesized a series of novel derivatives of 1,2,3,4-tetrahydroquinolines (4a-g, 5a-h, 6a-h, and 7a-h) and bioevaluated their in vitro activity against human cancer cell lines (NCI-H23, ACHN, MDA-MB-231, PC-3, NUGC-3, and HCT 15). Among all synthesized scaffolds, 6g exhibited the most potent inhibition (53 times that of a reference compound) of LPS-induced NF-κB transcriptional activity and the most potent cytotoxicity against all evaluated human cancer cell lines.

Synthesis and anti-platelet activity of obovatol derivatives

Obovatol derivatives were synthesized and evaluated for anti-platelet activity. Three derivatives (1, 2, 4i) displayed equipotent activity to obovatol in arachidonic acid-induced platelet aggregation. An initial SAR study revealed that the introduction of alkoxy group in B ring could enhance inhibitory activity.

Synthesis and cytotoxic activities of 2-alkyl-2,3-dihydro-1H-2,6,9-triazacyclopenta[b]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6,9-triazacyclopenta[b]anthracene-5,10-diones (4a-f) were synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, A549, SNB19, MCF7 and MCF7/ADR). A number of compounds including 4c and 4d showed 2–180 times more potent cytotoxic activity than doxorubicin against all human cancer cell lines tested. Furthermore, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors.

Stereoselective synthesis of (E)- and (Z)-enol ethers from β-amino aldehydes

Stereocontrolled methods for the direct and divergent synthesis of the silylenol ethers possessing amino group from β-amino aldehydes have been achieved. These enol ethers with the defined olefin geometry could be key building blocks for the synthesis of the medicinally important compounds.