Structure Confirmation of Dechlorotrichotoxin A through Stereoselective Total Synthesis.

The stereoselective total synthesis of dechlorotrichotoxin A, alongside the synthesis of a 1:1 10E/Z mixture of trichotoxin A, was successfully achieved, commencing from the natural monoterpenoid (-)-citronellal. Key steps in the synthesis involved introducing three alkenes and establishing a stereogenic secondary alcohol center. These transformations were accomplished through olefin cross-metathesis, Tebbe olefination, and enantioselective allylation using a chiral phosphoric acid. A comparison of the spectroscopic data between the synthetic dechlorotrichotoxin A and the reported spectra confirmed that the polyketide isolated from a Smenospongia species corresponds to trichotoxin A rather than dechlorotrichotoxin A.

Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol.

6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities. In this study, structural modification moved beyond side chains on the C(6)-position and reached to pyridine ring itself. It expedited us to synthesize diverse ring-modified analogues of a representative pyridine-3-ol, 6-acetamido-2,4,5-trimethylpyridin-3-ol (9). In the evaluation of compounds on their inhibitory actions against TNF-α-induced adhesion of monocytic cells to colonic epithelial cells, an in vitro model mimicking colon inflammation, the effects of compounds 9, 17, and 19 were greater than tofacitinib, an orally available anti-colitis drug, and compound 17 showed the greatest activity. In addition, TNF-α-induced angiogenesis, which permits more inflammatory cell migration into inflamed tissues, was significantly blocked by compounds 17 and 19 in a concentration-dependent manner. In the comparison of in vivo therapeutic effects of compounds 9, 17, and 19 on dextran sulfate sodium (DSS)-induced colitis in mice, compound 17 was the most potent and efficacious, and compound 19 was better than compound 9 which showed a similar degree of inhibitory effect to tofacitinib. Taken together, it seems that either the trimethyl system or the hydroxyl group on the pyridinol ring is essential to the activity. This finding might become a new milestone in the development of pyridinol-based anti-inflammatory bowel disease agents.

Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells.

Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17-28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 µM concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17-28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17-28 may be a lead compound to develop AMD therapeutics.

Antitumor effect of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole down-regulating the Gas6-Axl axis.

In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 compounds, compound 6-15, with a quinoline moiety, showed cytotoxic IC50 values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFRß, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 -3000-fold weaker than that of sunitinib. Interestingly, compound 6-15 exerted a 3.6-fold stronger cytotoxicity than sunitinib in the gemcitabine-resistant PANC-1 cell line and significantly inhibited Axl, which was in contrast with the effect of sunitinib. Nonetheless, both compounds suppressed the expression of growth arrest-specific 6 (Gas6), the ligand of Axl. The inhibitory effect of compound 6-15 on the Gas6-Axl axis was similar to that of Gas6 knockdown by siRNA in PANC-1 cells in terms of apoptosis induction, increase in Bax/Bcl-2 ratio, Axl down-regulation, and PI3K/Akt inhibition. The inhibitory effect of compound 6-15 on tumor growth in mouse tumor models with A549 and PANC-1 xenografts was much greater than that of cisplatin or gemcitabine. Taken together, the current findings demonstrate that compound 6-15 is a promising anticancer drug candidate that acts by inhibiting the Gas6-Axl axis.