Solution-phase synthesis and biological evaluation of triostin A and its analogues.

Triostin A is a biosynthetic precursor of echinomycin which is one of the most potent hypoxia inducible factor 1 (HIF-1) inhibitors. An improved solution-phase synthesis of triostin A on a preparative scale has been achieved in 17.5% total yield in 13 steps. New analogues of triostin A with various aromatic chromophores, oxidized intra-peptide disulfide bridges and diastereoisomeric cyclic depsipeptide cores were also successfully synthesized. All analogues had a significant inhibitory effect on HIF-1 transcriptional activation in hypoxia and cytotoxicity on MCF-7 cells, with the exception of the derivatives containing a naphthalene chromophore or a thiosulfonate bridge. For the first time, triostin A, echinomycin and the thiosulfinate analogue of triostin A have been revealed to inhibit not only DNA binding of HIF-1 but also HIF-1α protein accumulation in MCF-7 cells. Furthermore, the thiosulfinate analogue and triostin A exhibited a hypoxia-selective cytotoxicity on MCF-7 cells. The improved solution-phase synthetic procedure described herein will contribute to the development of diverse bicyclic depsipeptide drug candidates with the potential to act as novel anti-cancer agents targeting hypoxic tumor microenvironments.

Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia.

Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 µg) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.

Synthesis of spirocyclic C-arylribosides via cyclotrimerization.

[reaction: see text] Spirocyclic C-arylribosides were synthesized from the known gamma-ribonolactone derivative. Lithium acetylide addition followed by glycosylation with 3-(trimethylsilyl)propargyl alcohol converted the ribonolactone to silylated diynes. After desilylation or iodination, subsequent ruthenium-catalyzed cycloaddition of resultant diynes with alkynes or chloroacetonitrile gave spirocyclic C-arylribosides.

Synthesis of bicyclic p-diiodobenzenes via silver-catalyzed Csp-H iodination and ruthenium-catalyzed cycloaddition.

Highly substituted iodobenzenes were efficiently and regioselectively synthesized from readily available 1,6-diynes via two-step process consisting of silver-catalyzed Csp-H iodination and subsequent ruthenium-catalyzed [2 + 2 + 2] cycloaddition of resultant iododiynes. Some of the obtained iodobenzenes were subjected to palladium-catalyzed C-C bond-forming reactions such as Mizoroki-Heck reaction, Sonogashira reaction, and Suzuki-Miyaura coupling, giving highly conjugated molecules.

Synthesis of bi- and tricyclic arylboronates via Cp*RuCl-catalyzed cycloaddition of alpha,omega-diynes with ethynylboronate.

In the presence of 5-10 mol% Cp*RuCl(cod), 1,6- and 1,7-diynes were allowed to react with an ethynylboronate at ambient temperature to give rise to bi- and tricyclic arylboronates in 64-93% isolated yields.