ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Hypoxia/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , DNA, Neoplasm/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , MCF-7 Cells , Models, Molecular , Molecular Structure , Protein Binding/drug effects , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/pharmacology , Solutions , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/metabolism , NADPH Oxidases/metabolism , Sulfonamides/pharmacology , Toll-Like Receptor 4/metabolism , Animals , Apoptosis/drug effects , Brain Ischemia/physiopathology , Case-Control Studies , Cell Death/drug effects , Disease Models, Animal , Female , Humans , Infarction, Middle Cerebral Artery/drug therapy , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred Strains , Middle Aged , NADPH Oxidase 4 , NF-kappa B/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Reperfusion Injury/prevention & control , Signal Transduction/drug effects , Young AdultABSTRACT
[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.
Subject(s)
Lithium/chemistry , Ribose/chemical synthesis , Spiro Compounds/chemical synthesis , Alkynes/chemistry , Cyclization , Diynes/chemistry , Glycosylation , Lactones/chemistry , Molecular Structure , Ribose/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
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.
ABSTRACT
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.
