Eul Kgun Yum

A facile synthesis of 2,3-disubstituted pyrrolo[2,3-b]pyridines via palladium-catalyzed heteroannulation with internal alkynes

2,3-Disubstituted pyrrolo[2,3-b]pyridines were synthesized by palladium-catalyzed heteroannulation of 2-amino-3-iodopyridine derivatives and internal alkynes with Pd(OAc)2, LiCl, and KOAc in DMF. The 2-trimethylsilyl-3-methylpyrrolo[2,3-b]pyridine was transformed to 2-substituted-3-methylpyrrolo[2,3-b]pyridines.

Palladium-catalyzed functionalization of 5- and 7-azaindoles

Abstract Palladium-catalyzed functionalization at the 2-position of various 5- and 7-azaindoles was performed by Suzuki, Heck, and Stille reactions. The 2-substituted azaindoles were obtained with 5% Pd(OAc) 2 , LiCl, and KOAc in DMF at 110°C with moderate to high yields.

Synthesis of 1,2,3-trisubstituted pyrrolo[3,2-c]quinolines via palladium-catalyzed heteroannulation with internal alkynes

Abstract Various 1,2,3-trisubstituted pyrrolo[3,2- c ]quinolines were synthesized by palladium-catalyzed heteroannulation of 4-amino-3-iodoquinoline derivatives and internal alkynes. The 1,2,3-trisubstituted pyrrolo[3,2- c ]quinolines could be further transformed by desilylation, debenzylation, or substitution.

Synthesis and Biological Evaluation of N‐aryl‐4‐aryl‐1,3‐Thiazole‐2‐Amine Derivatives as Direct 5‐Lipoxygenase Inhibitors

Biological evaluation of N‐aryl‐4‐aryl‐1,3‐thiazole‐2‐amine derivatives was examined for anti‐inflammatory activity in in vitro and in vivo assays. The thiazole compounds showed direct inhibition of 5‐lipoxygenase (LOX) that is a key enzyme of leukotrienes synthesis and involved in the inflammation‐related diseases, including asthma and rheumatoid arthritis. To optimize biological activity, we synthesized 1,3‐thiazole‐2‐amine derivatives and investigated for structure and activity relationship. Especially, N‐(3,5‐dimethylphenyl)‐4‐(4‐chlorophenyl)‐1,3‐thiazole‐2‐amine was shown to have a potent anti‐inflammatory activity as a 5‐LOX inhibitor.

Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors

A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 μM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 μM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs.

Synthesis and pharmacological profile of 1-aryl-3-substituted pyrrolo[3,2-c]quinolines

A series of 1-aryl-3-substituted pyrrolo[3,2-c]quinolines were synthesized and evaluated for their anti-ulcer activity. While 3-substituents of pyrrolo[3,2-c]quinolines mostly affected the in vitro H+/K+ ATPase activity, 1-aryl substituents of pyrrolo[3,2-c]quinolines affected the in vivo gastric acid secretion. In addition, the compounds with good in vivo activity protected from ethanol-induced ulcer.

Synthesis and Biological Evaluation of N-Aryl-5-aryloxazol-2-amine Derivatives as 5-Lipoxygenase Inhibitors

We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2-amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders.

Effects of newly synthesized benzimidazole derivatives on gastric H+/K+ ATPase

The effects of various synthetic benzimidazole derivatives on gastric H+/K+ ATPase activityin vitro were examined. The results showed that the effects of substituents on the benzimidazole ring were not significant. However, replacement of sulfoxide connecting two ring systems to sulfide resulted in a completely inactive compoundin vitro, suggesting the essential role of sulfoxide group in the inhibition. In addition, compounds with 5 or 6-membered oxacyclic substituents attached to the pyridine ring displayed the most effective inhibitory activity. Among these derivatives, AU-47 was the most potent, and detailed mechanistic studies with the compound were carried out. AU-47 inhibited gastric H+/K+ ATPase in a concentration and time dependent manner with 50% inhibition at 6 μM. The presence of sulfhydryl reducing agents or substrate analogue protected H+/K+ ATPase from the inactivation. The inhibition by AU-47 was potentiated by acid pretreatment of the compound, suggesting the structural conversion of AU-47 into a more active intermediate which was favored in acidic condition. Consistent within vitro results, AU-47 inhibitedin vivo gastric acid secretion. The results suggest that AU-47 is a relevant candidate for the development of new antiulcer agent.