Discovery and mechanistic study of thiazole-4-acylsulfonamide derivatives as potent and orally active ChemR23 inhibitors with a long-acting effect in cynomolgus monkeys.

Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that can secrete large amounts of type I interferon. ChemR23, a G protein-coupled receptor (GPCR) expressed on the surface of pDCs, contributes to the recruitment of pDCs to inflamed tissues through chemotaxis signaling, and is therefore considered an attractive target for the treatment of autoimmune diseases. We previously reported benzoxazole-based compounds that can inhibit ChemR23 signaling through receptor internalization.

The design, synthesis and evaluation of 2-aminobenzoxazole analogues as potent and orally efficacious ChemR23 inhibitors.

We previously reported 2-aminobenzoxazole analogue 1 as a potent ChemR23 inhibitor. The compound showed inhibitory activity against chemerin-induced calcium signaling through ChemR23 internalization in CAL-1 cells, which are cell lines of plasmacytoid dendric cells (pDCs). Furthermore, compound 2 inhibited chemotaxis of CAL-1 triggered by chemerin in vitro.

The discovery and optimization of a series of 2-aminobenzoxazole derivatives as ChemR23 inhibitors.

A structural class of 2-aminobenzoxazole derivatives possessing biphenyltetrazole was discovered to be potent human ChemR23 inhibitors. We initially tried to improve the potency of compound 1, which was found through in-house screening using the human plasmacytoid dendritic cell (pDC)-like cell line CAL-1. The introduction of a chiral methyl moiety at a benzylic position in a center of compound 1 showed a large impact on the inhibitory activity against calcium signaling of ChemR23 induced by the natural ligand chemerin.

Nicotinamide phosphoribosyltransferase is a molecular target of potent anticancer agents identified from phenotype-based drug screening.

Phenotypic screening in drug discovery has been revived with the expectation of providing promising lead compounds and drug targets and improving the success rate of drug approval. However, target identification remains a major bottleneck in phenotype-based drug discovery. We identified the lead compounds K542 and K405 with a selective inhibition of cell viability against sphingosine-1-phosphate lyase 1 (SGPL1)-transduced ES-2 cells by phenotypic screening.

The synthesis and evaluation of the antiproliferative activity of deacidified GEX1A analogues.

GEX1A/herboxidiene (1) is a natural product isolated from Streptomyces sp. and has been reported to target the pre-mRNA splicing process. Although 1 was shown to have antitumor activity in vivo, weight loss was observed in mice when 1 was consecutively administered.

Total Synthesis and Biological Evaluation of Irciniastatin A (a.k.a. Psymberin) and Irciniastatin B.

Irciniastatin A (a.k.a.

Eu(OTf)3-catalyzed highly regioselective nucleophilic ring opening of 2,3-epoxy alcohols: an efficient entry to 3-substituted 1,2-diol derivatives.

In our study of the total synthesis of (+)-irciniastatin A, we found a need to develop a method that enables a C3-selective nucleophilic ring opening of 2,3-epoxy alcohol by MeOH, by which we found that the use of combined catalytic amounts of Eu(OTf)3 and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) enables the intended transformation to obtain 3-methoxy-1,2-diol efficiently. Promising features of a protocol that effects a highly regioselective nucleophilic ring opening of 2,3- and 3,4-epoxy alcohols using various nucleophiles including alcohols, thiols, and unprotected amines are described.

Irciniastatin A induces JNK activation that is involved in caspase-8-dependent apoptosis via the mitochondrial pathway.

Irciniastatin A (ISA)/psymberin, a pederin-type natural product isolated from marine sponge, exhibits extremely potent and selective cytotoxicity against certain human cancer cell lines, but its molecular target and cytotoxic mechanisms are still unknown. Here we show that ISA is a potent inhibitor of protein translation, and induces apoptosis accompanied with activation of the stress-activated protein kinases via the mitochondrial pathway in human leukemia Jurkat cells. ISA potently inhibited protein translation, and induced a slow but prolonged activation of the stress-activated protein kinases, JNK and p38, at between 1h and 6h after treatment.

Syntheses and biological evaluation of irciniastatin A and the C1-C2 alkyne analogue.

Syntheses of both natural (+)- and unnatural (-)-irciniastatin A (aka psymberin) as well as a C1-C2 alkyne analogue of (+)-irciniastatin A have been achieved. The key features of the syntheses include a highly regioselective epoxide-opening reaction and a late-stage assembly of C1-C6, C8-C16, and C17-C25 fragments. (+)-Alkymberin retained a high level of cytotoxicity, whereas (-)-irciniastatin A showed almost no activity.