Misc

Fuligocandin A (1) and B (2) are novel natural cycloanthranilylproline derivatives isolated from Fuligo candida. We found the ability of 2 to overcome TRAIL-resistance of cancer cells. Enatiometically pure Fuligocandin B (2) and its derivative 5'-I Fuligocandin B (9) were synthesized, and the latter had an improved TRAIL-resistance overcoming activity against AGS cells. A biotin probe of 9 that had a photo-activatable aryl diazirine group was synthesized, and a pull-down assay revealed that Valosin-containing protein (VCP/p97), an AAA+ ATPase, was a target protein of 9. Knock-down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, 9 enhanced ubiqutination of proteins and CHOP expression, which was a regulator of DR5. These data suggest that ER stress caused by VCP inhibition by 9 increases CHOP-mediated DR5 up regulation, which enhances TRAIL induced cell death. To the best of our knowledge, this is the first experimental data linking VCP and TRAIL-resistance overcoming activity in cancer cells.

We are interested in a diverse compounds library based on natural products and searching for useful small molecules. Heterocyclic-substituted chromones and flavonoids would be expected to have important bioactivity related with some disease.4'-Benzyloxy-2'-hydroxyacetophenone reacted with various pyridinecarboxaldehydes or benzaldehydes to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde to give various heterocyclic substituted chromones or flavonoids.On solid-phase synthesis, we can achieve these reactions under similar conditions of liquid-phase.For more diversity, Suzuki-Miyaura cross coupling progressed on both aromatic units.Some of synthesized compounds showed the inhibition of GLI-mediated transcription, cytotoxicity against some cancer cells and promoted differentiation of neural stem cell.

We describe the one-pot synthesis by Michael-aldol reaction of chromone and flavonoid derivatives bearing pyridine units. 4'-Benzyloxy-2'-hydroxyacetophenone (1) reacted with various pyridinecarboxaldehyde (2) to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde. The endo 2,3-disubstituted chromones were obtained in one step as the only or major product. Furthermore, use of substituted benzaldehydes (Aldehyde A) and subsequent addition of 2 (Aldehyde B) gave 3-pyridyl-substituted flavones. Some of synthesized compounds showed the inhibition of GLI-mediated transcription, and cell growth inhibitory activity against HeLa cells.