K K -4 MK-4 MK-4. Steroid and Xenobiotic Receptor (SXR)

HTML
DOWNLOAD

Μέγεθος: px

Εμφάνιση ξεκινά από τη σελίδα:

Download "K K -4 MK-4 MK-4. Steroid and Xenobiotic Receptor (SXR)"

ÍΕρρίκος Αποστόλου
6 χρόνια πριν
Προβολές:

1 K K -4 MK-4 MK-4 K MK-4 K Steroid ad Xeobiotic Receptor (SXR) We focused o vitami K aalogues amog fat-soluble vitamis to explore therapeutic agets for degeerative disease of brai. It has bee clarified that meaquioe-4 (MK-4), oe of the vitami K homologues, is biosythesized i a livig body ad accumulated to the various tissues. MK-4 also protected oligodedrocyte precursors ad immature fetal cortical euros from oxidative ijury, idepedet of the vitami K-depedet γ-carboxylative reactio. Therefore, MK-4 should play a importat role for a livig body, especially i brai. the basis of these fidigs, we evaluated the biological actio of vitami K homologues with chemical techiques usig fluorescet labeled ad deuterated labeled aalogues. Furthermore, we also sythesized ew vitami K aalogues ad evaluated biological activities such as their differetiatio-iducig activity from stem cells to euro ad gee trascriptio through the steroid ad xeobiotic receptor (SXR)

2 A E i vitro K A E K K K K -4 MK-4 Steroid ad Xeobiotic Receptor (SXR) K MK-4 MG-6 K K MK-4 K MG-6 HepG2 48 K LC-APCI-MS/MS MK-4 MK-4 K K 2 ➀ 24 7 ➁ SXR HepG2 SXR-GAL4 CYPA4 K K K K 1 PK (1) K 2 MK- (2) K K

3 K 1 (1) K 2 (2) K K K K 2- -1,4- (5) 7 8 Wittig (11) K (1) FITC FITC-PK () FITC-MK-4 (4) K PK 10 MG-6 FITC 1µM FITC FITC-MK-4 (4) PK K FITC-PK () ER-Tracker Red ER-Tracker Red FITC FITC-PK () K - K HC Et H Ac K 2C, MeI H Me Me Me Na 2S 2 4 MeH, H 2 H Ac Ac 2 pyridie Acetoe HC NaH, Na 2S 2 4 MeH, H 2 Ac H Ac NaH, Na 2S 2 4 MeH-H2 (Et) 2PCH 2C 2Et NaH, THF 11 Me 12 Me 1 H H. K MK-4 MK-4 K PK-d 7 (17) MK-4-d 7 (18) MK ,4--d 8 (K -d 8 ) (19) 10% (20) S HN N H N H CH R H, BF Et 2. K H H Et ioxae, EtAc 15: R 1 14 H 16: R C Na 2 S R C 17: R 1 = R 18: R 2 = CAN H Me H 2, CH CN FITC-PK (): R 1= FITC-MK-4 (4): R 2= H H C TiCl 4, Ci 2CHCH H R CH 2Cl 2 Ac Me Pd/C, H 2 EtH, THF FITC BP reaget, IEA BF Et 2 R H

4 /1,4-(1:1) BF Et 2 60 C K LC-APCI-MS/MS 18 NMR MK MK-4 K MK-4 ➀ K K K 1,4-10% 2 K (21)-(25) 10% Na 2S 2 4 H (THP) 6a 6b 7a 7b K 2 7a 7b 8a 8b 2- -1,4- () (4) 7a 7b Ac 1N NaH aq. H 5a: (=1) 5b: (=2) 9,4-dihydro-2H-pyrae 7a: (=1) 7b: (=2) 8a or 8b BF Et 2 Se 2, tbuh THP. ➁ SXR K -4 SXR SXR SXR-GAL4 (CYPA4 ) SXR-GAL4 MK- 2 Ac PhMgBr THF H : (=1) 4: (=2) 6a: (=1) 6b: (=2) THP 8a: (=1) 8b: (=2) 27 + H BF Et 2 H H -1 BF Et 2 29: = 1 0: = 2 1: = 2: = 4 22: = 1 2: = 2 24: = 25: = SXR-GAL4 (A) CYPA4 (B)

5 Sigificat differeces betwee cotrol group ad each compouds group: ***, p < (by uett s test). Sigificat differeces betwee the MK- group ad the MK--W group: ###, p < 0.001; ##, p < 0.01 (by Studet s t test). (MK-2-H MK-4-H) 4 4 SXR (RIF) K SXR ➀ K ➁ Suhara, Y.; Wataabe, M.; Motoyoshi, S.; Nakagawa, K.; Wada, A.; Takeda, K.; Takahashi, K.; Tokiwa, H.; kao, T. Sythesis of ew vitami K aalogues as steroid ad xeobiotic receptor (SXR) agoists: Isight ito the biological role of the side chai part of vitami K. J. Med. Chem. i press. ➂ Suhara, Y.; Wataabe, M.; Nakagawa, K.; Wada, A.; Ito, Y.; Takeda, K.; Takahashi, K.; kao, T. Sythesis of ovel vitami K 2 aalogues with modificatio at the ω -termial positio ad their biological evaluatio as potet steroid ad xeobiotic receptor (SXR) agoists. J. Med. Chem. i press. SXR-GAL4 (A) CYPA4 (B) Sigificat differece: *, p < 0.05; **, p < 0.01; ##, p < 0.01 (by Studet s t test). ➂ MK-1 MK-2 MK- MK K ➃ Nakagawa, K.; Hirota, Y.; Sawada, N.; Yuge, N.; Wataabe, M.; Uchio, Y.; kuda, N.; Shimomura, Y.; Suhara, Y.; kao, T. Idetificatio of UBIA1 as a ovel huma meaquioe-4 biosythetic ezyme. Nature 468, , ➄ Wada, A.; Wag, F.; Suhara, Y.; Yamao, Y.; kitsu, T.; Nakagawa, K.; kao, T. Efficiet sythesis ad biological evaluatio of demethyl geraylgeraoic acid derivatives. Bioorg. Med. Chem. 18(16), , ➅ Suhara, Y.; Wada, A.; Tachibaa, Y.; Wataabe, M.; Nakamura, K.; Nakagawa, K.; kao, T. Structure-activity relatioships i the coversio of vitami K aalogues ito meaquioe-4. Substrates essetial to the sythesis of meaquioe-4 i cultured huma cell lies. Bioorg. Med. Chem. 18(9), , 2010.

6 ➆ Saito, N.; Suhara, Y.; Abe,.; Kusudo, T.; hta, M.; Yasuda, K.; Sakaki, T.; Hozawa, S.; Fujishima, T.; Kittaka A. Sythesis of 2α-propoxy-1α,25-dihydroxyvitami ad compariso of its metabolism by huma CYP24A1 ad rat CYP24A1. Bioorg. Med. Chem. 17(1), , ➇ Suhara, Y.; Wada, A.; kao, T. Elucidatio of the mechaism producig meaquioe-4 i osteoblastic cells. Bioorg Med Chem Lett. 19(4), , ➈ Suhara, Y.; Abe, S.; Murakami, A.; Shimomura, Y.; Nakagawa, K.; Kamao, M.; Tsugawa, N.; kao, T. Sythesis ad developmet of biologically Active fluorescet-labeled vitami K aalogues ad moitorig of their subcellular distributio. Tetrahedro 64, , ➀ K SXR ➁ K SXR SXR ➆ ➇ ➀ ➂ ➃ SXR K ➄ K ➅ K

Σχετικά έγγραφα

Electrolyzed-Reduced Water as Artificial Hot Spring Water

/-,**- + +/ 0 +, - + + +, - + +. ++,3 +/. +. Electrolyzed-Reduced Water as Artificial Hot Spring Water Shoichi OKOUCHI +, Daisuke TAKEZAKI +, Hideyuki OHNAMI +, Yuhkoh AGISHI,, Yasuo KANROJI -, and Shigeo