Journal of Medicinal Chemistry p. 407 - 415 (1990)
Update date:2022-07-31
Topics:
Nagahara
Anderson
Kini
Dalley
Larson
Smee
Jin
Sharma
Jolley
Robins
Cottam
Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (7, guanosine analogue), 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H)-trione (8, xanthosine analogue), 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the β-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoreactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.
View MoreJintan City Mego Chemical Co., Ltd
Contact:+86-0519-82814387
Address:23# Dengguan Town, Jintan, Jiangsu Province, China
Contact:+1-973-357-0577
Address:10 Taft Rd.
Contact:+86-10-59484199
Address:No.58-A1026 Liangguan Street
Shanghai ZaiQi Bio-Tech Co., Ltd.,
Contact:+86-21-6722 0633
Address:Bldg. No.7, No.201 MinYi Rd,Songjiang CaoHeJing High-Tech Park Shanghai 201516 P,R,China
Changzhou Medi-tech Bioscientific Co., Ltd.
Contact:86-519-83246372
Address:Number 115 Menghedadao Road, Changzhou, Jiangsu, China
Doi:10.1016/j.tetlet.2005.08.156
(2005)Doi:10.1016/0040-4039(93)88069-U
(1993)Doi:10.1021/om100249s
(2010)Doi:10.1016/j.cclet.2009.07.011
(2010)Doi:10.1016/S0040-4039(00)74548-5
(1980)Doi:10.1002/ejoc.201200382
(2012)