Journal of Medicinal Chemistry p. 8131 - 8144 (2017)
Update date:2022-08-17
Topics:
Okon, Aniekan
Han, Jingjing
Dawadi, Surendra
Demosthenous, Christos
Aldrich, Courtney C.
Gupta, Mamta
Wagner, Carston R.
The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester. We have employed this ProTide strategy for intracellular delivery of a nucleotide antagonist of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated that chemical inhibition of cap-dependent translation results in suppression of c-Myc expression, increased p27 expression, and enhanced chemosensitization to doxorubicin, dexamethasone, and ibrutinib. In addition, the new ProTide strategy was shown to enhance oral bioavailability of the corresponding monoester phosphoramidate.
View MoreHangzhou Neway Chemicals Co., Ltd.
Contact:+86-571-85095566
Address:Room 803, Qinglian Bldg, No 139 Qingchun Road, Hangzhou, Zhejiang China
Zibo Kunran Enterprises Co. LTD
website:http://www.kunranchem.com
Contact:0086 533 5200669
Address:No. 96 Jinjing Avenue, Zibo, Shandong, China
Nanjing Vincero International Trading Co.,Ltd
Contact:8618936897229
Address:NO.68, ZhuShan Road, JiangNing WanDa Plaza, Building E Room 1703
Dongtai Xinyuan Chemical Co., Ltd.
Contact:+86-21-56733000
Address:404F, 99Nong No.117 Zhongtan Rd. Shanghai
Contact:+86-371-86058576
Address:NO.32, Jingsan Road, Zhengzhou, China
Doi:10.1248/cpb.40.705
(1992)Doi:10.1039/c39810000741
(1981)Doi:10.1021/acs.orglett.8b00786
(2018)Doi:10.1039/c1cc15783c
(2012)Doi:10.1007/BF00961478
(1990)Doi:10.1134/S1070428009050261
(2009)