Journal of Medicinal Chemistry p. 717 - 723 (1990)
Update date:2022-08-05
Topics:
Kumar, Rakesh
Xu, Lihua
Knaus, Edward E.
Wiebe, Leonard I.
Tovell, Dorothy R.
et al.
A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine cpmpounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine (10a), 5-vinyl-2'-fluoro-2'-deoxyuridine (10b), 5-vinyl-uridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b).Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c).In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-β-D-ribofuranosyl)furano<2,3-d>pyrimidin-6(5H)-one (14).The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID50 = 0.1 μg/mL) which exhibited antiviral activity (HSV-1) 100-fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID50 = 0.01 - 0.1 μg/mL range).The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) > CH(OH)CH2I (11a) ca.CH(OH)CH2OMe (13).The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine > 2'-fluoro-2'-deoxyuridine > uridine (11a > 11b <*> 11c; 12a > 12b > 12c).The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 μg/mL), exhibited an activity approaching that of melphalan (ED50 = 0.15 μg/mL).All compounds tested, except for 13 and 14, exhibited high affinity (Ki = 0.035 - 0.22 mM range relative to deoxyuridine, Ki = 0.125) for the murine NBMPR-sensitive erthyrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes.
View MoreSuzhou SuKaiLu Chemical Technology Co., Ltd.
Contact:+86-512-62766020
Address:Floor 4, Building 1, Xinyi Pharmaceutical Valley Wisdom Industrial Park, 415 Changyang Street, Suzhou Industrial Park, Jiangsu Province
Henan PURUI Pharmaceutical Co., Ltd.
website:http://www.puruipharm.com
Contact:17739583555
Address:Yezhuangqiao,Xihua town, Henan province
NingBO Hong Xiang Biochem.Co.Ltd
website:http://www.hxbiochem.com
Contact:0574-66003444
Address:Ning Bo Bei Lun
SuZhou Hua-Emy Chemical Import and Export Co., LTD.
Contact:+86-512-88804994; +86-512-88804550;
Address:710, Building B, International Trade Center, 12 Huanghelu, Changshu, Jiangsu,China
website:http://www.simagchem.com
Contact:+86-592-2680277
Address:21/F Hualong Office Building,No.6 Hubin East Road, Xiamen,China
Doi:10.3987/COM-08-S(D)24
(2009)Doi:10.1016/j.bmcl.2005.05.120
(2005)Doi:10.1134/S1070427208080156
(2008)Doi:10.1021/jm050242f
(2005)Doi:10.1016/j.bmc.2006.01.005
(2006)Doi:10.1002/hlca.19830660131
(1983)