Nucleosides and nucleotides. 175. Structural requirements of the sugar moiety for the antitumor activities of new nucleoside antimetabolites, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and -uracil1.
We previously designed 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)uracil (EUrd) and its cytosine congener (ECyd) as potential multifunctional antitumor nucleoside antimetabolites. They showed potent and broad-spectrum antitumor activity against various human and mouse tumor cells in vitro and in vivo. To clarify the structure-activity relationship of the sugar moiety, various 3'-C-carbon-substituted analogues, such as 1-propynyl, 1-butynyl, ethenyl, ethyl, and cyclopropyl derivatives, of ECyd and EUrd were synthesized. We also prepared 3'-deoxy analogues and 3'-homologues of ECyd and EUrd with different configurations to determine the role of the 3'-hydroxyl group and the length between the 3'-carbon atom and the ethynyl group and a 2'-ethynyl derivative of ECyd to determine the spatial requirements of the ethynyl group. The in vitro tumor cell growth inhibitory activities of these nucleosides against mouse leukemic L1210 and human KB cells showed that ECyd and EUrd were the most potent inhibitors in the series, with IC50 values of 0.016 and 0.13 microM for L1210 cells and 0.028 and 0.029 microM for KB cells, respectively. Only 3'-C-1-propynyl and -ethenyl derivatives of ECyd showed greatly reduced cytotoxicity. We found that the cytotoxic activity of these nucleosides predominantly depended on their first phosphorylation by uridine/cytidine kinase.
Hattori
H
H
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Nozawa
E
E
Iino
T
T
Yoshimura
Y
Y
Shuto
S
S
Shimamoto
Y
Y
Nomura
M
M
Fukushima
M
M
Tanaka
M
M
Sasaki
T
T
Matsuda
A
A
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002240:Carbohydrate Sequence; D002455:Cell Division / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007624:KB Cells; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012510:Sarcoma 180 / Q000201:enzymology / Q000473:pathology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014541:Uridine Kinase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D012263:Ribonucleosides; D014498:Uracil; D003596:Cytosine; D014541:Uridine Kinase