Sulfinosine congeners: synthesis and antitumor activity in mice of certain N9-alkylpurines and purine ribonucleosides.
A number of N9-alkyl-substituted purines and purine ribonucleosides have been synthesized as congeners of sulfinosine and evaluated for their antileukemic activity in mice. NaH-mediated alkylation of 6-chloropurine (4) and 2-amino-6-chloropurine (5) with certain alkyl bromides gave N7- and N9-alkylated derivatives (7a-d and 6a-d), the N9-isomer being the major product. Treatment of 6a-d and 7a-d with thiourea furnished the corresponding 6-thio derivatives (9a-d and 8a-d). Amination of 9a-e with aqueous chloramine solution afforded the corresponding purine-6-sulfenamides (10-a-e), which on controlled oxidation with 3-chloroperoxbenzoic acid (MCPBA) gave the respective (R,S)-9-alkylpurine-6-sulfinamides (11a-e). A similar oxidation of 2-amino-6-(methyl/benzylthio)-9-beta-D-ribofuranosylpurine (12a and 12b) and 2-amino-9-(2-deoxy-beta-D-erythro-pentofuranosyl)-6- (methylthio)-purine (12c) with MCPBA gave the corresponding sulfoxides (13a-c), which on further oxidation furnished the respective sulfones (14a-c). Of the 20 compounds evaluated, six exhibited biologically significant anti-L1210 activity in BD2F1 mice and reduced body burdens of viable L1210 cells more than 90-97% by single treatment. Although compounds 9b and 9c at 44 mg and 40 mg/kg per day x 1 showed a T/C of 147 and 149, respectively, this group of compounds was found to be less effective than some of the sulfur-containing drugs that we previously described (e.g. sulfenosine and sulfinosine).
Hanna
N B
NB
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Bhattacharya
B K
BK
Robins
R K
RK
Avery
T L
TL
Revankar
G R
GR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D011684:Purine Nucleosides / Q000737:chemistry* / Q000627:therapeutic use; D011687:Purines / Q000138:chemical synthesis* / Q000627:therapeutic use; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D012995:Solubility
D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D011687:Purines; D012263:Ribonucleosides; C063670:sulfenosine; C063871:sulfinosine