Synthesis, antiproliferative, and antiviral activity of certain 4-substituted and 4,5-disubstituted 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidines.
The sodium salts of 4-chloro- and several 4-chloro-5-substituted-7H-pyrrolo[2,3-d]pyrimidines were treated with [1,3-bis(benzyloxy)-2-propoxy]methyl chloride (6) to provide the corresponding 4-chloro- and 4-chloro-5-substituted-7-[[1,3-bis(benzyloxy)-2-propoxy]methyl]pyrrolo [2,3-d]pyrimidines (7-11). Debenzylation with boron trichloride at -78 degrees C furnished 4-chloro- and several 4-chloro-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (12.16). Subsequent amination of 12-16 yielded the 4-amino-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (17-21). Treatment of 14 with methylamine and 13 and 14 with ethylamine yielded the 4-(alkylamino)-5-halo-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidines (22-24). Treatment of 12-15 with hydroxylamine in refluxing 2-propanol yielded the 5-substituted-4-(hydroxyamino)-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrol o [2,3-d]pyrimidines (25-28). Treatment of compound 12 with Pd/C under a hydrogen atmosphere has furnished the nebularine analogue 31. The antiproliferative activity of compounds 17-28 and 31 was studied using L1210 cells in vitro. The 4-amino- and 4-(hydroxyamino)-5-halogenated derivatives (compounds 18-20, 26-28) inhibited cell growth. Although the effect of compounds 18-20 and 27 on final growth rate was pronounced (IC50 = 2.3, 0.7, 2.8, and 3.7 microM, respectively), cells underwent at least one doubling before cell division stopped. The remaining compounds were less cytotoxic, with IC50's greater than 30 microM for 21, 23, 26, and 28, whereas no inhibition of L1210 cell growth was observed with compounds 17, 22, 24, 25, and 31 at 100 microM. The antiviral activity of these compounds also was tested. Compounds 18-20 and 26-28 were active against human cytomegalovirus and herpes simplex type 1. The 4-amino derivatives (18-20) were more active than the 4-hydroxyamino derivatives (26-28), the 4-amino-5-bromo and 4-amino-5-iodo derivatives produced more than five log reductions in virus titer at concentrations of 10-100 microM. Although some cytotoxicity was observed at these concentrations, compound 19 was active against murine cytomegalovirus in vivo. At 5.6 mg/kg, 14/15 animals survived compared to 10/15 treated with 5.6 mg/kg of ganciclovir or 1/15 treated with placebo.
Pudlo
J S
JS
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Nassiri
M R
MR
Kern
E R
ER
Wotring
L L
LL
Drach
J C
JC
Townsend
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development; D003586:Cytomegalovirus Infections / Q000188:drug therapy; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007624:KB Cells; D007939:Leukemia L1210; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D018139:Simplexvirus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007202:Indicators and Reagents; D011743:Pyrimidines; D011758:Pyrroles