A new controlled-pore glass (CPG) support is described that allows for the direct synthesis of oligonucleotides bearing a 3'-aminohexyl tail. This solid support (AH-CPG) exhibits superior performance as compared to a commercially available 3'-amine CPG. The AH-CPG is prepared from 6-aminohexan-1-ol with a unique protecting group for the amine that also functions as the site of attachment to the CPG. A 3'-amine-tailed oligodeoxynucleotide (ODN) was prepared from this support using standard phosphoramidite coupling and deprotection conditions. The 3'-amine-tailed ODN was subsequently modified with an acridinylpropionic acid tetrafluorophenyl ester. Facile synthesis of the AH-CPG and the stability of the deprotected product makes this functionalized solid support especially useful for preparation of oligonucleotides bearing 3'-amine tails and other modifications.
The total synthesis of clitocine [6-amino-5-nitro-4-(beta-D-ribofuranosylamino)pyrimidine] (1), a nucleoside recently isolated from the mushroom Clitocybe inversa, has been accomplished. Glycosylation of 4,6-diamino-5-nitropyrimidine (4) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose afforded the protected nucleoside 6-amino-5-nitro-4-[(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl) amino]pyrimidine (5) in good yield exclusively as the beta-anomer. Deprotection of 5 with NaOMe/MeOH gave 1 as an 11.5:1 mixture of the beta- and alpha-anomers, respectively. Recrystallization from MeOH, followed by chromatography, afforded 1 containing less than 1% of its alpha-anomer. X-ray crystal data revealed a planar aglycon moiety in clitocine with each oxygen atom of the nitro group intramolecularly hydrogen bonded to the hydrogen atoms of the two adjacent amino functions. Clitocine inhibited L1210 cells in vitro with an ID50 of 3 X 10(-8) M. Clitocine was also found to be a substrate and inhibitor of adenosine kinase with a Ki value of 3 X 10(-6) M.
A number of 3,4-disubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides were synthesized and tested for their biological activity. Glycosylation of persilylated as well as nonsilylated 3-bromoallopurinol with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4) provided the key intermediate 3-bromo-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-pyrazolo[3,4-d] pyrimidin-4(5H)-one (5a). Similar glycosylations of 3-cyanoallopurinol and 3-(methylthio)allopurinol furnished the corresponding protected N-1 glycosyl derivatives (5b and 5c). Debenzoylation of these nucleosides (5a-c) gave the corresponding 3-bromo-, 3-cyano-, and 3-(methylthio)allopurinol nucleosides (6a-c). The site of glycosylation and anomeric configuration of 6a and 6c were assigned on the basis of spectral studies as well as conversion to allopurinol ribonucleoside, whereas the structural assignment of 6b was made by single-crystal X-ray analysis. Conventional functional group transformation of 5a and 5b provided a number of novel 3-substituted allopurinol nucleosides, which included 10a and 18a-d. Glycosylation of 4-amino-3-bromopyrazolo[3,4-d]pyrimidine (14) with 4 and subsequent debenzoylation gave 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine ribonucleoside (13a) from which 3,4-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidine (13b) was obtained by amination. Thiation of 5b, followed by deblocking, gave 3-cyanothiopurinol ribonucleoside (20). All of these compounds were tested in vitro against certain viruses, tumor cells, and the parasite Leishmania tropica. Among the 3-substituted allopurinol nucleosides, 18b and 18c showed significant activity against Para 3 virus and were found to be potent inhibitors of growth of L1210 and P388 leukemia. Compound 20 exhibited the most significant broad-spectrum in vitro antiviral and antitumor activity. 3-Bromoallopurinol ribonucleoside (6a) was found to be more active than allopurinol ribonucleoside against Leishmania tropica within human macrophages in vitro.
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