Synthesis and biological activity of certain 4'-thio-D-arabinofuranosylpurine nucleosides.
A series of 4'-thio-D-arabinofuranosylpurine nucleosides was prepared and evaluated as potential anticancer agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained through an X-ray crystal structure of 9alpha as well as through NOE experiments on 9beta and 9alpha. All six target compounds were evaluated in a series of human cancer cell lines in culture. Two target compounds, beta anomers with diaminopurine (12) and guanine (16) as the bases, had significant cytotoxicity. One of these compounds (12) was selected for animal studies but was found to have no selectivity at the maximum tolerated dose in the murine colon 36 tumor model.
Secrist
J A
JA
Section of Biochemistry, Molecular and Cell Biology, Biotechnology Building, Cornell University, Ithaca, New York 14855, USA.
Tiwari
K N
KN
Shortnacy-Fowler
A T
AT
Messini
L
L
Riordan
J M
JM
Montgomery
J A
JA
Meyers
S C
SC
Ealick
S E
SE
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C114813:2-chloro-9-(4-thioarabinofuranosyl)adenine; D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D000241:Adenosine