The cytotoxicity of 3'-aminocyanoborane-2', 3'-dideoxypyrimidines in murine and human tissue cultured cell lines.
3'-Aminocyanoborane-2', 3'-dideoxythymidine (VIIa) and 3'-aminocyanoborane-2', 3'-dideoxyuridine (VIIIb) were successfully synthesized. The thymidine derivative (VIIIa) was shown to be a potent cytotoxic agent in murine and selected human suspended and solid tumor cell lines. Compound VIIIa inhibited L-1210 leukemia DNA and RNA synthesis with the protein synthesis requiring a higher concentration of drug for inhibition within 60 min. The purine pathway appeared to be the major target of Compound VIIIa with inhibition of IMP dehydrogenase and dihydrofolate reductase activities. The compound affected metabolic enzyme activities in the pyrimidine pathway as well as the nucleoside kinase activities. The DNA molecule did not appear to be target of the 3'-aminocyanoborane-2', 3'-dideoxythymidine (VIIIa), in that there was no change in ct-DNA viscosity, thermal denaturation or absorption of nucleosides of DNA nor was there any L-1210 DNA strand scission or inhibition of L-1210 DNA topoisomerase II activity when compound VIIIa was incubated at 100 microM.
Burnham
B S
BS
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Chen
S Y
SY
Sood
A
A
Spielvogel
B F
BF
Miller
M C
MC
Hall
I H
IH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity*; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007202:Indicators and Reagents; D007939:Leukemia L1210; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009691:Nucleic Acid Denaturation; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014783:Viscosity
D000970:Antineoplastic Agents; D001896:Boron Compounds; D004273:DNA, Neoplasm; D007202:Indicators and Reagents; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D004250:DNA Topoisomerases, Type II; D013936:Thymidine; D003857:Deoxyuridine