Boron substituted deoxyribonucleosides as cytotoxic agents.
Base substituted boronated nucleosides and phosphate modified nucleotides were examined for their cytotoxic activity in both murine and human tissue cultured cancer cells. These derivatives demonstrated better activity against the growth of single cell suspensions than solid cell tumor cell growth. A detailed mode of action study showed that 2'deoxyriboadenosine-N7-cyanoborane 6 suppressed Tmolt3 DNA synthesis preferentially with the major target of the agent being the purine de novo pathway. The activities of one of the regulatory enzymes of the pathway were reduced by the agents, i.e. PRPP-amido transferase. Other sites in the cell which were moderately affected by the agent were nucleoside kinase activities. DNA polymerase alpha and dihydrofolate reductase activities. The DNA molecule itself did not appear to be a target of the compound.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Elkins
A
A
Sood
A
A
Tomasz
J
J
SpielVogel
B F
BF
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001896:Boron Compounds / Q000737:chemistry / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003853:Deoxyribonucleosides / Q000737:chemistry / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D001896:Boron Compounds; D004273:DNA, Neoplasm; D003853:Deoxyribonucleosides; D011500:Protein Synthesis Inhibitors; D004259:DNA-Directed DNA Polymerase