Studies on the synthesis of compounds related to adenosine 3',5'-cyclic phosphate. IX. Synthesis and cytotoxic effect of adenosine 3',5'-cyclic alkylphosphoramidates.
A series of adenosine 3',5'-cyclic monophosphoramidates (3, cAMP amidates), including long-chain alkyl amidates, were synthesized from adenosine 3',5'-cyclic monophosphate (1, cAMP) by means of a one-pot reaction. This reaction proceeded by the treatment of cAMP tributylammonium salt (2) with phosphorus pentachloride (PCl5) and alkylamine in N,N-dimethylformamide (DMF). Compounds 3 synthesized were investigated to determine their cytotoxic activities on the growth of mouse mastocytoma P-815 cells, mouse mammary tumor FM3A cells, and human mammary tumor ZR-75 cells in culture. It was found that compounds 3h-m showed significant cytotoxic activities against these cell lines, and that cAMP decylamidate (3j) was the most cytotoxic compound (the concentration required for 50% inhibition of cell growth, ID50 = 6.0, 15.0, 2.2 microM, respectively); the antitumor effect on P-815 cells by a total packed cell volume method showed 81.8% inhibition. The cytotoxic activity of 3 increased with the increase in alkyl chain length up to 10 carbon atoms and decreased in compounds having longer alkyl chain.
Saito
M
M
Noda Institute for Scientific Research, Chiba, Japan.
Kataoka
S
S
Nasu
A
A
Yamaji
N
N
Ichikawa
A
A
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D000249:Adenosine Monophosphate