Structure-activity relationship of phosmidosine: importance of the 7,8-dihydro-8-oxoadenosine residue for antitumor activity.
To study the structure-activity relationship of phosmidosine, a variety of phosmidosine derivatives 9a-g were synthesized by condensation of N-diisopropyl N'-(N-tritylprolyl)phosphorodiamidite 6 with appropriately protected nucleoside derivatives 7a-g. As the result, replacement of the 7,8-dihydro-8-oxoadenine base by adenine and 6-N-acetyladenine did not affect the antitumor activity. However, phosmidosine derivatives containing uracil, cytosine, and guanine in place of the 7,8-dihydro-8-oxoadenine base did not show significant activity. A plausible explanation for the selective expression of phosmidosine compared with that of phosmidosine analogs having other amino acids in place of proline is also discussed. These results suggest that phosmidosine serves as an inhibitor of prolyl adenosine 5'-phosphate (prolyl-AMP) to inhibit the peptide synthesis in cancer-related cells.
Sekine
Mitsuo
M
Department of Life Science, Tokyo Institute of Technology, Nagatsuda, Midoriku, Yokohama 226-8501, Japan. msekine@bio.titech.ac.jp <msekine@bio.titech.ac.jp>
Okada
Kazuhisa
K
Seio
Kohji
K
Kakeya
Hideaki
H
Osada
Hiroyuki
H
Sasaki
Takuma
T
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D014176:Protein Biosynthesis / Q000187:drug effects; D011685:Purine Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D011685:Purine Nucleotides; C068885:phosmidosine; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine