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Synthesis and Biological Evaluation of Iodinated and Fluorinated 9-(2-Hydroxypropyl) and 9-(2-Hydroxyethoxy)methyl Purine Nucleoside Analogues

Authors :
Prekupec, S.
Svedruzic, D.
Gazivoda, T.
Mrvos-Sermek, D.
Nagl, A.
Grdisa, M.
Pavelic, K.
Balzarini, J.
Clercq, E. De
Folkers, G.
Scapozza, L.
Mintas, M.
Raic-Malic, S.
Source :
Journal of Medicinal Chemistry; December 2003, Vol. 46 Issue: 26 p5763-5772, 10p
Publication Year :
2003

Abstract

The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (<BO>1a</BO><BO>−</BO><BO>7a </BO>and <BO>9a</BO><BO>−</BO><BO>13a</BO>) and 9-(2-hydroxyethoxymethyl) (<BO>1b</BO><BO>−</BO><BO>3b, 5b</BO>, and <BO>7b</BO><BO>−</BO><BO>12c</BO>) side chains were synthesized by a multistep synthetic route involving Baltz−Schiemann's fluorination and diazotation/iodination as key reactions. An unequivocal proof for the stereostructure of <BO>5b</BO> was obtained by X-ray structure analysis. New compounds were evaluated for their cytostatic activity against murine leukemia (L1210); mammary carcinoma (FM3A); and human T-lymphocytes (Molt4/C8 and CEM), melanoma (HBL), cervical carcinoma (HeLa), colon carcinoma (HT29 and SW620), laryngeal carcinoma (Hep2), and pancreatic carcinoma (MiaPaCa2) as well as diploid fibroblasts (WI38). Of all the compounds, the 2-aminopurin-6-thione derivative <BO>9a </BO>showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative <BO>9b</BO> exhibited the most selective inhibitory activity against human HeLa, Hep2, SW620, and murine L1210 cell proliferation as compared to normal fibroblast (WI38) cell proliferation. None of the compounds showed inhibitory activities against HIV-1, HIV-2, HSV-1, and HSV-2, vaccinia, vesicular stomatitis, parainfluenza-3, reovirus-1, Sindbis, Coxsackie B4, or respiratory syncytial virus. The new purine derivatives, and particularly <BO>9a </BO>and <BO>9b</BO>, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.

Details

Language :
English
ISSN :
00222623 and 15204804
Volume :
46
Issue :
26
Database :
Supplemental Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Periodical
Accession number :
ejs5502818