Synthesis and biological evaluation of iodinated and fluorinated 9-(2-hydroxypropyl) and 9-(2-hydroxyethoxy)methyl purine nucleoside analogues.

Abstract

The novel fluorinated and iodinated purine derivatives containing 9-(2-hydroxypropyl) (1a-7a and 9a-13a) and 9-(2-hydroxyethoxymethyl) (1b-3b, 5b, and 7b-12c) 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 5b 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 9a showed the most pronounced inhibitory activity against human SW620 cells. The 2-aminopurin-6-thione derivative 9b 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 9a and 9b, appear to demonstrate sufficient cytostatic potency and selectivity to justify further evaluation of their potential.

• Authors: Svjetlana Prekupec, Drazenka Svedruzić, Tatjana Gazivoda, Draginja Mrvos-Sermek, Ante Nagl, Mira Grdisa, Kresimir Pavelić, Jan Balzarini, Erik De Clercq, Gerd Folkers, Leonardo Scapozza, Mladen Mintas, Silvana Raić-Malić
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 26 Pg. 5763-72 (Dec 18 2003) ISSN: 0022-2623 [Print] United States
• PMID: 14667229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 9-((2-acetoxyethoxy)methyl)-2-amino-1,9-dihydro-6H-purin-6-thione
• 9-(2-acetoxypropyl)-2-amino-1,9-dihydro-6H-purin-6-thione
• Antineoplastic Agents
• Antiviral Agents
• Purine Nucleosides
• Thiones
• Fluorine
• Guanine
• Iodine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Cell Line, Tumor
• Crystallography, X-Ray
• Drug Screening Assays, Antitumor
• Fluorine
• Guanine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Humans
• Iodine
• Magnetic Resonance Spectroscopy
• Mice
• Molecular Structure
• Purine Nucleosides (chemical synthesis, chemistry, pharmacology)
• Thiones (chemical synthesis, chemistry, pharmacology)