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Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans

  • Jack C. Kim
  • Ji-A Kim
  • Jin II Park
  • Si-Hwan Kim
  • Seon-Hee Kim
  • Soon-Kyu Choi
  • Won-Woo Park
Research Articles

Abstract

Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH3, CH3, CH2CH3, CH=CH2, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K2CO3 (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC50) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC50:0.4∼2.8 μg/ml).

Key words

5′-Methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)-2′-oxo-3′-methylenetetra-hydrofuran 1-(5-Substituted uracil-1-yl)-3-butanone Stille coupling reaction Tris(dibenzylidenacetonyl)bispalladium (Pd2dba3Tri(2-furyl)phosphine Antitumor activity IC50 Reformatsky reaction Human chronic myelogenous (K-562) Mouse lymphoid neoplasma (P-388) Mouse mammary carcinoma (FM-3A) Human histiocytic lymphoma (U-937) 

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Copyright information

© The Pharmaceutical Society of Korea 1997

Authors and Affiliations

  • Jack C. Kim
    • 1
  • Ji-A Kim
    • 1
  • Jin II Park
    • 1
  • Si-Hwan Kim
    • 1
  • Seon-Hee Kim
    • 2
  • Soon-Kyu Choi
    • 3
  • Won-Woo Park
    • 4
  1. 1.Department of Chemistry, College of Natural SciencePusan National UniversityPusanKorea
  2. 2.Department of Biochemistry, College of MedicinePusan National UniversityPusanKorea
  3. 3.Department of ChemistryDong-A UniversityPusanKorea
  4. 4.Pusan Junior CollegePusanKorea

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