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Medicinal Chemistry Research

, Volume 20, Issue 3, pp 280–286 | Cite as

Synthesis, cytostatic and anti-viral activity evaluation of the novel acyclic nucleoside analogues containing a sterically constrained (Z)-4-amino-2-butenyl moiety

  • Karlo Wittine
  • Krešimir Benci
  • Sandra Kraljević Pavelić
  • Krešimir Pavelić
  • Siniša Bratulić
  • Karlo Hock
  • Jan Balzarini
  • Mladen MintasEmail author
Original Research

Abstract

A series of the novel pyrimidine (36) and purine (1215, 1821) acyclic nucleoside analogues in which the sugar moiety was replaced by a sterically constrained Z-4-amino-, 4-aminohydrochloride-2-butenyl, or aliphatic 4-aminohydrochloride-2-butyl moiety were synthesized and evaluated for their anti-viral and cytostatic activity potency. Cytostatic evaluation of the novel compounds on selected panel of human tumour-cell lines showed that the majority of compounds exerted a non-specific anti-proliferative effect at the highest tested concentration (i.e. 1 × 10−4 M) against all cell lines. Nevertheless, a rather moderate but selective anti-proliferative effects on HeLa cell cultures in comparison to normal fibroblasts WI 38, were observed for compounds 15 and 21. No anti-viral activity was observed, except for compounds 3, 4, 5 and 19 that showed anti-HIV activity at 50% effective concentration ranging between 10 and 96 μM.

Keywords

Acyclic nucleoside analogues Purine and pyrimidine derivatives Cytostatic activity Anti-viral activity 

Notes

Acknowledgements

Support for this study was provided by the Ministry of Science of the Republic of Croatia (Projects # 125-0982464-2922, # 098-0982464-2393) and by the “Geconcerteerde Onderzoeksacties” of the Katholieke Universiteit Leuven (project # 05/19). We thank Lizette van Berckelaer for excellent technical assistance in performing part of the anti-tumour cell activity assays, as well as Leen Ingels, Leentje Persoons, Frieda De Meyer, Vicky Broeckx, Anita Camps and Lies Vandenheurck for excellent technical assistance in performing the anti-viral activity assays.

Supplementary material

44_2010_9318_MOESM1_ESM.docx (151 kb)
Fig. S1 Dose response curves for compounds 36, 1215 and 1821 tested on (A) HeLa and (B) MCF-7 cell lines in vitro. Means of survival for each cell line were estimated and shown as percentages of growth (PG). The substances 15 and 21 acted in a dose-dependent manner on the growth of HeLa cells. Non-specific antiproliferative effect dose response curves were observed for the other cell lines as illustrated in panel (B), where all valuated compounds strongly inhibited the cell growth only at the highest tested concentration (1 × 10−4 M)
44_2010_9318_MOESM2_ESM.docx (55 kb)
Supplementary material 2 (DOCX 54 kb)

References

  1. Chen L, Kode N, Murthi D, Phadtare S (2005) N9- and N7-(Chloromethyl phenylmethyl)chloropurine derivatives from α, α′-dichloroxylenes: synthesis and anticancer activity. Med Chem Res 14(8/9):445–474CrossRefGoogle Scholar
  2. Gazivoda T, Plevnik M, Plavec J, Kraljević-Pavelić S, Kralj M, Pavelić K, Balzarini J, De Clerq E, Mintas M, Raić-Malić S (2005) The novel pyrimidine and purine derivatives of l-ascorbic acid: synthesis, one- and two-dimensional 1H and 13C NMR study, cytostatic and antiviral evaluation. Bioorg Med Chem 13:131–139PubMedCrossRefGoogle Scholar
  3. Gazivoda T, Raić-Malić S, Krištafor V, Makuc D, Plavec J, Bratulić S, Kraljević-Pavelić S, Pavelić K, Naesens L, Andrei G, Snoeck R, Balzarini J, Mintas M (2008) Synthesis, cytostatic and anti-HIV evaluations of the new unsaturated acyclic C-5 pyrimidine nucleoside analogues. Bioorg Med Chem 16:5624–5634PubMedCrossRefGoogle Scholar
  4. Haines DR, Tseng CKH, Marquez VE (1987) Synthesis and biological activity of unsaturated carboacyclic purine nucleoside analogs. J Med Chem 30:943–947PubMedCrossRefGoogle Scholar
  5. Hernández A, Balzarini J, Rodríguez-Barrios F, San-Félix A, Karlsson A, Gago F, Camarasa M, Pérez-Pérez MJ (2003) Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides. Bioorg Med Chem Lett 13:3027–3030PubMedCrossRefGoogle Scholar
  6. Krištafor V, Raić-Malić S, Cetina M, Kralj M, Pavelić K, Balzarini J, DeClercq E, Mintas M (2006) Synthesis, X-ray crystal structural study, antiviral and cytostatic evaluations of the novel unsaturated acyclic and epoxide nucleoside analogues. Bioorg Med Chem 14:8126–8138PubMedCrossRefGoogle Scholar
  7. Wu Y, Hong JH (2005) Synthesis and anti-HIV activity of novel phenyl branched cyclopropyl nucleosides. Farmaco 60:739–744PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Karlo Wittine
    • 1
  • Krešimir Benci
    • 1
  • Sandra Kraljević Pavelić
    • 2
  • Krešimir Pavelić
    • 2
  • Siniša Bratulić
    • 2
  • Karlo Hock
    • 2
  • Jan Balzarini
    • 3
  • Mladen Mintas
    • 1
    Email author
  1. 1.Department of Organic Chemistry, Faculty of Chemical Engineering and TechnologyUniversity of ZagrebZagrebCroatia
  2. 2.Division of Molecular Medicine, Laboratory for systems biomedicineRuđer Bošković InstituteZagrebCroatia
  3. 3.Rega Institute for Medical ResearchKatholieke Universiteit LeuvenLeuvenBelgium

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