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Pregled bibliografske jedinice broj: 514748

The new 5- or 6-azapyrimidine and cyanuric acid derivatives of L-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD-spectral absolute configuration determination and biological activity evaluations


Wittine, Karlo; Stipković Babić, Maja; Košutić, Marija; Cetina, Mario; Rissanen, Kari; Kraljević Pavelić, Sandra; Tomljenović Paravić, Andrea; Sedić, Mirela; Pavelić, Krešimir; Mintas, Mladen
The new 5- or 6-azapyrimidine and cyanuric acid derivatives of L-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD-spectral absolute configuration determination and biological activity evaluations // European journal of medicinal chemistry, 46 (2011), 7; 2770-2785 doi:10.1016/j.ejmech.2011.03.066 (međunarodna recenzija, članak, znanstveni)


Naslov
The new 5- or 6-azapyrimidine and cyanuric acid derivatives of L-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD-spectral absolute configuration determination and biological activity evaluations

Autori
Wittine, Karlo ; Stipković Babić, Maja ; Košutić, Marija ; Cetina, Mario ; Rissanen, Kari ; Kraljević Pavelić, Sandra ; Tomljenović Paravić, Andrea ; Sedić, Mirela ; Pavelić, Krešimir ; Mintas, Mladen

Izvornik
European journal of medicinal chemistry (0223-5234) 46 (2011), 7; 2770-2785

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Pyrimidine and cyanuric acid derivatives ; L-ascorbic acid ; circular dichroism ; cytostatic activity evaluation ; X-ray diffraction ; cell cycle analysis

Sažetak
We report on the synthesis of the novel types of cytosine and 5-azacytosine (1-9), uracil and 6-azauracil (13-18) and cyanuric acid (19-22) derivatives of L-ascorbic acid, and on their cytostatic activity evaluation in human malignant tumour cell lines vs. their cytotoxic effects on human normal fibroblasts (WI38). The CD spectra analysis revealed that cytosine (5 and 6), uracil (14-16), 6-azauracil (17) and cyanuric acid (21) derivatives of L-ascorbic acid bearing free amino group at ethylenic spacer existed as a racemic mixture of enantiomers, whereas L-ascorbic derivatives containing the C-5 substituted hydroxy group at the ethylenic spacer were obtained in (4R, 5S) enantiomeric form. The stereochemistry of 6-azauracil derivative of L-ascorbic acid (13) was confirmed by X-ray crystal structure analysis. The molecules are self-assembled by one N-H•••O hydrogen bond, two C-H•••O hydrogen bonds and two C−H••• interactions into three-dimensional framework. Cytostatic activity evaluation indicated that compounds did not show distinctive antiproliferative effects on tested cell line panel. However, the cytosine derivative of L-ascorbic acid (1) containing the C4-C5 double bond conjugated with the lactone moiety produced rather marked growth inhibitory effect on hepatocellular carcinoma (HepG2), metastatic breast epithelial carcinoma (MCF-7) and cervical carcinoma (HeLa) cell lines at micromolar concentrations, but also exerted strong cytostatic effect on WI38. 5-Azacytosine derivative of L-ascorbic acid (2) with a double bond at the C4-C5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with mean IC50 values ranging from 0.92 to 5.91 μM. However, this compound also exhibited pronounced cytotoxicity towards WI38. Flow cytometric analysis of the cell cycle revealed that compound 2 triggers S phase arrest, which clearly demonstrates its interference with DNA replication, a key event of cell proliferation. Marked anticancer efficacy of compound 2 supports further in vivo investigation into its possible clinical utility.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

Napomena
Rad je kao sažetak objavljen u Cheminform 42 (2011) (41) ; https://onlinelibrary.wiley.com/doi/full/10.1002/chin.201141186 ; https://onlinelibrary.wiley.com/doi/full/10.1002/chin.201141186



POVEZANOST RADA


Projekt / tema
125-0982464-2922 - RAZVOJ NOVIH PROLIJEKOVA I LIJEKOVA PROTIV VIRUSA I RAKA (Mladen Mintas, )
335-0000000-3532 - Uloga IGF2 i signalni putovi nizvodno u karcinomima pluća čovjeka (Sandra Kraljević Pavelić, )
335-0982464-2393 - Molekularna obilježja miofibroblasta Dupuytrenove bolesti (Krešimir Pavelić, )

Ustanove
Institut "Ruđer Bošković", Zagreb,
Tekstilno-tehnološki fakultet, Zagreb,
Fakultet kemijskog inženjerstva i tehnologije, Zagreb,
Sveučilište u Rijeci - Odjel za biotehnologiju

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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