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Novel 1, 2, 4-Triazole and Imidazole Derivatives of L-Ascorbic and Imino-Ascorbic Acid: Synthesis, Anti-HCV and Antitumor Activity Evaluations


Wittine, Karlo; Stipković Babić, Maja; Makuc, Damjan; Plavec, Janez; Kraljević Pavelić, Sandra; Sedić, Mirela; Pavelić, Krešimir; Leyssene, Pieter; Neytse, Johan; Balzarinie, Jan; Mintas, Mladen
Novel 1, 2, 4-Triazole and Imidazole Derivatives of L-Ascorbic and Imino-Ascorbic Acid: Synthesis, Anti-HCV and Antitumor Activity Evaluations // Bioorganic & medicinal chemistry, 20 (2012), 11; 3675-3685 doi:10.1016/j.bmc.2012.01.054 (međunarodna recenzija, članak, znanstveni)


Naslov
Novel 1, 2, 4-Triazole and Imidazole Derivatives of L-Ascorbic and Imino-Ascorbic Acid: Synthesis, Anti-HCV and Antitumor Activity Evaluations

Autori
Wittine, Karlo ; Stipković Babić, Maja ; Makuc, Damjan ; Plavec, Janez ; Kraljević Pavelić, Sandra ; Sedić, Mirela ; Pavelić, Krešimir ; Leyssene, Pieter ; Neytse, Johan ; Balzarinie, Jan ; Mintas, Mladen

Izvornik
Bioorganic & medicinal chemistry (0968-0896) 20 (2012), 11; 3675-3685

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

Ključne riječi
1; 2; 4-triazole; imidazole; L-ascorbic acid; anti-HCV activity; antitumor activity; IMPDH

Sažetak
Several novel 1, 2, 4-triazole and imidazole L- ascorbic acid (1, 2, 3, 5, 6 and 9) and imino- ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC50s of 104 and 7.30.1 µM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on the host cell rather than with selective effect on the replication of the virus itself. In conclusion, results of this study put forward compound 6 as a potential novel antitumor agent (IMPDH inhibitor) for treating leukaemia. Its significant biological activity and low toxicity in human diploid fibroblasts encourage further development of this compound as a lead.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
125-098-2464-2922
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
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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