Maja Stipković Babić - Academia.edu (original) (raw)
Papers by Maja Stipković Babić
Knjiga sažetaka/ XXIV. Hrvatski skup kemičara i kemijskih inženjera, 2015
Razlicito supstituirani kumarinski derivati imaju sirok raspon bioloskog djelovanja u biokemiji i... more Razlicito supstituirani kumarinski derivati imaju sirok raspon bioloskog djelovanja u biokemiji i fiziologiji biljaka kao antioksidansi, antifungicidi i inhibitori enzima.1 Derivati kumarina supstituirani u položajima 3, 4, 7 ili 8 pokazuju bioloska djelovanja, poput antioksidativnog, protuupalnog, antitumorskog, antivirusnog i antimikrobnog.2 Uvođenjem metilnog supstituenta u položaj C-4 kumarina smanjuje se toksicnost, dok se uvođenjem arilnih supstituenata u položaj C-4 3-hidroksikumarina poboljsavaju antioksidativna svojstva.3 Nadalje, hibridi kumarina i 1, 2, 3-triazola pokazali su antimikrobnu aktivnost protiv M. catarrhalis.5 Novi 3-aril-7-hidroksi-4-metilkumarinski derivati pripravljeni su Pd-kataliziranom Suzuki reakcijom 7-hidroksi-3-klor-4-metilkumarina i odgovarajucih fenilboronskih kiselina. „Click“ reakcijom 3- azido-7-hidroksi-4-metilkumarina s razlicito supstituiranim fenilacetilenima uz bakar kao katalizator u položaj 3 kumarina uveden je 1, 2, 3-triazolni prsten. N...
Bioorganic & Medicinal Chemistry, 2012
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorb... more 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 IC 50 s of 10 ± 4 and 7.3 ± 0.1 lM, 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.
N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medi... more N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medicine and have shown rather marked antitumor and antiviral activities. In light of these findings we efficiently synthesized the novel N-1 substituted and C-5 alkynylated N4-benzoylcytosine and uracil derivatives by N-alkylation of pyrimidine bases and subsequent Pd-catalysed Sonogashira cross-coupling reaction. N-1 triazolyl derivatives were afforded via "click" reaction, while C-6 substituted pyrrolo[2, 3-d]pyrimidine derivatives were prepared by in situ N-heteroannulation of C-5 alkynylated derivatives.
![Research paper thumbnail of N-1 and C-5 substituted cytosine, uracil and C-6 substituted pyrrolo[2, 3-d]pyrimidine derivatives: synthesis and biological evaluation](https://attachments.academia-assets.com/87863717/thumbnails/1.jpg)
](N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medi... more N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medicine and have shown rather marked antitumor and antiviral activities. The novel N-1 substituted and C-5 alkynylated N4-benzoylcytosine and uracil derivatives have been synthesized by N-alkylation of pyrimidine bases and subsequent Pd-catalysed Sonogashira cross-coupling reaction. N-1 triazolyl derivatives were afforded via 'click' reaction, while pyrrolo[2, 3-d]pyrimidine derivatives were prepared by in situ N-heteroannulation of C-5 alkynylated derivatives. The novel compounds were evaluated against HeLa, CaCo-2, Raji and K562 tumor cell lines.
European Journal of Medicinal Chemistry, 2015
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazap... more Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and L-ascorbic acid (L-AA) in mind, we have synthesized new 3-, 7-and 9-deazapurine derivatives of Lascorbic (1e4, 8e10, 13e15) and imino-L-ascorbic acid (5e7, 11, 12, 16e19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of L-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC 50 ¼ 4.1 ± 1.8 mM) and strong antiproliferative effect against L1210/0 (IC 50 ¼ 4.7 ± 0.1 mM) while the 9deazahypoxanthine derivative of L-AA (15) showed the best effect against HeLa cells (IC 50 ¼ 5.6 ± 1.3 mM) and prominent effect on L1210/0 (IC 50 ¼ 4.5 ± 0.5 mM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-L-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC 50 ¼ 4.4 ± 0.3 mM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC 50 ¼ 5.7 ± 0.2 mM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3deazapurine derivative of L-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC 50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.
![Research paper thumbnail of Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives](https://attachments.academia-assets.com/76131430/thumbnails/1.jpg)
](Croatica Chemica Acta
C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reactio... more C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O-heteroannulation ring closure of N-1-alkyl-C-5-alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2,3-d]pyrimidine derivatives (7 and 8). 1,4-Disubstituted 1,2,3-triazole tethered 5-alkynylpyrimidines (14-19) and 6-substituted furo[2,3-d]pyrimidines (20-22) were successfully prepared by the copper(I)-catalyzed click reaction of 5-iodo-N-1-propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross-coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2,3-d]pyrimidine (22) derivatives with 3,5-difluorophenyl at pyrimidine and furo[2,3-d]pyrimidine as well as p-(trifluoromethyl)phenyl at 1,2,3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p-tolylethynyl at C-5 of pyrimidine and benzyl at 1,2,3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.
European Journal of Medicinal Chemistry, 2011
We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-a... more We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-azauracil (13e18) and cyanuric acid (19e22) 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 (14e16), 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 NeH/O hydrogen bond, two CeH/O hydrogen bonds and two CeH/p interactions into threedimensional 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 C4eC5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC 50 values ranging from 0.92 to 5.91 mM. 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.
European Journal of Medicinal Chemistry, 2011
We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-a... more We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-azauracil (13e18) and cyanuric acid (19e22) 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 (14e16), 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 NeH/O hydrogen bond, two CeH/O hydrogen bonds and two CeH/p interactions into threedimensional 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 C4eC5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC 50 values ranging from 0.92 to 5.91 mM. 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.
Bioorganic & Medicinal Chemistry, 2012
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorb... more 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 IC 50 s of 10 ± 4 and 7.3 ± 0.1 lM, 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.
European Journal of Medicinal Chemistry, 2015
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazap... more Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and l-ascorbic acid (l-AA) in mind, we have synthesized new 3-, 7- and 9-deazapurine derivatives of l-ascorbic (1-4, 8-10, 13-15) and imino-l-ascorbic acid (5-7, 11, 12, 16-19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of l-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC50 = 4.1 ± 1.8 μM) and strong antiproliferative effect against L1210/0 (IC50 = 4.7 ± 0.1 μM) while the 9-deazahypoxanthine derivative of l-AA (15) showed the best effect against HeLa cells (IC50 = 5.6 ± 1.3 μM) and prominent effect on L1210/0 (IC50 = 4.5 ± 0.5 μM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-l-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC50 = 4.4 ± 0.3 μM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC50 = 5.7 ± 0.2 μM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3-deazapurine derivative of l-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.
Knjiga sažetaka/ XXIV. Hrvatski skup kemičara i kemijskih inženjera, 2015
Razlicito supstituirani kumarinski derivati imaju sirok raspon bioloskog djelovanja u biokemiji i... more Razlicito supstituirani kumarinski derivati imaju sirok raspon bioloskog djelovanja u biokemiji i fiziologiji biljaka kao antioksidansi, antifungicidi i inhibitori enzima.1 Derivati kumarina supstituirani u položajima 3, 4, 7 ili 8 pokazuju bioloska djelovanja, poput antioksidativnog, protuupalnog, antitumorskog, antivirusnog i antimikrobnog.2 Uvođenjem metilnog supstituenta u položaj C-4 kumarina smanjuje se toksicnost, dok se uvođenjem arilnih supstituenata u položaj C-4 3-hidroksikumarina poboljsavaju antioksidativna svojstva.3 Nadalje, hibridi kumarina i 1, 2, 3-triazola pokazali su antimikrobnu aktivnost protiv M. catarrhalis.5 Novi 3-aril-7-hidroksi-4-metilkumarinski derivati pripravljeni su Pd-kataliziranom Suzuki reakcijom 7-hidroksi-3-klor-4-metilkumarina i odgovarajucih fenilboronskih kiselina. „Click“ reakcijom 3- azido-7-hidroksi-4-metilkumarina s razlicito supstituiranim fenilacetilenima uz bakar kao katalizator u položaj 3 kumarina uveden je 1, 2, 3-triazolni prsten. N...
Bioorganic & Medicinal Chemistry, 2012
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorb... more 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 IC 50 s of 10 ± 4 and 7.3 ± 0.1 lM, 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.
N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medi... more N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medicine and have shown rather marked antitumor and antiviral activities. In light of these findings we efficiently synthesized the novel N-1 substituted and C-5 alkynylated N4-benzoylcytosine and uracil derivatives by N-alkylation of pyrimidine bases and subsequent Pd-catalysed Sonogashira cross-coupling reaction. N-1 triazolyl derivatives were afforded via "click" reaction, while C-6 substituted pyrrolo[2, 3-d]pyrimidine derivatives were prepared by in situ N-heteroannulation of C-5 alkynylated derivatives.
N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medi... more N-alkylated pyrimidine and pyrrolo[2, 3-d]pyrimidine derivatives have a great role in modern medicine and have shown rather marked antitumor and antiviral activities. The novel N-1 substituted and C-5 alkynylated N4-benzoylcytosine and uracil derivatives have been synthesized by N-alkylation of pyrimidine bases and subsequent Pd-catalysed Sonogashira cross-coupling reaction. N-1 triazolyl derivatives were afforded via 'click' reaction, while pyrrolo[2, 3-d]pyrimidine derivatives were prepared by in situ N-heteroannulation of C-5 alkynylated derivatives. The novel compounds were evaluated against HeLa, CaCo-2, Raji and K562 tumor cell lines.
European Journal of Medicinal Chemistry, 2015
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazap... more Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and L-ascorbic acid (L-AA) in mind, we have synthesized new 3-, 7-and 9-deazapurine derivatives of Lascorbic (1e4, 8e10, 13e15) and imino-L-ascorbic acid (5e7, 11, 12, 16e19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of L-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC 50 ¼ 4.1 ± 1.8 mM) and strong antiproliferative effect against L1210/0 (IC 50 ¼ 4.7 ± 0.1 mM) while the 9deazahypoxanthine derivative of L-AA (15) showed the best effect against HeLa cells (IC 50 ¼ 5.6 ± 1.3 mM) and prominent effect on L1210/0 (IC 50 ¼ 4.5 ± 0.5 mM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-L-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC 50 ¼ 4.4 ± 0.3 mM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC 50 ¼ 5.7 ± 0.2 mM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3deazapurine derivative of L-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC 50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.
Croatica Chemica Acta
C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reactio... more C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O-heteroannulation ring closure of N-1-alkyl-C-5-alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2,3-d]pyrimidine derivatives (7 and 8). 1,4-Disubstituted 1,2,3-triazole tethered 5-alkynylpyrimidines (14-19) and 6-substituted furo[2,3-d]pyrimidines (20-22) were successfully prepared by the copper(I)-catalyzed click reaction of 5-iodo-N-1-propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross-coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2,3-d]pyrimidine (22) derivatives with 3,5-difluorophenyl at pyrimidine and furo[2,3-d]pyrimidine as well as p-(trifluoromethyl)phenyl at 1,2,3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p-tolylethynyl at C-5 of pyrimidine and benzyl at 1,2,3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.
European Journal of Medicinal Chemistry, 2011
We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-a... more We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-azauracil (13e18) and cyanuric acid (19e22) 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 (14e16), 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 NeH/O hydrogen bond, two CeH/O hydrogen bonds and two CeH/p interactions into threedimensional 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 C4eC5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC 50 values ranging from 0.92 to 5.91 mM. 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.
European Journal of Medicinal Chemistry, 2011
We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-a... more We report on the synthesis of the novel types of cytosine and 5-azacytosine (1e9), uracil and 6-azauracil (13e18) and cyanuric acid (19e22) 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 (14e16), 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 NeH/O hydrogen bond, two CeH/O hydrogen bonds and two CeH/p interactions into threedimensional 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 C4eC5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC 50 values ranging from 0.92 to 5.91 mM. 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.
Bioorganic & Medicinal Chemistry, 2012
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorb... more 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 IC 50 s of 10 ± 4 and 7.3 ± 0.1 lM, 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.
European Journal of Medicinal Chemistry, 2015
Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazap... more Keeping the potential synergy of biological activity of synthetic anomalous derivatives of deazapurines and l-ascorbic acid (l-AA) in mind, we have synthesized new 3-, 7- and 9-deazapurine derivatives of l-ascorbic (1-4, 8-10, 13-15) and imino-l-ascorbic acid (5-7, 11, 12, 16-19). These novel compounds were evaluated for their cytostatic and antiviral activity in vitro against a panel of human malignant tumour cell lines and normal murine fibroblasts (3T3). Among all evaluated compounds, the 9-deazapurine derivative of l-AA (13) exerted the most potent inhibitory activity on the growth of CEM/0 cells (IC50 = 4.1 ± 1.8 μM) and strong antiproliferative effect against L1210/0 (IC50 = 4.7 ± 0.1 μM) while the 9-deazahypoxanthine derivative of l-AA (15) showed the best effect against HeLa cells (IC50 = 5.6 ± 1.3 μM) and prominent effect on L1210/0 (IC50 = 4.5 ± 0.5 μM). Furthermore, the 9-deazapurine derivative disubstituted with two imino-l-AA moieties (18) showed the best activity against L1210/0 tumour cells (IC50 = 4.4 ± 0.3 μM) and the most pronounced antiproliferative effects against MiaPaCa-2 cells (IC50 = 5.7 ± 0.2 μM). All these compounds showed selective cytostatic effect on tumour cell lines in comparison with embryonal murine fibroblasts (3T3). When evaluating their antiviral activity, the 3-deazapurine derivative of l-AA (3) exhibited the highest activity against both laboratory-adapted strains of human cytomegalovirus (HCMV) (AD-169 and Davis) with EC50 values comparable to those of the well-known anti-HCMV drug ganciclovir and without cytotoxic effects on normal human embryonal lung (HEL) cells.