Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners
The goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Arabian Journal of Chemistry |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535217300011 |
| _version_ | 1819050261050556416 |
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| author | Małgorzata Sztanke Jolanta Rzymowska Małgorzata Janicka Krzysztof Sztanke |
| author_facet | Małgorzata Sztanke Jolanta Rzymowska Małgorzata Janicka Krzysztof Sztanke |
| author_sort | Małgorzata Sztanke |
| collection | DOAJ |
| description | The goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two novel classes of potential antimetabolites based on the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold. Well-established, scalable and optimised synthetic approaches leading to two novel classes of the desired compounds (7–12 and 13–17) were developed. These original fused azaisocytosine-like congeners were screened in vitro with the purpose of identifying molecules with better biological profiles that are suitable for further more detailed drug development studies. All the synthesised compounds proved to be strongly antiproliferative active against human neoplastic cell lines (A549, HeLa, T47D and TOV112D) and revealed higher cytotoxic effects in A549, HeLa and T47D cells than the known antitumour agent – pemetrexed. Four potent fused azaisocytosine-like congeners (10, 12, 15 and 16) proved to be the most promising lead structures as they reveal the explicitly lower cytotoxicity for non-tumoural cells. These molecules could be employed for novel effective anticancer strategies directed towards designing more selective and safer cytotoxic agents. In addition, a number of compounds (that target epithelial cancer cells and inhibit their growth) have been preselected because they present optimum lipophilicity ranges significantly correlated with in silico bioactivity descriptors (such as %F, Caco-2, Pe,jejunum, logBB, fu,brain, logPHSA) important for the optimal pharmacokinetic profile in vivo. Keywords: Fused azaisocytosine-like structures, Structural studies, Antiproliferative effects, Lipophilicity, PCA, In silico pharmacokinetic descriptors |
| first_indexed | 2024-12-21T11:45:14Z |
| format | Article |
| id | doaj.art-3dd9120c0aff4a1496e5d4fa98f74654 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-12-21T11:45:14Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-3dd9120c0aff4a1496e5d4fa98f746542022-12-21T19:05:11ZengElsevierArabian Journal of Chemistry1878-53522019-12-0112853025324Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congenersMałgorzata Sztanke0Jolanta Rzymowska1Małgorzata Janicka2Krzysztof Sztanke3Chair and Department of Medical Chemistry, Medical University, 4A Chodźki Street, 20-093 Lublin, Poland; Corresponding author.Department of Biology and Genetics, Medical University, 4A Chodźki Street, 20-093 Lublin, PolandDepartment of Physical Chemistry, Faculty of Chemistry, Maria Curie-Skłodowska University, Maria Curie-Skłodowska Sq. 3, 20-031 Lublin, PolandLaboratory of Bioorganic Synthesis and Analysis, Chair and Department of Medical Chemistry, Medical University, 4A Chodźki Street, 20-093 Lublin, PolandThe goals of the present investigation were the development of two independent synthetic approaches, the original spectroscopic characterisation, the identification of in vitro antitumour activities and the correlation of determined retention factors with in silico pharmacokinetic descriptors of two novel classes of potential antimetabolites based on the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold. Well-established, scalable and optimised synthetic approaches leading to two novel classes of the desired compounds (7–12 and 13–17) were developed. These original fused azaisocytosine-like congeners were screened in vitro with the purpose of identifying molecules with better biological profiles that are suitable for further more detailed drug development studies. All the synthesised compounds proved to be strongly antiproliferative active against human neoplastic cell lines (A549, HeLa, T47D and TOV112D) and revealed higher cytotoxic effects in A549, HeLa and T47D cells than the known antitumour agent – pemetrexed. Four potent fused azaisocytosine-like congeners (10, 12, 15 and 16) proved to be the most promising lead structures as they reveal the explicitly lower cytotoxicity for non-tumoural cells. These molecules could be employed for novel effective anticancer strategies directed towards designing more selective and safer cytotoxic agents. In addition, a number of compounds (that target epithelial cancer cells and inhibit their growth) have been preselected because they present optimum lipophilicity ranges significantly correlated with in silico bioactivity descriptors (such as %F, Caco-2, Pe,jejunum, logBB, fu,brain, logPHSA) important for the optimal pharmacokinetic profile in vivo. Keywords: Fused azaisocytosine-like structures, Structural studies, Antiproliferative effects, Lipophilicity, PCA, In silico pharmacokinetic descriptorshttp://www.sciencedirect.com/science/article/pii/S1878535217300011 |
| spellingShingle | Małgorzata Sztanke Jolanta Rzymowska Małgorzata Janicka Krzysztof Sztanke Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners Arabian Journal of Chemistry |
| title | Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners |
| title_full | Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners |
| title_fullStr | Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners |
| title_full_unstemmed | Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners |
| title_short | Synthesis, structure confirmation, identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine-like congeners |
| title_sort | synthesis structure confirmation identification of in vitro antiproliferative activities and correlation of determined lipophilicity parameters with in silico bioactivity descriptors of two novel classes of fused azaisocytosine like congeners |
| url | http://www.sciencedirect.com/science/article/pii/S1878535217300011 |
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