Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs
N6-Isopentenyladenosine (<b>i6A</b>) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we d...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/23/7146 |
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| author | Verdiana Covelli Manuela Grimaldi Rosario Randino Mohammad Firoznezhad Maria Chiara Proto Veronica De Simone Gianluca Matteoli Patrizia Gazzerro Maurizio Bifulco Anna Maria D’Ursi Manuela Rodriquez |
| author_facet | Verdiana Covelli Manuela Grimaldi Rosario Randino Mohammad Firoznezhad Maria Chiara Proto Veronica De Simone Gianluca Matteoli Patrizia Gazzerro Maurizio Bifulco Anna Maria D’Ursi Manuela Rodriquez |
| author_sort | Verdiana Covelli |
| collection | DOAJ |
| description | N6-Isopentenyladenosine (<b>i6A</b>) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that <b>i6A</b> targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of <b>i6A</b> derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds <b>2a–m</b>) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds <b>2</b>, <b>2a</b> and <b>2c</b> showed a persistent antiproliferative effect on human CRC lines and compound <b>2f</b> exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of <b>2f</b> was related to the ability to inhibit FPPS activity. |
| first_indexed | 2024-03-10T04:48:00Z |
| format | Article |
| id | doaj.art-078b9ea022d94256b3e83b71616844b1 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T04:48:00Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-078b9ea022d94256b3e83b71616844b12023-11-23T02:47:58ZengMDPI AGMolecules1420-30492021-11-012623714610.3390/molecules26237146Towards an Improvement of Anticancer Activity of Benzyl Adenosine AnalogsVerdiana Covelli0Manuela Grimaldi1Rosario Randino2Mohammad Firoznezhad3Maria Chiara Proto4Veronica De Simone5Gianluca Matteoli6Patrizia Gazzerro7Maurizio Bifulco8Anna Maria D’Ursi9Manuela Rodriquez10Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49-3000 Leuven, BelgiumDepartment of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49-3000 Leuven, BelgiumDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Molecular, Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini, 5-80131 Naples, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132-84084 Fisciano, ItalyN6-Isopentenyladenosine (<b>i6A</b>) is a naturally occurring modified nucleoside displaying in vitro and in vivo antiproliferative and pro-apoptotic properties. In our previous studies, including an in silico inverse virtual screening, NMR experiments and in vitro enzymatic assays, we demonstrated that <b>i6A</b> targeted farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway and prenylation of downstream proteins, which are aberrant in several cancers. Following our interest in the anticancer effects of FPPS inhibition, we developed a panel of <b>i6A</b> derivatives bearing bulky aromatic moieties in the N6 position of adenosine. With the aim of clarifying molecular action of N6-benzyladenosine analogs on the FPPS enzyme inhibition and cellular toxicity and proliferation, herein we report the evaluation of the N6-benzyladenosine derivatives’ (compounds <b>2a–m</b>) effects on cell viability and proliferation on HCT116, DLD-1 (human) and MC38 (murine) colorectal cancer cells (CRC). We found that compounds <b>2</b>, <b>2a</b> and <b>2c</b> showed a persistent antiproliferative effect on human CRC lines and compound <b>2f</b> exerted a significant effect in impairing the prenylation of RAS and Rap-1A proteins, confirming that the antitumor activity of <b>2f</b> was related to the ability to inhibit FPPS activity.https://www.mdpi.com/1420-3049/26/23/7146N6-benzyladenosine derivativescolorectal cancerFPPS |
| spellingShingle | Verdiana Covelli Manuela Grimaldi Rosario Randino Mohammad Firoznezhad Maria Chiara Proto Veronica De Simone Gianluca Matteoli Patrizia Gazzerro Maurizio Bifulco Anna Maria D’Ursi Manuela Rodriquez Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs Molecules N6-benzyladenosine derivatives colorectal cancer FPPS |
| title | Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs |
| title_full | Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs |
| title_fullStr | Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs |
| title_full_unstemmed | Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs |
| title_short | Towards an Improvement of Anticancer Activity of Benzyl Adenosine Analogs |
| title_sort | towards an improvement of anticancer activity of benzyl adenosine analogs |
| topic | N6-benzyladenosine derivatives colorectal cancer FPPS |
| url | https://www.mdpi.com/1420-3049/26/23/7146 |
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