Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization
We previously reported that chalcone <b>CM-M345</b> (<b>1</b>) and diarylpentanoid <b>BP-C4</b> (<b>2</b>) induced p53-dependent growth inhibitory activity in human cancer cells. Herein, <b>CM-M345</b> (<b>1</b>) and <b>BP...
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MDPI AG
2023-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/10/1354 |
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| author | Joana Moreira Joana B. Loureiro Danilo Correia Andreia Palmeira Madalena M. Pinto Lucília Saraiva Honorina Cidade |
| author_facet | Joana Moreira Joana B. Loureiro Danilo Correia Andreia Palmeira Madalena M. Pinto Lucília Saraiva Honorina Cidade |
| author_sort | Joana Moreira |
| collection | DOAJ |
| description | We previously reported that chalcone <b>CM-M345</b> (<b>1</b>) and diarylpentanoid <b>BP-C4</b> (<b>2</b>) induced p53-dependent growth inhibitory activity in human cancer cells. Herein, <b>CM-M345</b> (<b>1</b>) and <b>BP-C4</b> (<b>2</b>) analogues were designed and synthesized in order to obtain more potent and selective compounds. Compounds <b>16</b>, <b>17</b>, <b>19</b>, <b>20</b>, and <b>22</b>–<b>24</b> caused pronounced in vitro growth inhibitory activity in HCT116 cells (0.09 < GI<sub>50</sub> < 3.10 μM). Chemical optimization of <b>CM-M345</b> (<b>1</b>) led to the identification of compound <b>36</b> with increased selectivity for HCT116 cells expressing wild-type p53 compared to its p53-null isogenic derivative and low toxicity to non-tumor HFF-1 cells. The molecular modification of <b>BP-C4</b> (<b>2</b>) resulted in the discovery of compound <b>16</b> with more pronounced antiproliferative activity and being selective for HCT116 cells with p53, as well as <b>17</b> with enhanced antiproliferative activity against HCT116 cells and low toxicity to non-tumor cells. Compound <b>16</b> behaved as an inhibitor of p53–MDM2 interaction, and compound <b>17</b> was shown to induce apoptosis, associated with an increase in cleaved PARP and decreased levels of the anti-apoptotic protein Bcl-2<b>.</b> In silico studies allowed us to predict the druglikeness and ADMET properties for <b>16</b> and <b>17</b>. Docking and molecular dynamics studies predicted that <b>16</b> could bind stably to the MDM2 binding pocket. |
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| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T20:58:48Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-8786cacc1ddf46e7a76db44d185ae5062023-11-19T17:41:17ZengMDPI AGPharmaceuticals1424-82472023-09-011610135410.3390/ph16101354Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity OptimizationJoana Moreira0Joana B. Loureiro1Danilo Correia2Andreia Palmeira3Madalena M. Pinto4Lucília Saraiva5Honorina Cidade6Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, PortugalLaboratório Associado para a Química Verde (LAQV)/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, PortugalLaboratório Associado para a Química Verde (LAQV)/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, PortugalWe previously reported that chalcone <b>CM-M345</b> (<b>1</b>) and diarylpentanoid <b>BP-C4</b> (<b>2</b>) induced p53-dependent growth inhibitory activity in human cancer cells. Herein, <b>CM-M345</b> (<b>1</b>) and <b>BP-C4</b> (<b>2</b>) analogues were designed and synthesized in order to obtain more potent and selective compounds. Compounds <b>16</b>, <b>17</b>, <b>19</b>, <b>20</b>, and <b>22</b>–<b>24</b> caused pronounced in vitro growth inhibitory activity in HCT116 cells (0.09 < GI<sub>50</sub> < 3.10 μM). Chemical optimization of <b>CM-M345</b> (<b>1</b>) led to the identification of compound <b>36</b> with increased selectivity for HCT116 cells expressing wild-type p53 compared to its p53-null isogenic derivative and low toxicity to non-tumor HFF-1 cells. The molecular modification of <b>BP-C4</b> (<b>2</b>) resulted in the discovery of compound <b>16</b> with more pronounced antiproliferative activity and being selective for HCT116 cells with p53, as well as <b>17</b> with enhanced antiproliferative activity against HCT116 cells and low toxicity to non-tumor cells. Compound <b>16</b> behaved as an inhibitor of p53–MDM2 interaction, and compound <b>17</b> was shown to induce apoptosis, associated with an increase in cleaved PARP and decreased levels of the anti-apoptotic protein Bcl-2<b>.</b> In silico studies allowed us to predict the druglikeness and ADMET properties for <b>16</b> and <b>17</b>. Docking and molecular dynamics studies predicted that <b>16</b> could bind stably to the MDM2 binding pocket.https://www.mdpi.com/1424-8247/16/10/1354chalconesdiarylpentanoidsantitumor activityp53-MDM2in silico studies |
| spellingShingle | Joana Moreira Joana B. Loureiro Danilo Correia Andreia Palmeira Madalena M. Pinto Lucília Saraiva Honorina Cidade Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization Pharmaceuticals chalcones diarylpentanoids antitumor activity p53-MDM2 in silico studies |
| title | Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization |
| title_full | Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization |
| title_fullStr | Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization |
| title_full_unstemmed | Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization |
| title_short | Structure–Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization |
| title_sort | structure activity relationship studies of chalcones and diarylpentanoids with antitumor activity potency and selectivity optimization |
| topic | chalcones diarylpentanoids antitumor activity p53-MDM2 in silico studies |
| url | https://www.mdpi.com/1424-8247/16/10/1354 |
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