Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies
In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (<b>7</b>) based on the combination of subunits of two promising antiproliferative compounds (<b>CM-M345</b> (<b>1</b>) and <b>BP-M345</b> (<b>2</b>)), prev...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/6/879 |
| _version_ | 1797593107040043008 |
|---|---|
| author | Joana Moreira Patrícia M. A. Silva Matilde Barros Lucília Saraiva Madalena Pinto Hassan Bousbaa Honorina Cidade |
| author_facet | Joana Moreira Patrícia M. A. Silva Matilde Barros Lucília Saraiva Madalena Pinto Hassan Bousbaa Honorina Cidade |
| author_sort | Joana Moreira |
| collection | DOAJ |
| description | In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (<b>7</b>) based on the combination of subunits of two promising antiproliferative compounds (<b>CM-M345</b> (<b>1</b>) and <b>BP-M345</b> (<b>2</b>)), previously obtained by our research group, are reported. In order to expand the structure–activity relationship (SAR) knowledge, a new series of <b>7</b>-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (<b>6</b>, <b>7</b>, and <b>13</b>) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI<sub>50</sub> = 2.66–3.26 μM), showing hybrid <b>7</b> selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53–MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound <b>7</b> emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death. |
| first_indexed | 2024-03-11T02:03:05Z |
| format | Article |
| id | doaj.art-4c6fd94802ad40ec8a789c435befe7c5 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T02:03:05Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-4c6fd94802ad40ec8a789c435befe7c52023-11-18T12:02:50ZengMDPI AGPharmaceuticals1424-82472023-06-0116687910.3390/ph16060879Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship StudiesJoana Moreira0Patrícia M. A. Silva1Matilde Barros2Lucília Saraiva3Madalena Pinto4Hassan Bousbaa5Honorina Cidade6Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalUNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra, PortugalLAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalUNIPRO—Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra, PortugalLaboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalIn this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (<b>7</b>) based on the combination of subunits of two promising antiproliferative compounds (<b>CM-M345</b> (<b>1</b>) and <b>BP-M345</b> (<b>2</b>)), previously obtained by our research group, are reported. In order to expand the structure–activity relationship (SAR) knowledge, a new series of <b>7</b>-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (<b>6</b>, <b>7</b>, and <b>13</b>) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI<sub>50</sub> = 2.66–3.26 μM), showing hybrid <b>7</b> selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53–MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound <b>7</b> emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death.https://www.mdpi.com/1424-8247/16/6/879chalconesdiarylpentanoidshybridsantitumor activityapoptosisp53 |
| spellingShingle | Joana Moreira Patrícia M. A. Silva Matilde Barros Lucília Saraiva Madalena Pinto Hassan Bousbaa Honorina Cidade Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies Pharmaceuticals chalcones diarylpentanoids hybrids antitumor activity apoptosis p53 |
| title | Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies |
| title_full | Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies |
| title_fullStr | Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies |
| title_full_unstemmed | Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies |
| title_short | Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies |
| title_sort | discovery of a new chalcone trimethoxycinnamide hybrid with antimitotic effect design synthesis and structure activity relationship studies |
| topic | chalcones diarylpentanoids hybrids antitumor activity apoptosis p53 |
| url | https://www.mdpi.com/1424-8247/16/6/879 |
| work_keys_str_mv | AT joanamoreira discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT patriciamasilva discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT matildebarros discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT luciliasaraiva discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT madalenapinto discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT hassanbousbaa discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies AT honorinacidade discoveryofanewchalconetrimethoxycinnamidehybridwithantimitoticeffectdesignsynthesisandstructureactivityrelationshipstudies |