Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues
Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (<b>4</b>...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/209 |
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| author | Caroline Marques Xavier Costa Cristiane Aparecida-Silva Luis Eduardo Reina Gamba Thalita Neves de Melo Gisele Barbosa Manoel Oliveira de Moraes Junior Victoria Regina Thomaz de Oliveira Carolinne Souza de Amorim João A. Moraes Eliezer Jesus Barreiro Lídia Moreira Lima |
| author_facet | Caroline Marques Xavier Costa Cristiane Aparecida-Silva Luis Eduardo Reina Gamba Thalita Neves de Melo Gisele Barbosa Manoel Oliveira de Moraes Junior Victoria Regina Thomaz de Oliveira Carolinne Souza de Amorim João A. Moraes Eliezer Jesus Barreiro Lídia Moreira Lima |
| author_sort | Caroline Marques Xavier Costa |
| collection | DOAJ |
| description | Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (<b>4</b>). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (<b>5a-f</b>). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound <b>5f</b> (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t<sub>1/2</sub> = 462 min; Clapp = 0.058 mL/min/g). The ability of <b>5f</b> to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib. |
| first_indexed | 2024-03-11T08:17:44Z |
| format | Article |
| id | doaj.art-3c9088700c7840cb84fed14bd8f8e546 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:17:44Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-3c9088700c7840cb84fed14bd8f8e5462023-11-16T22:36:30ZengMDPI AGPharmaceuticals1424-82472023-01-0116220910.3390/ph16020209Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib AnaloguesCaroline Marques Xavier Costa0Cristiane Aparecida-Silva1Luis Eduardo Reina Gamba2Thalita Neves de Melo3Gisele Barbosa4Manoel Oliveira de Moraes Junior5Victoria Regina Thomaz de Oliveira6Carolinne Souza de Amorim7João A. Moraes8Eliezer Jesus Barreiro9Lídia Moreira Lima10Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Biologia Redox (LABIO-RedOx<sup>®</sup>), Instituto de Ciências Biológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, BrazilLaboratório de Biologia Redox (LABIO-RedOx<sup>®</sup>), Instituto de Ciências Biológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio<sup>®</sup>), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, BrazilTargeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (<b>4</b>). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (<b>5a-f</b>). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound <b>5f</b> (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t<sub>1/2</sub> = 462 min; Clapp = 0.058 mL/min/g). The ability of <b>5f</b> to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.https://www.mdpi.com/1424-8247/16/2/209cancerPI3K inhibitorsgedatolisibflow cytometryMTT |
| spellingShingle | Caroline Marques Xavier Costa Cristiane Aparecida-Silva Luis Eduardo Reina Gamba Thalita Neves de Melo Gisele Barbosa Manoel Oliveira de Moraes Junior Victoria Regina Thomaz de Oliveira Carolinne Souza de Amorim João A. Moraes Eliezer Jesus Barreiro Lídia Moreira Lima Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues Pharmaceuticals cancer PI3K inhibitors gedatolisib flow cytometry MTT |
| title | Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues |
| title_full | Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues |
| title_fullStr | Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues |
| title_full_unstemmed | Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues |
| title_short | Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues |
| title_sort | design synthesis and phenotypic profiling of simplified gedatolisib analogues |
| topic | cancer PI3K inhibitors gedatolisib flow cytometry MTT |
| url | https://www.mdpi.com/1424-8247/16/2/209 |
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