Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer
Chronic inflammation plays a crucial role in bladder cancer (BCa) development and progression. To offer a unique treatment opportunity for this type of cancer, a hydrazide derivative namely, DAB-1, was recently identified in our laboratory as a potential drug to target cancer-related inflammation. I...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | European Journal of Medicinal Chemistry Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417422000413 |
| _version_ | 1811294996332019712 |
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| author | Yassine Oufqir Laurie Fortin Julie Girouard Francis Cloutier Maude Cloutier Marie-France Leclerc Denise Belgorosky Ana María Eiján Gervais Bérubé Carlos Reyes-Moreno |
| author_facet | Yassine Oufqir Laurie Fortin Julie Girouard Francis Cloutier Maude Cloutier Marie-France Leclerc Denise Belgorosky Ana María Eiján Gervais Bérubé Carlos Reyes-Moreno |
| author_sort | Yassine Oufqir |
| collection | DOAJ |
| description | Chronic inflammation plays a crucial role in bladder cancer (BCa) development and progression. To offer a unique treatment opportunity for this type of cancer, a hydrazide derivative namely, DAB-1, was recently identified in our laboratory as a potential drug to target cancer-related inflammation. In preclinical models of murine BCa, this particular compound exhibited remarkable anticancer activities. Structurally, DAB-1 is made from para-aminobenzoic acid and bears two different components, a maleimide and a hydrazide moieties, which are critical for its anti-inflammatory activity and its anticancer properties. In order to improve its biological potential, the hydrazide moiety was further modified to provide 3 s-generation molecules named, DAB-2-28, DAB-2-31A, and DAB-2-31B, and two third-generation molecules named, DAB-3-27 and DAB-3-33. Data from in vitro studies revealed that, among the different DAB molecules under study, DAB-2-28 has less cytotoxic activity with greater efficiency than DAB-1 to inhibit the production of nitric oxide (NO) induced by the combination of IFNγ with TNFα, as well as the activation of pro-tumoral and pro-inflammatory signaling pathways IL6/STAT3 and TNFα/NFκB. Moreover, while DAB-2-28 exhibited similar anti-inflammatory activity in vivo to DAB-1 in a model of carrageenan-induced acute inflammation, it efficiently inhibited the expression of the enzymes iNOS and COX-2 induced by the combined activation of IFNγ with LPS in peritoneal macrophages. Notably, analysis of the growth kinetics of MB49-I tumors implanted subcutaneously in C57Bl/6 mice showed that DAB-2-28 was more efficient to inhibit tumor development. In conclusion, this study provided preclinical proof-of-principle for DAB-2-28 molecule in the treatment of BCa. |
| first_indexed | 2024-04-13T05:25:46Z |
| format | Article |
| id | doaj.art-7c24b9d922da41028e43e066f7c5efdf |
| institution | Directory Open Access Journal |
| issn | 2772-4174 |
| language | English |
| last_indexed | 2024-04-13T05:25:46Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj.art-7c24b9d922da41028e43e066f7c5efdf2022-12-22T03:00:35ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742022-12-016100069Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancerYassine Oufqir0Laurie Fortin1Julie Girouard2Francis Cloutier3Maude Cloutier4Marie-France Leclerc5Denise Belgorosky6Ana María Eiján7Gervais Bérubé8Carlos Reyes-Moreno9Laboratoire de Recherche en Oncologie et Immunobiologie (LROI) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Biologie Médicale, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaLaboratoire de Recherche en Oncologie et Immunobiologie (LROI) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Biologie Médicale, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaLaboratoire de Recherche en Oncologie et Immunobiologie (LROI) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Biologie Médicale, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaLaboratoire de Recherche en Chimie Médicinale (LRCM) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Chimie, Biochimie et Physique, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaLaboratoire de Recherche en Chimie Médicinale (LRCM) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Chimie, Biochimie et Physique, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaLaboratoire de Recherche en Chimie Médicinale (LRCM) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Chimie, Biochimie et Physique, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, CanadaInstituto de Oncología Ángel H. Roffo, Área de Investigación, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Oncología Ángel H. Roffo, Área de Investigación, Universidad de Buenos Aires, Buenos Aires, ArgentinaLaboratoire de Recherche en Chimie Médicinale (LRCM) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Chimie, Biochimie et Physique, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, Canada; Corresponding author.Laboratoire de Recherche en Oncologie et Immunobiologie (LROI) et Groupe de Recherche en Signalisation Cellulaire (GRSC), Département de Biologie Médicale, Université Du Québec à Trois-Rivières, Trois-Rivières, QC, Canada; Corresponding author.Chronic inflammation plays a crucial role in bladder cancer (BCa) development and progression. To offer a unique treatment opportunity for this type of cancer, a hydrazide derivative namely, DAB-1, was recently identified in our laboratory as a potential drug to target cancer-related inflammation. In preclinical models of murine BCa, this particular compound exhibited remarkable anticancer activities. Structurally, DAB-1 is made from para-aminobenzoic acid and bears two different components, a maleimide and a hydrazide moieties, which are critical for its anti-inflammatory activity and its anticancer properties. In order to improve its biological potential, the hydrazide moiety was further modified to provide 3 s-generation molecules named, DAB-2-28, DAB-2-31A, and DAB-2-31B, and two third-generation molecules named, DAB-3-27 and DAB-3-33. Data from in vitro studies revealed that, among the different DAB molecules under study, DAB-2-28 has less cytotoxic activity with greater efficiency than DAB-1 to inhibit the production of nitric oxide (NO) induced by the combination of IFNγ with TNFα, as well as the activation of pro-tumoral and pro-inflammatory signaling pathways IL6/STAT3 and TNFα/NFκB. Moreover, while DAB-2-28 exhibited similar anti-inflammatory activity in vivo to DAB-1 in a model of carrageenan-induced acute inflammation, it efficiently inhibited the expression of the enzymes iNOS and COX-2 induced by the combined activation of IFNγ with LPS in peritoneal macrophages. Notably, analysis of the growth kinetics of MB49-I tumors implanted subcutaneously in C57Bl/6 mice showed that DAB-2-28 was more efficient to inhibit tumor development. In conclusion, this study provided preclinical proof-of-principle for DAB-2-28 molecule in the treatment of BCa.http://www.sciencedirect.com/science/article/pii/S2772417422000413Aminobenzoic acidBladder cancerHydrazide derivativesInflammationInterferon gammaInterleukin 6 |
| spellingShingle | Yassine Oufqir Laurie Fortin Julie Girouard Francis Cloutier Maude Cloutier Marie-France Leclerc Denise Belgorosky Ana María Eiján Gervais Bérubé Carlos Reyes-Moreno Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer European Journal of Medicinal Chemistry Reports Aminobenzoic acid Bladder cancer Hydrazide derivatives Inflammation Interferon gamma Interleukin 6 |
| title | Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer |
| title_full | Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer |
| title_fullStr | Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer |
| title_full_unstemmed | Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer |
| title_short | Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer |
| title_sort | synthesis of new para aminobenzoic acid derivatives in vitro biological evaluation and preclinical validation of dab 2 28 as a therapeutic option for the treatment of bladder cancer |
| topic | Aminobenzoic acid Bladder cancer Hydrazide derivatives Inflammation Interferon gamma Interleukin 6 |
| url | http://www.sciencedirect.com/science/article/pii/S2772417422000413 |
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