Publicação
N-Substituted 5-amino-4-cyanopyrazoles: synthesis and reactivity studies
| Resumo: | A literature search indicates that the presence of the pyrazole nucleus in different structures allowed to prepare materials that were applied in technological areas, in medicine, pharmacology or agriculture. Pyrazoles are important building blocks in synthetic and medicinal chemistry because they can be incorporated into a variety of aromatic/heteroaromatic structures and, depending on the substitution pattern, can present a wide range of biological activities, including anticancer activity. In this work, 5-amino-4-cyanopyrazoles were synthetized by the reaction of 2-ethoxymethylene-malononitrile and substituted hydrazines, using experimental methods previously developed and optimized in the research group. The o-aminonitrile unit present in these pyrazoles allowed them to be used as starting materials in the preparation of an imidate derivative that was subsequently used in the synthesis of dimeric structures, by reaction with triethylorthoformate and acid catalysis. The use of acid also induced cleavage of the imidate function, regenerating the starting pyrazole ring, and this contributed to reduce the yield of the dimeric structures that were prepared. 5-Amino-4-cyanopyrazoles were also used as precursors in the synthesis of pyrazolo[3,4- d]pyrimidines through the reaction with N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or triethylorthoformate, followed by the addition of aromatic, heteroaromatic or alkyl amines, in the presence of acid. An optimization study of the experimental conditions for the synthesis of these compounds and also to isolate the product, was also performed. This approach allowed to prepare 59 pyrazolo[3,4-d]pyrimidines by reaction with aromatic amines, 4 with heteroaromatic amines and 3 with alkyl amines. The presence of acetic acid resulted in partial acetylation of the amines, reducing the amount of free amine available to generate the pyrazolo[3,4-d]pyrimidine, which contributed to reduce the yield of the product. A selection of these pyrazolo[3,4-d]pyrimidine derivatives was tested for their anticancer activity using the cell line Hs578t of triple negative breast cancer, at ICVS (University of Minho). One of the tested structures demonstrated promising anticancer activity, with an IC50 of 4.95 µM. Future work should focus on the synthesis of analogous pyrazolo[3,4-d]pyrimidines, aiming to complete the SAR study of this family of compounds. |
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| Autores principais: | Alves, Diana Isabel Sousa |
| Assunto: | 5-amino-4-cyanopyrazoles Anticancer activity Triple-negative breast cancer N,N-dimethylacetamide dimethyl acetal N,N-dimethylformamide diethyl acetal Pyrazolo[3,4-d]pyrimidines Triethylorthoformate 5-amino-4-cianopirazoles Atividade anticancerígena Cancro da mama triplo negativo N,N-dimetilacetamida dimetil acetal N,N-dimetilformamida dietil acetal Pirazolo[3,4- d]pirimidinas Trietilortoformiato |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | A literature search indicates that the presence of the pyrazole nucleus in different structures allowed to prepare materials that were applied in technological areas, in medicine, pharmacology or agriculture. Pyrazoles are important building blocks in synthetic and medicinal chemistry because they can be incorporated into a variety of aromatic/heteroaromatic structures and, depending on the substitution pattern, can present a wide range of biological activities, including anticancer activity. In this work, 5-amino-4-cyanopyrazoles were synthetized by the reaction of 2-ethoxymethylene-malononitrile and substituted hydrazines, using experimental methods previously developed and optimized in the research group. The o-aminonitrile unit present in these pyrazoles allowed them to be used as starting materials in the preparation of an imidate derivative that was subsequently used in the synthesis of dimeric structures, by reaction with triethylorthoformate and acid catalysis. The use of acid also induced cleavage of the imidate function, regenerating the starting pyrazole ring, and this contributed to reduce the yield of the dimeric structures that were prepared. 5-Amino-4-cyanopyrazoles were also used as precursors in the synthesis of pyrazolo[3,4- d]pyrimidines through the reaction with N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide diethyl acetal or triethylorthoformate, followed by the addition of aromatic, heteroaromatic or alkyl amines, in the presence of acid. An optimization study of the experimental conditions for the synthesis of these compounds and also to isolate the product, was also performed. This approach allowed to prepare 59 pyrazolo[3,4-d]pyrimidines by reaction with aromatic amines, 4 with heteroaromatic amines and 3 with alkyl amines. The presence of acetic acid resulted in partial acetylation of the amines, reducing the amount of free amine available to generate the pyrazolo[3,4-d]pyrimidine, which contributed to reduce the yield of the product. A selection of these pyrazolo[3,4-d]pyrimidine derivatives was tested for their anticancer activity using the cell line Hs578t of triple negative breast cancer, at ICVS (University of Minho). One of the tested structures demonstrated promising anticancer activity, with an IC50 of 4.95 µM. Future work should focus on the synthesis of analogous pyrazolo[3,4-d]pyrimidines, aiming to complete the SAR study of this family of compounds. |
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