Publicação
Desenvolvimento de moléculas híbridas para o tratamento do melanoma maligno metastático
| Resumo: | Skin cancer is classified as non-melanoma skin cancer or malignant melanoma. The last one is considered the most dangerous skin cancer since it is the most aggressive malignant tumour of the human species. Currently, the therapeutic approaches exhibit low response levels and limited survival rates. The incidence of malignant melanoma is increasing in western countries. Thus, the development of novel drugs for malignant melanoma treatment is crucial. Hybridization of compounds is one of the latest and most promising approaches for designing new molecular entities with anticancer properties. In this dissertation we synthesized a new series of hybrid molecules with two different pharmacophores: the monomethyltriazene, a DNA alkylator is coupled with a sulfur analogue of tyrosine with specific melanocytotoxic properties. The melanocytotoxic agent acts as a tyrosinase substrate in the malign melanocyte environment, and then releases the cytotoxic agent in loco, improving the targeting properties of the compounds. The synthesized hybrid molecules were evaluated for their chemical and enzymatic stability. All compounds revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t1/2 > 10 days) and are slowly hydrolysed in human plasma (76 h < t1/2 < 173 h). Additionally, the synthesized hybrid molecules were also evaluated as tyrosinase substrates. All the compounds are excellent tyrosinase substrates (10 sec < t1/2 < 30 sec). The most rapidly oxidized compound releases MMT after 10 seconds. In vitro cytotoxic evaluation of the synthesized hybrids showed IC50 values in the micromolar range in murine (B16F10, CT-26) and human (MNT-1, HCT-116) melanoma and colon cancer cell lines, respectively. Moreover, a keratinocyte human cell line, HaCat, was also tested as control and IC50 values were higher than those obtained for cancer cell lines demonstrating the specificity of the synthesized compounds towards tumour cells. Hybrid compounds 31 constitute very promising candidates to malignant melanoma chemotherapy. |
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| Autores principais: | Gonçalves, Andreia Filipa Alcanena |
| Assunto: | Cancro Melanoma maligno Triazenos Tirosinase Análogos de enxofre da tirosina Teses de mestrado - 2018 |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | português |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Skin cancer is classified as non-melanoma skin cancer or malignant melanoma. The last one is considered the most dangerous skin cancer since it is the most aggressive malignant tumour of the human species. Currently, the therapeutic approaches exhibit low response levels and limited survival rates. The incidence of malignant melanoma is increasing in western countries. Thus, the development of novel drugs for malignant melanoma treatment is crucial. Hybridization of compounds is one of the latest and most promising approaches for designing new molecular entities with anticancer properties. In this dissertation we synthesized a new series of hybrid molecules with two different pharmacophores: the monomethyltriazene, a DNA alkylator is coupled with a sulfur analogue of tyrosine with specific melanocytotoxic properties. The melanocytotoxic agent acts as a tyrosinase substrate in the malign melanocyte environment, and then releases the cytotoxic agent in loco, improving the targeting properties of the compounds. The synthesized hybrid molecules were evaluated for their chemical and enzymatic stability. All compounds revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t1/2 > 10 days) and are slowly hydrolysed in human plasma (76 h < t1/2 < 173 h). Additionally, the synthesized hybrid molecules were also evaluated as tyrosinase substrates. All the compounds are excellent tyrosinase substrates (10 sec < t1/2 < 30 sec). The most rapidly oxidized compound releases MMT after 10 seconds. In vitro cytotoxic evaluation of the synthesized hybrids showed IC50 values in the micromolar range in murine (B16F10, CT-26) and human (MNT-1, HCT-116) melanoma and colon cancer cell lines, respectively. Moreover, a keratinocyte human cell line, HaCat, was also tested as control and IC50 values were higher than those obtained for cancer cell lines demonstrating the specificity of the synthesized compounds towards tumour cells. Hybrid compounds 31 constitute very promising candidates to malignant melanoma chemotherapy. |
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