Publicação
Desenvolvimento de moléculas híbridas de agentes alquilantes para tratamento do glioma
| Resumo: | Glioma is a type of primary brain tumor that arises from glial cells. The most common of malignant gliomas, glioblastoma multiforme, has a median survival of approximately 14 months after diagnosis. Temozolomide is the major anticancer agent for gliomas. It is a triazene alkylating agent and, owing to its lipophilicity, has two features that make it an antitumor of choice: can be given orally and is able to cross the blood-brain barrier. However, therapeutic effectiveness is often disappointing, largely in consequence of the lack of selectivity for tumor cells, insufficient drug concentration in the tumor and notorious resistance. Valproic acid is an anticonvulsant used in the treatment of epilepsy. Also, valproic acid inhibits a subset of histone deacetylases (HDAC) and affects gene transcription. Furthermore, it inhibits DNA repair, thereby potentiating cytotoxic treatments such as chemotherapy or radiation therapy. A promising research line in this field is the development of the so-called hybrid molecules, which has shown to be more effective by having a superior therapeutic effect. This research work is based on the design of novel hybrid compounds (HYBCOM, HYBBUT, HYBISO, HYBETHYL and HYBGLINIB) with two units, an aryltriazene and one HDAC inhibitor, connected by an amide linkage . The synthesis of the hybrid compound was attempted with different methodologies, based on carboxylic acid activation with low to average yields. The most efficient method was CDI / HOBt with yields ranging from 22 to 87 %. The stability in phosphate buffer pH 7.4 and human plasma (80% v/v) was acessed by HPLC and hybrid compounds showed to be generally stable in phisiological conditions, with half-lives ranging from 14 to values greater than 72h. Moreover, lipophilicity and other molecular properties determined, showed favorable druglikeness of the hybrid compounds. Additionally, hybrid compounds were screened for their inhibitory activity against HDAC, showing that HYBCOM 2 and HYBBUT presented enhanced activity comparing to the respective HDAC inhibitors alone. Also, preliminary results towards a glioma cell line (GL261), demonstrated that HYBCOM 1 and HYBETHYL have higher efficacy with lower concentrations, when compared to Temozolomide. Triazene hybrid molecules revealed to be a promising approach for glioma treatment, providing enhanced HDAC inhibitors, with remarkable anti-tumor potential. |
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| Autores principais: | Braga, Cláudia Marisa Fernandes |
| Assunto: | Brain Glioma Hybrids Triazenes Histone deacetylase inhibitors Teses de mestrado - 2016 |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Glioma is a type of primary brain tumor that arises from glial cells. The most common of malignant gliomas, glioblastoma multiforme, has a median survival of approximately 14 months after diagnosis. Temozolomide is the major anticancer agent for gliomas. It is a triazene alkylating agent and, owing to its lipophilicity, has two features that make it an antitumor of choice: can be given orally and is able to cross the blood-brain barrier. However, therapeutic effectiveness is often disappointing, largely in consequence of the lack of selectivity for tumor cells, insufficient drug concentration in the tumor and notorious resistance. Valproic acid is an anticonvulsant used in the treatment of epilepsy. Also, valproic acid inhibits a subset of histone deacetylases (HDAC) and affects gene transcription. Furthermore, it inhibits DNA repair, thereby potentiating cytotoxic treatments such as chemotherapy or radiation therapy. A promising research line in this field is the development of the so-called hybrid molecules, which has shown to be more effective by having a superior therapeutic effect. This research work is based on the design of novel hybrid compounds (HYBCOM, HYBBUT, HYBISO, HYBETHYL and HYBGLINIB) with two units, an aryltriazene and one HDAC inhibitor, connected by an amide linkage . The synthesis of the hybrid compound was attempted with different methodologies, based on carboxylic acid activation with low to average yields. The most efficient method was CDI / HOBt with yields ranging from 22 to 87 %. The stability in phosphate buffer pH 7.4 and human plasma (80% v/v) was acessed by HPLC and hybrid compounds showed to be generally stable in phisiological conditions, with half-lives ranging from 14 to values greater than 72h. Moreover, lipophilicity and other molecular properties determined, showed favorable druglikeness of the hybrid compounds. Additionally, hybrid compounds were screened for their inhibitory activity against HDAC, showing that HYBCOM 2 and HYBBUT presented enhanced activity comparing to the respective HDAC inhibitors alone. Also, preliminary results towards a glioma cell line (GL261), demonstrated that HYBCOM 1 and HYBETHYL have higher efficacy with lower concentrations, when compared to Temozolomide. Triazene hybrid molecules revealed to be a promising approach for glioma treatment, providing enhanced HDAC inhibitors, with remarkable anti-tumor potential. |
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