Publicação
Spirooxadiazole oxindoles as potential anticancer agents
| Resumo: | Cancer is a large group of diseases which arises from one single cell, grows uncontrolled and may spread to other organs 1. According to WHO Cancer Report (2015), it is one of the leading causes of morbidity and mortality in the modern world with 8.2 million deaths in 2012 and 22 million expected cases within the next 2 decades 2. Latest statistics show that colon cancer is globally the third most commonly diagnosed cancer type and specifically the only cancer observed with approximately equal frequency in men and women 3. Cancer is globally an important area of therapeutic interest. The high number of deaths is a crucial reason for science to develop new approaches and novel compounds for its treatment. The non-selectivity and acute toxicity of many antitumor agents has prompted the search for new antitumor agents with improved tumor selectivity, efficiency and safety. Herein, our latest results on the synthesis of a novel chemical family of spirooxindoles containing an 1,3,4-oxadiazoline five-membered ring will be presented. These two scaffolds (spirooxindole and oxadiazole) are separately reported to have in vitro antitumor activity as p53/MDM2 inhibitor 4,5. However, oxindole joined with 1,3,4-oxadiazoline ring in the same molecule was never studied before as anti-tumor agents. The synthesis was performed by 1,3-dipolar cycloaddition between derivatives of indoline-2,3-diones and hydrazonyl chlorides. Using this method, twelve compounds were obtained with high yields. Additionally, all compounds were tested in vitro in three different colorectal cancer cell lines: an isogenic matched pair of wild type p53 and deleted human colorectal cancer cell lines [HCT116 p53(+/+) and p53(-/-)], and a human colorectal adenocarcinoma cell line [SW620 (mut p53)], in order to report cell growth inhibitory activity. From the library of spirooxadiazoline oxindoles, quite remarkably, IC50 values of four compounds were calculated. Three compounds displayed IC50 values below 10 μM and antiproliferative activity in SW620 cell line. Importantly, one compound significantly decreased SW620 cell viability, while it did not decrease normal fibroblasts viability. This indicates that compound 32a associated cytotoxicity is specific for tumor cells. In sum, spirooxadiazole oxindoles may represent a promising scaffold for the development of new antitumor agents. Ongoing studies are directed to ascertain their molecular mechanism of action and cellular toxicity, in order to confirm their potential as antitumor agents. |
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| Autores principais: | Uyar, Damla |
| Assunto: | Spirooxindoles Spirooxadiazoline 1,3-dipolar cycloaddition Colorectal cancer Biological activity Teses de mestrado - 2016 |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Cancer is a large group of diseases which arises from one single cell, grows uncontrolled and may spread to other organs 1. According to WHO Cancer Report (2015), it is one of the leading causes of morbidity and mortality in the modern world with 8.2 million deaths in 2012 and 22 million expected cases within the next 2 decades 2. Latest statistics show that colon cancer is globally the third most commonly diagnosed cancer type and specifically the only cancer observed with approximately equal frequency in men and women 3. Cancer is globally an important area of therapeutic interest. The high number of deaths is a crucial reason for science to develop new approaches and novel compounds for its treatment. The non-selectivity and acute toxicity of many antitumor agents has prompted the search for new antitumor agents with improved tumor selectivity, efficiency and safety. Herein, our latest results on the synthesis of a novel chemical family of spirooxindoles containing an 1,3,4-oxadiazoline five-membered ring will be presented. These two scaffolds (spirooxindole and oxadiazole) are separately reported to have in vitro antitumor activity as p53/MDM2 inhibitor 4,5. However, oxindole joined with 1,3,4-oxadiazoline ring in the same molecule was never studied before as anti-tumor agents. The synthesis was performed by 1,3-dipolar cycloaddition between derivatives of indoline-2,3-diones and hydrazonyl chlorides. Using this method, twelve compounds were obtained with high yields. Additionally, all compounds were tested in vitro in three different colorectal cancer cell lines: an isogenic matched pair of wild type p53 and deleted human colorectal cancer cell lines [HCT116 p53(+/+) and p53(-/-)], and a human colorectal adenocarcinoma cell line [SW620 (mut p53)], in order to report cell growth inhibitory activity. From the library of spirooxadiazoline oxindoles, quite remarkably, IC50 values of four compounds were calculated. Three compounds displayed IC50 values below 10 μM and antiproliferative activity in SW620 cell line. Importantly, one compound significantly decreased SW620 cell viability, while it did not decrease normal fibroblasts viability. This indicates that compound 32a associated cytotoxicity is specific for tumor cells. In sum, spirooxadiazole oxindoles may represent a promising scaffold for the development of new antitumor agents. Ongoing studies are directed to ascertain their molecular mechanism of action and cellular toxicity, in order to confirm their potential as antitumor agents. |
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