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Generation of a small library of indole derivatives to target drug resistance in cancer
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Inegavelmente, o cancro continua a ser um obstáculo à saúde pública, visto que, para além da preocupação inerente ao desenvolvimento de uma doença de propagação descontrolada e com mecanismos de sobrevivência, se tem verificado que as células cancerígenas têm sido capazes de desenvolver multirresistência contra os fármacos comercialmente disponíveis.
Com o objetivo de encontrar novos agentes anticancerígenos, o presente trabalho consistiu na síntese de novas moléculas baseadas nas estruturas da isatina e da triptolina. Os derivados de isatina resultaram de uma reação de Passerini multicomponente entre diferentes isatinas, isocianidas e ácidos carboxílicos. Foram obtidos quinze derivados de isatina (2.18-2.32), com rendimentos moderados a altos. Os derivados de triptolina foram obtidos a partir de um processo sequencial de três passos. O primeiro compreendeu a formação da 3-bromo propano tripolina por alquilação da triptolina com 3-dibromo propano por meio de uma reação SN2, o segundo consistiu na formação da 3-azido propano triptolina, por reação da 3-bromo propano triptolina com azida de sódio, e no terceiro, foi realizada uma reação click, entre a azida da triptolina e alcinos terminais com diferentes substituintes. Foram obtidos oito derivados de triptolina (2.44-2.51), com rendimentos moderados a bons. Através de colaboração externa, a atividade anti-proliferativa dos derivados de isatina (2.18-2.32) foi avaliada in vitro contra linhas celulares do cancro do pulmão (A549 e SW1573), pancreático (MIA PaCa-2), do cólon (WiDr), da mama (T-47D) e cervical (HeLa). O composto 2.23 foi destacado como promissor para o desenvolvimento adicional de agentes anticancerígenos, visto que reduziu a proliferação celular com valores de GI50 abaixo de 10 µM (6.3 ± 2.1 a 15 ± 1.6 µM).
Undeniably, cancer remains a major public health concern, since, aside of the inherent concerns of a disease characterized by uncontrolled growth and survival mechanisms, it has been observed that cancer cells can develop multidrug resistance against currently available drugs. Aiming at finding anticancer compounds, this thesis focuses on the synthesis of new molecules based on the structures of isatin and tryptoline, that are promising for cancer treatment. Isatin derivatives resulted from a multicomponent Passerini reaction between different isatins, isocyanides and carboxylic acids. Fifteen isatin derivatives (2.18-2.32) were obtained, with moderate to high yields. The tryptoline derivatives were obtained from a sequential three-step process. The first comprehended the formation of 3-bromopropane tryptoline, by alkylation of tryptoline with 1,3-dibromopropane by a SN2 reaction, the second consisted in the formation of 3-azidepropane tryptoline by reaction of 3-bromopropane tryptoline with sodium azide, and the third, a click reaction between the 3-azidepropane tryptoline and terminal alkynes with different substituents. Eight tryptoline derivatives (2.44-2.51) were obtained, with moderate to good yields. Through external collaboration, the antiproliferative activity of the isatin derivatives (2.18-2.32) was evaluated in vitro against lung (A549 and SW1573), pancreatic (MIA PaCa-2), colon (WiDr), breast (T-47D) and cervical (HeLa) cancer cell lines. Compound 2.23 was highlighted as promising for the further development of anticancer agents, as it reduced cell proliferation with GI50 values below 10 µM (6.3 ± 2.1 to 15 ± 1.6 µM).
Undeniably, cancer remains a major public health concern, since, aside of the inherent concerns of a disease characterized by uncontrolled growth and survival mechanisms, it has been observed that cancer cells can develop multidrug resistance against currently available drugs. Aiming at finding anticancer compounds, this thesis focuses on the synthesis of new molecules based on the structures of isatin and tryptoline, that are promising for cancer treatment. Isatin derivatives resulted from a multicomponent Passerini reaction between different isatins, isocyanides and carboxylic acids. Fifteen isatin derivatives (2.18-2.32) were obtained, with moderate to high yields. The tryptoline derivatives were obtained from a sequential three-step process. The first comprehended the formation of 3-bromopropane tryptoline, by alkylation of tryptoline with 1,3-dibromopropane by a SN2 reaction, the second consisted in the formation of 3-azidepropane tryptoline by reaction of 3-bromopropane tryptoline with sodium azide, and the third, a click reaction between the 3-azidepropane tryptoline and terminal alkynes with different substituents. Eight tryptoline derivatives (2.44-2.51) were obtained, with moderate to good yields. Through external collaboration, the antiproliferative activity of the isatin derivatives (2.18-2.32) was evaluated in vitro against lung (A549 and SW1573), pancreatic (MIA PaCa-2), colon (WiDr), breast (T-47D) and cervical (HeLa) cancer cell lines. Compound 2.23 was highlighted as promising for the further development of anticancer agents, as it reduced cell proliferation with GI50 values below 10 µM (6.3 ± 2.1 to 15 ± 1.6 µM).
Descrição
Tese de mestrado, Química Medicinal e Biofarmacêutica, 2025, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Indole derivatives Kinase inhibitors Multidrug resistance Antiproliferative activity Teses de mestrado - 2025