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Doctoral Thesis
DOI
https://doi.org/10.11606/T.75.2018.tde-13112020-175102
Document
Author
Full name
Rafaely Nascimento Lima
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2018
Supervisor
Committee
Porto, André Luiz Meleiro (President)
Canduri, Fernanda
Clososki, Giuliano Cesar
Correa, Arlene Gonçalves
Leitão, Andrei
Milagre, Humberto Marcio Santos
Title in Portuguese
Síntese de amidas e amidas-graxas utilizando metodologias aplicadas ao princípios da química verde
Keywords in Portuguese
amidas-graxas
anti-câncer bactericida
CAL-B
fluxo contínuo
micro-ondas
química verde
Abstract in Portuguese
Várias são as metodologias disponíveis para a síntese de amidas, entretanto a motivação hoje em dia é desenvolver métodos sustentáveis que reduzam os desperdícios e custos dos produtos. Uma das principais abordagens da Química Verde é o uso de enzimas como catalisadores, e seguindo esse pressuposto, amidas (SM-Aa-Ak) derivadas do (S)-mandelato de etila SM foram obtidas pela reação de aminólise utilizando a lipase de Candida antactica (CAL-B) com rendimentos de 60 a 97% após 6 h de reação. Dentre as amidas obtidas com o enantiômero-(R) do mandelato de etila RM a amida RM-Ai foi capaz de inibir as células de carcinoma hepatocelular humano (HepG2, IC50=17,26 µg mL-1) e carcinoma do cólon humano (HCT116, IC50= 17,49 µg mL-1). As amidas-graxas derivadas das amidas SM-Aa-Ad (SM-Aa-AdC18, SM-Aa-AdC18N1 e SM-Aa-AdC18N2) foram obtidas com 14 a 91% de rendimentos isolados após 2 h de reação catalisada pela CAL-B. A reação de aminólise do salicilato de etila S produziu as amidas S-Aa-Ad (77 a 94%), e as amidas S-Af-Ak (11-91%, ácido fenilborônico como catalisador e 28-90% com o ácido bórico) após 24 h de reação em hexano. A produção das amidas S-Aa-Ak ainda foram otimizadas e obtidas sem o uso de solvente orgânico (23 a 99%) após 45 min de reação sob irradiação micro-ondas (~17 W). Dentre as amidas S-Aa-Ak, a amida S-Ah foi capaz de inibir o crescimento de quatro células tumorais: adenocarcinoma de mama humano (MCF7, IC50= 8,68 µg mL-1), HepG2 (IC50= 15,56 µg mL-1), carcinoma hepatocelular humano (HL-60, IC50= 16,30 µg mL-1) e HCT116 (IC50= 17,57µg mL-1). As amidas S-Af-Ah também foram capazes de inibir o crescimento das bactérias Bacillus cereus 6A, B. coagulans 6B, e Bacillus sp. 6F quando submetidas de 500 a 125 µg das substâncias pelo método de disco-difusão. As amidas-graxas S-Aa-AdC18, S-Aa-AdC18N1 e S-Aa-AdC18N2 derivadas das amidas S-Aa-Ad foram obtidas com 57 a 90% de rendimentos após 2 h de reação catalisada pela CAL-B. A amida-graxa S-AaC18 também foi obtida com 53% de rendimento pelo sistema one-pot (2 h e 45 min). Pela reação one-pot com óleo de coco a amida-graxa S-AaC12 foi obtida com 60% de rendimento após 2 h e 45 min de reação. As amidas P-Aa-Ak sintetizadas a partir do éster 3-(4-hidroxifenil)propanoato de etila P foram obtidas com rendimentos de 41 a 75% quando o éster P e as aminas Aa-Ak foram utilizados em proporções equivalentes, com uso de CAL-B, e hexano após 6 ou 72 h de reação, e obtidas com 69 a 99%, sem uso de solvente orgânico, 3 equiv. das aminas, após 24 ou 72 h de reação. As reações de aminólise em fluxo contínuo permitiu a otimização da obtenção das amidas P-Af-Ah (77-89%) para 10 min de tempo de residência com uso da CAL-B. Dentre as amidas P-Aa-Ak, a P-Ah apresentou potencial para inibir a bactéria Bacillus sp. CBMAI 1833 quando submetida a 500 µg da substância no teste de disco-difusão. As amidas-graxas P-Aa-AdC18, P-Aa-AdC18N1 e P-Aa-AdC18N2 derivadas das amidas P-Aa-Ad foram obtidas com 17 a 70% de rendimento após 2 h de reação catalisada pela CAL-B. Dessa forma, foram sintetizadas 78 amidas e amidas-graxas derivadas dos ésteres SM, RM, S e P, das quais 54 não estão reportadas na literatura a nosso conhecimento. Algumas amidas ainda foram submetidas a testes biológicos, e apresentaram atividade citotóxica contra células tumorais e propriedades bactericidas, reforçando a contribuição deste trabalho para a área da Química Verde e futuras formulações cosméticas e farmacológicas.
Title in English
Synthesis of Amides and Fatty-Amides by Methodologies Applied to Principles of Green Chemistry
Keywords in English
anti-cancer bactericide.
CAL-B
continuos-flow
fatty-amides
green chemistry
microwave
Abstract in English
There are various available methodologies for amide synthesis. However, the motivation nowadays is develop sustainable methods, which reduces waste and costs of products. One of the main approaches in Green Chemistry is the use of enzymes as catalysts, and behind this use, the amides SM-Aa-Ak derived from ethyl (S)-mandelate SM were synthetized by the aminolysis reaction using Candida antactica lipase B (CAL-B) with yields of 60 to 97% after 6 h of reaction. Among the amides obtained with ethyl (R)-mandelate RM, the amide RM-Ai was able to inhibit human hepatocellular carcinoma cells (HepG2, IC50 = 17.26 µg mL-1) and human colon carcinoma (HCT116, IC50 = 17.49 µg mL-1). The fatty acid amides derived from amides SM-Aa-Ad (SM-Aa-AdC18, SM-Aa-AdC18N1 and SM-Aa-AdC18N2) were obtained in 14% to 91% yield after 2 h of reaction catalyzed by CAL-B. The aminolysis reaction of ethyl salicylate S produced the amides S-Aa-Ad (77 to 94%), and amides S-Af-Ak (11-91%, phenylboronic acid as catalyst and 28-90% with boronic acid) after 24 h of reaction in hexane. The production of amides S-Aa-Ak were still optimized and obtained without use organic solvent (23 to 99%) after 45 min under microwave irradiation (~ 17 W). Among the amides S-Aa-Ak, the amide S-Ah was able to inhibit the growth of four tumor cells: human breast adenocarcinoma (MCF7, IC50 = 8.68 µg mL-1), HepG2 (IC50 = 15.56µg mL-1), human hepatocellular carcinoma (HL-60, IC50 = 16.30µg mL-1) and HCT116 (IC50 = 17.57 µg mL-1). The amides S-Af-Ah were also able to inhibit the growth of bacteria Bacillus cereus 6A, B. coagulans 6B, and Bacillus sp. 6F When 500 to 125 µg of amides were tested in the disk-diffusion method. The fatty acid amides S-Aa-AdC18, S-Aa-AdC18N1 and S-Aa-AdC18N2 derived from amides S-Aa-Ad were obtained with 57 to 90% yield after 2 h of the reaction catalyzed by CAL-B. The fatty acid amide S-AaC18 was also obtained in 53% yield by the one-pot system (2 h and 45 min). The one-pot reaction using coconut oil was able to produce the fatty acid amide S-AaC12 with 60% yield after 2 h and 45 min of reaction. The amides P-Aa-Ak synthesized from ethyl 3-(4-hydroxyphenyl) propanoate P were obtained with 41 to 75%, when the ester P and the amines Aa-Ak were applied in equivalent proportions, using CAL-B and hexane after 6 or 72 h of reaction. The same amides were obtained with 69 to 99%, using 3 equiv. of amines, without use organic solvent or CAL-B after 24 or 72 h of reaction. The approche using continuos-flow allowed the obtation of amides P-Af-Ah (77-89%) after 10 min of residence time in presence of CAL-B. Among amides P-Aa-Ak, the amide P-Ah presented potential in inhibt the growth of Bacillus sp. CBMAI 1833 when subjected to 500 µg of amide at disk-diffusion assay. Fatty acid amides P-Aa-AdC18, P-Aa-AdC18N1 and P-Aa-AdC18N2 derived from amides P-Aa-Ad were obtainded with 17 to 70% yield after 2 h of the reaction catalyzed by CAL-B. Thus, 78 amides and fatty acid amides derived from esters SM, RM S and P were synthesized, of which 54 are not reported in the literature to our knowledge. Some of these amides were still submitted to biological tests, and presented cytotoxic activity against tumor cells lines and bactericidal properties, reinforcing the contribution of this work for Green Chemistry synthesis and future cosmetic and pharmacological formulations.
 
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2020-11-19
 
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