Recebido em 1/7/05; aceito em 20/9/05; publicado na web em 6/6/06 THE INCREDIBLE USE OF DANGEROUS CHEMICALS IN THE PAST. This work describes an overview of the use of chemicals in several commercial applications along the XXth century. The use of chemicals by men was largely empirical for many centuries, since there was no organized chemical and toxicological knowledge. During the XIXth century the chemical industry gained a crucial role in the development of technology, as evidenced by the extraordinary increase of new products and their incorporation into everyday life. Chemistry was considered a science capable of solving any problem, little regard being paid to the consequences of the widespread use of new chemicals. Efficiency was more important than safety and consumer information. From tragedies and the development of knowledge on toxicology men adopted more careful protocols before a new chemical was proposed for use. Modern life could not exist without the large-scale employment of a variety of chemicals but information on their responsible and conscious use is now essential. Products that were once considered the "last word in technology" have eventually proven dangerous to humans and the environment in the short or long time range. Previous knowledge on the toxicological dangers and the properties of a given substance or product before commercialization is necessary for safe handling.Keywords: dangerous chemicals; safety; commercial chemistry. INTRODUÇÃOO uso de produtos químicos data dos primórdios da civilização. A descoberta do fogo pode fornecer elementos básicos para o desenvolvimento cultural de nossos antepassados. A fabricação de algumas armas e objetos metálicos rudimentares, além de tintas utilizadas na expressão de objetos e animais nas cavernas, demonstram este fato.Antes mesmo do início da era cristã o homem já dominava as técnicas de cunhagem de moedas, metalurgia, fabricação de espelhos de bronze, assim como a obtenção de mercúrio e amálgamas 1 . O início do século XVI foi marcado pela publicação de um livro de Hieronymus Brunschwygk (1450-1513) com o nome "Liber de arte distillandi de simplicibus". Este livro teve grande importância porque marcou o início da preocupação do homem em preparar produtos quí-micos, oriundos de extratos de plantas, que pudessem curar doenças e aliviar a dor. Esta tendência iria se refletir por todo o século XVI e também no XVII, sob o nome de iatroquímica (atualmente, química medicinal), tendo como um dos seus grandes precursores Phillipus Aureolus Paracelsus (1490-1541). Apesar do misticismo que empregava em suas técnicas, induzindo-o a avaliações errôneas, teve sucesso em algumas iniciativas, tais como a utilização de tinturas (extratos alcoólicos), o enxofre (antimicótico) e o ópio (sedativo) 1 . Após esta fase de utilização mais ou menos empírica de produtos químicos, com o início da I Revolução Industrial (por volta de 1800), houve a mecanização da produção devido ao grande avanço tecnológico decorrente da inserção de máquinas a vapor e de melhorias nos...
Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC50 of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC50 value of 35.8 μM (imatinib, IC50 = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.
The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.
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