Síntese e avaliação da ação antitumoral de derivados 1,2,4-oxadiazólicos em modelos in vitro de linhagens de tumores humanos e animais

Abstract

Cancer is among one of the biggest causes of deaths in the world. It is well known that incidence and mortality related with this disease are increasing, also there is a deficiency in chemotherapeutic treatment; so, the scientific society still looking for new compounds that show antitumor activity and have greater efficiency and high selectivity. Considering the panorama, this work consists in the synthesis and evaluation of antitumor activity of 1,2,4- oxadiazolic derivatives substituted in positions 3 and 5. Twenty-two compounds were synthesized from three different nitriles with hydroxylamine, generating three amidoximes. Then the reaction of amidoximes with bromo acetyl bromide followed by cyclization led to three 5-(bromomethyl)-1,2,4-oxadiazole intermediates. Further, more six other oxadiazol derivatives were obtained by action of these three intermediates with ethylenediamine, propanediamine, butanediamine and piperazine. Finally, more ten compounds were synthesized by reaction of three piperazine-containing derivatives with long chain alkyl halides. All synthesized compounds had their structures elucidated by infrared and 1H and 13C NMR spectra. All compounds were evaluated for antitumor activity by cytotoxicity assay for IC50 and selectivity index (SI) determination in animal and human cell lines. The synthesized compounds showed significant cytotoxicity and selectivity against animal tumor cell lines B16F10 (6,0 ± 2,2 μM ≤ IC50 ≤ 27,6 ± 5,1 μM; 0,5 ≤ SIBHK-21 ≤ 2,5) e CT26-WT (2,5 ± 0,7 μM ≤ IC50 ≤ 36,1 ± 2,4 μM; 0,5 ≤ SIBHK-21 ≤ 4,9). Specially three 5-(bromomethyl)-1,2,4-oxadiazole intermediates and N-alkylated oxadiazoles containing 12 carbon chain. Against human tumor cell line RKO-AS45-1 were obtained IC50 values between 29,2μg/mL and 672 μg/mL with selective index (SIWI-26 VA4) lower than 2,0. Cell death by apoptosis was evaluated for two of the most cytotoxic and selective compounds (compounds 20 and 22) in RKO-AS45-1 (human colon carcinoma) and WI-26 VA4 (human lung fibroblast) cell lines. With these data it was possible to observe that compound 22 induced death by necrosis, undesirable mechanism of cell death, since it can generate inflammatory processes and other side effects. On the other hand, the treatment with compound 20 induced little cell death, so, its cytotoxicity may be related with other mechanism that regulate cell function. Until now, preliminary results from cellular cycle analysis by flow cytometry indicates that cells treated with compound 20 lead to stay in G1 phase.