SYNTHESIS AND CYTOTOXIC ACTIVITY OF 1,2,3-TRIAZOLE DERIVATIVES OF EUGENOL

Eugenol is an aromatic compound found in several plant species. It presents important biological activities including cytotoxicity. In this paper, it is described the synthesis and the evaluation of the cytotoxic activity of eugenol derivatives bearing 1,2,3-triazole functionalities. Eugenol, extracted via hydrodistillation from dried flower buds of Eugenia caryophyllata (=Syzygium aromaticum), was submitted to alkylation reactions to afford two terminal alkynes in good yields. The key reaction involved in the preparation of eugenol derivatives corresponded to the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC), between alkynylated eugenol derivatives and different benzyl azides. The evaluation of the cytotoxicity of twenty seven synthesized derivatives against HL60 leukemia cell line revealed that at 100 µmol L-1, five of them, namely 4-((4-allyl-2-methoxyphenoxy)methyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (6n), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-benzyl-1H-1,2,3-triazole (7a), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-chlorobenzyl)-1H-1,2,3-triazole (7c), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-iodobenzyl)-1H-1,2,3-triazole (7e) and 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (7m), were capable of significantly decreasing cell viability. These most active triazolic derivatives were also evaluated against B16F10 melanoma and Nalm6 leukemia cell lines. While only compound 7a was active against the former, compounds 6n, 7a, and 7m displayed activity against the latter. Derivative 7a was active against all cell lines. It is believed that eugenol derivatives bearing triazole functionalities may represent a scaffold to be explored toward the development of new agents against cancer.丁子香酚（Eugenol）是一类存在于多种植物中的芳香族化合物，具有包括细胞毒性在内的多种重要生物活性。本文报道了一类带有1,2,3-三唑（1,2,3-triazole）官能团的丁子香酚衍生物的合成方法及其细胞毒性活性评价。丁子香酚通过水蒸馏法从干燥的丁香（Eugenia caryophyllata，又名Syzygium aromaticum）花蕾中提取，经烷基化反应以良好收率得到两种端基炔烃。该类丁子香酚衍生物的制备核心反应为一价铜催化叠氮-炔烃环加成反应（Copper(I)-catalyzed Azide-Alkyne Cycloaddition, CuAAC），反应底物为炔基化丁子香酚衍生物与不同苄基叠氮。对27种合成衍生物针对HL60白血病细胞系的细胞毒性评价结果显示，在100 µmol·L⁻¹浓度下，其中5种化合物可显著降低细胞存活率，分别为：4-((4-烯丙基-2-甲氧基苯氧基)甲基)-1-(3-溴苄基)-1H-1,2,3-三唑（6n）、4-(3-(4-烯丙基-2-甲氧基苯氧基)丙基)-1-苄基-1H-1,2,3-三唑（7a）、4-(3-(4-烯丙基-2-甲氧基苯氧基)丙基)-1-(4-氯苄基)-1H-1,2,3-三唑（7c）、4-(3-(4-烯丙基-2-甲氧基苯氧基)丙基)-1-(4-碘苄基)-1H-1,2,3-三唑（7e）以及4-(3-(4-烯丙基-2-甲氧基苯氧基)丙基)-1-(3-溴苄基)-1H-1,2,3-三唑（7m）。对上述活性最优的三唑类衍生物，进一步针对B16F10黑色素瘤细胞系与Nalm6白血病细胞系开展了活性评价：其中仅化合物7a对B16F10黑色素瘤细胞系具有活性，而化合物6n、7a与7m对Nalm6白血病细胞系均表现出活性；衍生物7a对所有受试细胞系均具有活性。研究表明，带有三唑官能团的丁子香酚衍生物可作为一类优势骨架，用于开发新型抗肿瘤药物。