Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Department of Chemistry, Universidade Federal de Viçosa, Av. P. H. Rolfs, s/n, CEP 36570-900, Viçosa, MG, Brazil.
Eur J Med Chem. 2017 Nov 10;140:624-635. doi: 10.1016/j.ejmech.2017.09.045. Epub 2017 Sep 22.
Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of Sapindus saponaria and reacted with propargyl bromide to afford as a major product bis-propargylic derivative 1 in 74%. Submitting this compound to Huisgen 1,3-dipolar cycloaddition reactions with several azides afforded the derivatives 2-19 with yields in the range of 40-87%. All compounds have been screened for in vitro cytotoxic activity in a panel of five human cancer cell lines by a SRB assay. The bioassays showed that compound 19 was the most cytotoxic against all human cancer cell lines with EC = 7.4-12.1 μM. Moreover, leishmanicidal activity was evaluated through the in vitro effect in the growth of Leishmania infantum, and derivatives 1, 2, 5 and 17 were highly effective preventing proliferation of intracellular amastigote forms of L. infantum (IC = 28.8, 25.9, 5.6 and 7.4 μM, respectively). All these compounds showed a higher selectivity index and low toxicity against two strains of kidney BGM and liver HepG2 cells. Compound 5 has higher selectivity (1780 times) in comparison with the commercial antimony drug and is around 8 times more selective than the most active compound previously reported hederagenin derivative. Such high activity associated with low toxicities make the new bis-traiazolyl derivatives promising candidates for the treatment of leishmaniasis. In addition, hederagenin and some derivatives (2, 5 and 17) showed interaction in the binding site of the enzyme CYP51.
为了从天然来源中获得新的有效的杀利什曼原虫和细胞毒性化合物，将三萜齐墩果酸转化为几种新的 1,2,3-三唑基衍生物，连接在 C-23 和 C-28 上。为此，从无患子果实中分离出齐墩果酸，与丙炔溴反应，以 74%的产率得到主要产物双丙炔基衍生物 1。将该化合物提交给几种叠氮化物的 Huisgen 1,3-偶极环加成反应，得到产率在 40-87%范围内的衍生物 2-19。所有化合物均通过 SRB 测定法在五种人类癌细胞系的细胞毒性活性的小组中进行了筛选。生物测定表明，化合物 19 对所有人类癌细胞系的细胞毒性最强，EC = 7.4-12.1 μM。此外，通过在体外抑制 Leishmania infantum 生长的作用评估杀利什曼原虫活性，衍生物 1、2、5 和 17 对抑制 L. infantum 的细胞内无鞭毛体形式的增殖非常有效（IC = 28.8、25.9、5.6 和 7.4 μM）。所有这些化合物对两种肾 BGM 和肝 HepG2 细胞株均表现出更高的选择性指数和低毒性。与商业锑药物相比，化合物 5 的选择性更高（1780 倍），比之前报道的最有效齐墩果酸衍生物高 8 倍。这种高活性与低毒性相结合，使新的双三唑基衍生物成为治疗利什曼病的有前途的候选药物。此外，齐墩果酸和一些衍生物（2、5 和 17）在 CYP51 酶的结合位点显示出相互作用。
