Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071, Granada, Spain; Laboratory Productions, Plant and Microbial Valuations (LP2VM), Department of Biotechnology, University of Sciences and Technology of Oran Mohamed Boudiaf, BP 1525, EL M'Naouer, Oran, Algeria.
Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071, Granada, Spain.
Eur J Med Chem. 2018 Oct 5;158:863-873. doi: 10.1016/j.ejmech.2018.09.051. Epub 2018 Sep 17.
The synthesis of podocarpanes, including 12,19-dihydroxy-13-acetyl-8,11,13-podocarpatriene (23), isolated from Gaultheria yunnanensis and not previously synthesized, and totarane-type terpenoids, starting from the natural labdane trans-communic acid (15), is described. Their antiproliferative activities against MCF-7, T-84 and A-549 human tumoural cell lines are studied. An antiproliferative effect was induced by compounds 23, 27 and 28, with IC < 10 μM in two (27) or three cell lines (23 and 28). No correlation with log P values was observed. The totarane o-quinone 27, and especially the catechol 28, which is readily oxidisable to compound 27, were the most active compounds, highlighting the functional groups present in C11 and C12. Compound 28 showed limited toxicity in normal peripheral blood mononuclear cells (78.5% cell viability versus non-treated control cultures at 10 μM), and appeared to exert an antiproliferative effect in A-549 cells (IC 0.6 μM) through a mechanism that involves the induction of apoptosis mediated by an increased Bax/Bcl-2 ratio. The results of the present study indicate that compound 28, at least, might be useful as an antitumoral agent. Further studies are required to elucidate the cellular and molecular elements involved in its effect, and the activity/toxicity in preclinical models.
滇南山矾中分离得到的 12,19-二羟基-13-乙酰-8,11,13-贝壳杉三烯（23）和从未合成过的托烷型萜类化合物的合成，以天然的 labdane 反式--communic 酸（15）为起始原料。研究了它们对 MCF-7、T-84 和 A-549 人肿瘤细胞系的抗增殖活性。化合物 23、27 和 28 诱导了抗增殖作用，在两种（27）或三种细胞系（23 和 28）中 IC < 10 μM。未观察到与 log P 值的相关性。托烷醌 27，特别是儿茶酚 28，它很容易氧化为化合物 27，是最活跃的化合物，突出了 C11 和 C12 中存在的官能团。化合物 28 在正常外周血单核细胞中显示出有限的毒性（在 10 μM 时，细胞活力为 78.5%，而非未处理的对照培养物），并且似乎通过增加 Bax/Bcl-2 比值介导的细胞凋亡来发挥对 A-549 细胞的抗增殖作用。本研究的结果表明，化合物 28 至少可以作为一种抗肿瘤药物。需要进一步的研究来阐明其作用涉及的细胞和分子因素，以及临床前模型中的活性/毒性。
