Bioorganic Chemistry Department, Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland.
Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland.
Chem Biol Drug Des. 2018 Oct;92(4):1778-1787. doi: 10.1111/cbdd.13346. Epub 2018 Jul 1.
A series of 27 cinchona alkaloid derivatives (1f-w, 2a-e and 3a-d) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF-7, A-549, Hep-G2, U-87 and HL-60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds (1u, 1w, 2e and 3d) were identified with promising cytotoxic activity with 50% growth inhibition (GI ) values below 10 μM. Two (2e and 3d) of the four compounds also exhibited potent anti-trypanosomal activity with GI values of 0.3-0.4 μM. All four active compounds represented derivatives modified at their C-9 hydroxy group. With respect to anti-proliferative activity and selectivity, 2e (epi-N-quinidyl-N'-bis(3,5-trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u, 1w, 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti-cancer and anti-trypanosome drug candidates.
我们研究了一系列 27 种金鸡纳生物碱衍生物（1f-w、2a-e 和 3a-d），分别用 7 种不同的癌细胞系（KB、HeLa、MCF-7、A-549、Hep-G2、U-87 和 HL-60）、2 种正常细胞系（HDF 和 CHO）和布氏锥虫的血淋巴形式来评估它们的细胞毒性和杀锥虫活性。四种化合物（1u、1w、2e 和 3d）具有有前途的细胞毒性活性，其 50%生长抑制（GI）值低于 10μM。其中两种（2e 和 3d）化合物对锥虫也表现出很强的抗活性，GI 值为 0.3-0.4μM。这四种活性化合物均代表其 C-9 羟基修饰的衍生物。就增殖抑制活性和选择性而言，2e（表-N-奎尼丁-N'-双（3,5-三氟甲基）苯基硫脲）对癌细胞和布氏锥虫的血淋巴形式都是最有前途的衍生物。化合物 1u、1w、2e 和 3d 的细胞毒性活性归因于它们诱导癌细胞凋亡的能力。结果表明，金鸡纳生物碱衍生物具有作为新型抗癌和抗锥虫药物候选物的潜力。
