Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells,Journal of Natural Products

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Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells
Journal of Natural Products ( IF 3.3 ) Pub Date : 2022-02-11 , DOI: 10.1021/acs.jnatprod.1c00888
Akihiro Ochi ₁ , Makoto Yoritate ₁ , Tomofumi Miyamoto ₁ , Kazuteru Usui _{1,

2} , Gorawit Yusakul ₃ , Waraporn Putalun ₄ , Hiroyuki Tanaka ₅ , Go Hirai ₁ , Satoshi Morimoto ₁ , Seiichi Sakamoto ₁

Affiliation

Harringtonine (HT), produced from Cephalotaxus species, is known to exhibit potent antiproliferative activity against myeloid leukemia cells by inhibiting protein synthesis. A previous study using acute promyelocytic leukemia (HL-60) cells raised the possibility that the C-5′ methyl group of HT plays an important role in regulating leukemia cell line antiproliferative activity. In order to investigate the effect of hydrocarbon chains at C-5′ on the resultant activity, the C-5′ methyl group was replaced with various straight- and branched-chain hydrocarbons using the corresponding alcohols, and their antiproliferative activity against HL-60 and HeLa cells was investigated. As a result, 4′-n-heptyl-4′-demethylharringtonine (1f, n-heptyl derivative) showed the most potent cytotoxicity among the HT ester derivatives produced, with IC₅₀ values of 9.4 nM and 0.4 μM for HL-60 and HeLa cells, respectively. Interestingly, the cytotoxicity of derivative 1f against HL-60 and HeLa cells respectively was ∼5 (IC₅₀ = 50.5 nM) and ∼10 times (IC₅₀ = 4.0 μM) those of HT and ∼2 (IC₅₀ = 21.8 nM) and ∼4 times (IC₅₀ = 1.7 μM) more than homoharringtonine (HHT). These results demonstrate the potential of the derivative 1f as a lead compound against leukemia.

中文翻译：

对 HL-60 和 HeLa 细胞具有增强的抗增殖活性的 Harringtonine 酯衍生物

Harringtonine (HT) 是由Cephalotaxus物种产生的，已知通过抑制蛋白质合成对髓细胞白血病细胞表现出有效的抗增殖活性。先前使用急性早幼粒细胞白血病（HL-60）细胞的研究提出了HT的C-5'甲基在调节白血病细胞系抗增殖活性中起重要作用的可能性。为了研究 C-5' 烃链对合成活性的影响，使用相应的醇将 C-5' 甲基基团替换为各种直链和支链烃，以及它们对 HL-60 的抗增殖活性和 HeLa 细胞进行了研究。结果，4'- n -heptyl-4'-demethylharringtonine ( 1f , n-庚基衍生物）在产生的 HT 酯衍生物中显示出最强的细胞毒性，对 HL-60 和 HeLa 细胞的 IC ₅₀值分别为 9.4 nM 和 0.4 μM。有趣的是，衍生物1f对 HL-60 和 HeLa 细胞的细胞毒性分别是HT 和 ∼2 (IC ₅₀ = 21.8 nM)的 ∼5 (IC ₅₀ = 50.5 nM) 和 ∼10 倍 (IC ₅₀ = 4.0 μM ) 和约 4 倍 (IC ₅₀ = 1.7 μM) 比同型哈灵顿 (HHT) 高。这些结果证明了衍生物1f作为抗白血病的先导化合物的潜力。

更新日期：2022-02-11

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