2. Academic Validation
  3. Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells

Harringtonine Ester Derivatives with Enhanced Antiproliferative Activities against HL-60 and HeLa Cells

  • J Nat Prod. 2022 Feb 25;85(2):345-351. 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
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 2 Faculty of Pharmaceutical Sciences, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
  • 3 School of Pharmacy, Walailak University, Nakhon Si Thammarat 80160, Thailand.
  • 4 Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 5 Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-dori, Sanyo-Onoda City, Yamaguchi 756-0884, Japan.
PMID: 35148094 DOI: 10.1021/acs.jnatprod.1c00888
Abstract

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.

Figures