Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics.

Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics. Eur J Med Chem. 2018 Feb 01;146:588-598 Authors: Gao X, Li J, Wang M, Xu S, Liu W, Zang L, Li Z, Hua H, Xu J, Li D Abstract Natural derived enmein-type diterpenoids exert cytotoxicity against a wide range of human cancer cells. Yet their medicinal applications are hindered by insufficient potency for chemotherapy. Hence, a series of novel enmein-type diterpenoid hybrids coupled with nitrogen mustards were designed and synthesized to increase antitumor efficacy while reducing systemic toxicity. Most conjugates exhibited stronger antiproliferative activities than parent diterpenoids and nitrogen mustards, especially for multidrug-resistant tumor cell line Bel-7402/5-FU. Among them, compound E2 showed the most potent inhibitory activities in human leukemia HL-60 cells, human prostate cancer PC-3 cells, human liver cancer Bel-7402 cells and drug-resistant human liver cancer Bel-7402/5-FU cells with IC50 values of 7.83 μM, 3.97 μM, 0.77 μM and 2.07 μM, respectively. Additionally, high selectivity with selectivity index over 130 was also observed from cytotoxic evaluation between L-02 human normal liver cells and Bel-7402 malignant liver cells. Further studies on mechanism of action indicated that E2 induced both apoptosis and G1 phase cell cycle arrest in Bel-7402 hepatoma cells. Moreover, ...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research