Abstract

The introduction of the alkynyl moiety to the abietane diterpenic core by modification of the cycle E of methyl dihydroquinopimarate is described. The arylpropargyl, aminopropargyl, and 1,2,3-triazole derivatives are synthesized via Sonogashira reaction, Mannich reaction and click-chemistry, correspondingly. The antitumor effect towards the NCI-60 cancer cell line panel and antimicrobial activity against key ESKAPE pathogens of the synthesized compounds were studied in vitro. The cytotoxicity and hemolytic activity of the abietane derivatives was tested using HEK293 human embryonic kidney cell line and the human red blood cells, correspondingly. The methyl dihydroquinopimarate propargyl analogs showed high antitumor activity against leukemia (CCRF-CEM; SR), non-small cell lung cancer (NCI-H522), melanoma (LOX IMVI; MALME-3M), ovarian cancer (IGROV1), and renal cancer (786-0; UO-31) cell lines. The Mannich’s diterpene bases with pyrrolidine and diethylamine fragments exhibited fungicidal activity towards Cr. neoformans (MIC= 16 μg/ml), while possessing low toxicity. The described modifications of the abietane diterpenoids have great potential for further development of new cytotoxic and fungicidal compounds.

摘要

描述了通过修饰二氢喹诺松酸甲酯的循环E将炔基部分引入松香烷二萜核心。芳炔基、氨基炔基和1,2,3-三唑衍生物分别通过Sonogashira反应、Mannich反应和点击化学合成。体外研究了合成化合物对 NCI-60 癌细胞系的抗肿瘤作用和对关键 ESKAPE 病原体的抗菌活性. 相应地，使用 HEK293 人胚胎肾细胞系和人红细胞测试了松香烷衍生物的细胞毒性和溶血活性。二氢喹诺哌甲酯炔丙基类似物对白血病 (CCRF-CEM; SR)、非小细胞肺癌 (NCI-H522)、黑色素瘤 (LOX IMVI; MALME-3M)、卵巢癌 (IGROV1) 和肾癌具有高抗肿瘤活性(786-0; UO-31) 细胞系。带有吡咯烷和二乙胺片段的曼尼希二萜碱对Cr表现出杀真菌活性。新型隐球菌（MIC = 16 μg/ml），同时具有低毒性。所描述的松香烷二萜类化合物的修饰对于进一步开发新的细胞毒性和杀真菌化合物具有巨大的潜力。