莰烯醛O-取代肟的合成及其抗肿瘤活性

Synthesis and Antitumor Activities of Camphene Aldehyde O-Substituted Oximes

以莰烯醛肟与卤代物为原料经亲核取代反应合成了9个未见报道的莰烯醛O-取代肟类化合物,分别为2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-苄基肟(2a)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-丁基肟(2b)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(4-氯丁基)肟(2c)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(3-溴苄基)肟(2d)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(4-叔丁基苄基)肟(2e)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(4-氯苄基)肟(2f)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(4-氰基苄基)肟(2g)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(2,6-二氯苄基)肟(2h)、2-(3,3-二甲基双环[2.2.1]庚-2-亚基)乙醛O-(邻氟苄基)肟(2i)。利用FT-IR、GC-MS、1H NMR以及13C NMR对产物结构进行了表征。以化合物2a为例,探索了不同工艺条件对产物得率的影响,在甲苯为溶剂,n(莰烯醛肟)∶n(氯化苄)∶n(四丁基溴化铵)为1.0∶1.8∶0.08,反应温度为60℃,反应时间为20 h的最佳工艺条件下,产物的得率为84.1%。通过体外抗肿瘤活性测试,探讨了化合物2a^2i对肝癌细胞HepG2和人乳腺癌细胞MCF7的抑制作用,结果表明:化合物2b对HepG2细胞的抑制作用较好,其半数抑制浓度(IC 50)值为36.3μmol/L;化合物2d、2h、2i对MCF7有一定的抑制作用,其中化合物2h对MCF7的抑制作用较好,其IC50值为19.2μmol/L。

The unreported nine camphene aldehyde O-substituted oximes(2a 2i)were synthesized by nucleophilic substitution reaction using 2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime and halide as raw materials.They were 2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-benzyloxime(2a),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-butyloxime(2b),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(4-chlorobutyl)oxime(2c),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(3-bro minebenzyl)oxime(2d),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(4-tert-butyl benzyl)oxime(2e),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(4-chlorobenzyl)oxime(2f),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(4-cyanobenzyl)oxime(2g),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(2,6-dichlorobenzyl)oxime(2h),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde O-(ortho-fluorbenzyl)oxime(2i).These products were characterized by FT-IR,GC-MS,1 H NMR and 13 C NMR.Taking 2a as an example,the effects of types of solvent,quantity of tetrabutylammonium bromide and benzyl chloride,reaction temperature and reaction time on reaction rate and yield of the product 2a were discussed.The optimum condition were obtained as follows:Methylbenzene as solvent,n(camphene aldoxime)∶n(benzyl chloride)∶n(tetrabutylammonium bromide)=1.0∶1.8∶0.08,the reaction temperature was 60℃,the reaction time was 20 h.Under these conditions,the yield of 2a was 84.1%.The inhibitory effects of compounds 2a 2i on HepG2 cells and MCF7 cells were studied by in vitro antitumor activity tests.The results showed that compound 2b had good inhibitory effect on HepG2 cells,and its IC 50 value was 36.3μmol/L.Compounds 2d,2h and 2i had inhibitory effects on human MCF7 cells,especially compound 2h,with IC50 of 19.2μmol/L.