莰烯醛O-取代肟的合成及其抗肿瘤活性

doi:10.3969/j.issn.0253-2417.2020.01.008

摘要/Abstract

摘要：

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（IC₅₀）值为36.3 μmol/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19.2 μmol/L。

关键词: 莰烯醛肟, 亲核取代反应, 莰烯醛O-取代肟, 肟醚, 抗肿瘤活性

Abstract:

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, ¹H NMR and ¹³C 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 IC₅₀ value was 36.3 μmol/L. Compounds 2d, 2h and 2i had inhibitory effects on human MCF7 cells, especially compound 2h, with IC₅₀ of 19.2 μmol/L.

Key words: camphene aldoxime, nucleophilic substitution reaction, camphene aldehyde O-substituted oxime, oxime ether, antitumor activities

中图分类号:

TQ35
O621.3

黄静,刘辰婧,罗金岳. 莰烯醛O-取代肟的合成及其抗肿瘤活性[J]. 林产化学与工业, 2020, 40(1): 53-60.

Jing HUANG,Chenjing LIU,Jinyue LUO. Synthesis and Antitumor Activities of Camphene Aldehyde O-Substituted Oximes[J]. Chemistry and Industry of Forest Products, 2020, 40(1): 53-60.

图/表 7

图1

表1

图2

图3

表2

表3

表4

参考文献 15

1	罗金岳, 张晓萍, 安鑫南. MoO₃/ZrO₂催化α-蒎烯异构化反应的研究[J]. 林产化学与工业, 2004, 24 (3): 26- 30. doi: 10.3321/j.issn:0253-2417.2004.03.006
	LUO J Y , ZHANG X P , AN X N . Study on α-pinene isomerization catalyzed by MoO₃/ZrO₂ solid superacid[J]. Chemistry and Industry of Forest Products, 2004, 24 (3): 26- 30. doi: 10.3321/j.issn:0253-2417.2004.03.006
2	黄静, 鲍涵, 张夏, 等. 3'-(3, 3-二甲基双环[2.2.1]庚-2-亚基)-5'-苯基-异噁唑啉的合成和表征[J]. 林产化学与工业, 2018, 38 (6): 110- 116. doi: 10.3969/j.issn.0253-2417.2018.06.015
	HUANG J , BAO H , ZHANG X , et al. Synthesis and characterization of 3'-(3, 3-dimethylbicyclo[2.2.1] hept-2-ylidene)-5'-phenyl-isoxazoline[J]. Chemistry and Industry of Forest Products, 2018, 38 (6): 110- 116. doi: 10.3969/j.issn.0253-2417.2018.06.015
3	GRANICA S , LOHWASSER U , JOHRER K , et al. Qualitative and quantitative analyses of secondary metabolites in aerial and subaerial of Scorzonera hispanica L.(black salsify)[J]. Food Chemistry, 2015, 173, 321- 331. doi: 10.1016/j.foodchem.2014.10.006
4	周钱, 郑丹丹, 石玉军, 等. 新型含噁唑环结构的吡唑肟醚类化合物的合成与杀虫活性研究[J]. 有机化学, 2018, 38 (12): 3318- 3325.
	ZHOU Q , ZHENG D D , SHI Y J , et al. Synthesis and insecticidal activities of novel pyrazole oxime ethers containing an oxazole moiety[J]. Chinese Journal of Organic Chemistry, 2018, 38 (12): 3318- 3325.
5	KOSMALSKI T , KUTKOWSKA J , GZELLA A K , et al. New heterocyclic oxime ethers of 1-(benzofuran-2-yl) ethan-1-one and their antimicrobial activity[J]. Acta Poloniae Pharmaceutica, 2015, 72 (2): 289- 295.
6	WANG X B , CHEN M H , LI Q , et al. Synthesis and antiviral activities of novel penta-1, 4-diene-3-one oxime derivatives bearing a pyridine moiety[J]. Chemical Papers-Slovak Academy of Sciences, 2017, 71 (7): 1- 9.
7	黄燕敏, 苏绍烊, 贾琳怡, 等. 甾体肟醚化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2014, 34 (9): 1816- 1828.
	HUANG Y M , SU S Y , JIA L Y , et al. Synthesis and antiproliferative evaluation of some steroidal oxime ether[J]. Chinese Journal of Organic Chemistry, 2014, 34 (9): 1816- 1828.
8	WANG X B , CHEN M H , LI Q , et al. Synthesis and antiviral activities of novelpenta-1, 4-diene-3-one oxime derivatives bearing a pyridine moiety[J]. Chemical Papers-Slovak Academy of Sciences, 2017, 71 (7): 1- 9.
9	KHAN S A , ASIRI A M , SALEEM K . Synthesis and biological evaluation of new oxime-ether derivatives of steroid as anti-bacterial agents[J]. Journal of Saudi Chemical Society, 2012, 16 (1): 7- 11. doi: 10.1016/j.jscs.2010.10.013
10	KUMAR S , SHARMA R , GARCIA M , et al. Chemoselective amide formation using o-(4-nitrophenyl) hydroxyla mines and pyruvic acid derivatives[J]. The Journal of Organic Chemistry, 2012, 77, 10835- 10845. doi: 10.1021/jo302175g
11	GHOSH R , STRIDFELDT E , OLOFSSON B . Metal-free one-pot synthesis of benzofurans[J]. Chemistry:A European Journal, 2014, 20 (29): 8888- 8892.
12	王作第.(Z)-5-氨基-α-(乙氧亚胺基)-1, 2, 4-噻二唑-3-乙酸的制备方法: 10380432A[P]. 2014-05-21.
	WANG Z D.Preparation of (Z)-5-amino-α-(ethoxyi mino)-1, 2, 4-thiadiazole-3-acetic acid: 10380432A[P]. 2014-05-21.
13	陈玉, 王忠波, 张贤, 等. 含肟醚的姜黄素衍生物的合成及生物活性研究[J]. 有机化学, 2014, 34 (8): 1662- 1668.
	CHEN Y , WANG Z B , ZHANG X , et al. Synthesis and biological activity of oxime ethers of curcu min derivatives[J]. Chinese Journal of Organic Chemistry, 2014, 34 (8): 1662- 1668.
14	JINDAL D P , CHATTOPADHAYA R , GULERIA S , et al. Synthesis and antineoplastic activity of 2-alkyla minoethyl derivatives of various steroidal oximes[J]. European Journal of Medicinal Chemistry, 2003, 38 (11/12): 1025- 1034.
15	黄静, 鲍涵, 徐铭, 等. 2-(3, 3-二甲基双环[2.2.1]庚-2-亚基)乙醛肟的合成[J]. 化学研究与应用, 2018, 30 (11): 1886- 1891. doi: 10.3969/j.issn.1004-1656.2018.11.025
	HUANG J , BAO H , XU M , et al. Synthesis of 2-(3, 3-dimethylbicy[2.2.1] heptan-2-ylidene) acetaldehyde oxime[J]. Chemical Research and Application, 2018, 30 (11): 1886- 1891. doi: 10.3969/j.issn.1004-1656.2018.11.025

溶剂solvent	转化率conversion/%	选择性selectivity/%	得率yield/%
二甲基甲酰胺DMF	87.17	71.37	62.21
甲苯toluene	93.52	75.63	70.73
乙腈ACN	83.97	67.49	56.67
二甲亚砜DMSO	92.95	77.06	71.63
四氢呋喃THF	86.13	71.05	61.19

反应条件 reaction condition		转化率/% conversion	选择性/% selectivity	得率/% yield
反应温度 reaction temp.	40 ℃	83.98	64.06	53.80
	50 ℃	90.84	79.12	71.87
	60 ℃	95.93	82.60	79.24
	70 ℃	95.27	77.34	73.68
	80 ℃	95.31	67.82	64.64
反应时间 reaction time	14 h	81.46	64.08	52.20
	16 h	89.86	78.82	70.83
	18 h	93.67	86.10	80.85
	20 h	95.47	87.67	83.66
	22 h	95.93	82.60	79.24
	24 h	96.04	80.54	77.35
	26 h	95.97	74.50	71.50

因素 factor	A n(莰烯醛肟): n(四丁基溴化铵) n(camphene aldoxime): n(tetrabutylammonium bromide)	B n(莰烯醛肟): n(氯化苄) n(camphene aldoxime): n(benzyl chloride)	C 反应温度/℃ reaction temp.	D 反应时间/h reaction time	得率/% yield
1	1.0:0.08	1.0:1.4	50	18	64.79
2	1.0:0.08	1.0:1.6	60	20	80.91
3	1.0:0.08	1.0:1.8	70	22	78.43
4	1.0:0.10	1.0:1.4	60	22	70.85
5	1.0:0.10	1.0:1.6	70	18	67.79
6	1.0:010	1.0:1.8	50	20	73.85
7	1.0:0.12	1.0:1.4	70	20	72.47
8	1.0:0.12	1.0:1.6	50	22	68.11
9	1.0:0.12	1.0:1.8	60	18	72.91
k₁	74.71	69.37	68.92	68.50
k₂	70.83	72.27	74.89	75.74
k₃	71.16	75.06	72.90	72.46
R	3.88	5.69	5.97	7.24

化合物 compound	IC₅₀/(μmol·L^-1)
化合物 compound	HepG2	MCF7
2a	84.2±0.95	44.3±1.25
2b	36.3±1.27	45.8±0.56
2c	62.7±0.81	62.5±0.81
2d	66.9±0.87	38.8±0.94
2e	＞100	48.1±1.72
2f	79.3±0.35	45.6±1.59
2g	53.0±1.01	72.5±0.71
2h	73.0±1.43	19.2±1.29
2i	66.3±0.86	38.5±0.94
依托泊甙etoposide	25.4±0.03	2.7±0.11

[1]	冯雪贞, 肖转泉, 陈尚钘, 范国荣, 廖圣良, 王宗德. 莰烯醛肟及其烃基醚衍生物的合成与抑菌活性研究[J]. 林产化学与工业, 2020, 40(1): 77-83.
[2]	张夏,罗一铭,黄静,刘辰婧,罗金岳. 甲基柏木酮O-取代肟类化合物的合成与表征[J]. 林产化学与工业, 2019, 39(6): 37-43.
[3]	王洁,路娇娇,杜涵,张萌,刘盼盼,陈小强. 五味子果肉和种子精油的化学成分与生物活性对比研究[J]. 林产化学与工业, 2019, 39(6): 59-67.
[4]	姜萍,赵雅洁,包信业,王飞,段占泉,王茂霖. 红豆杉枝叶中总生物碱的提取及其抗肿瘤活性研究[J]. 林产化学与工业, 2019, 39(6): 115-122.
[5]	王晓宇,段文贵,林桂汕,康国强,商明昊,雷福厚. (Z)-/(E)-马鞭草烯酮肟醚的合成及抑菌活性[J]. 林产化学与工业, 2019, 39(4): 27-34.
[6]	黄静, 鲍涵, 张夏, 莫悦, 罗金岳, 刘祖广. 3'-(3,3-二甲基双环[2.2.1]庚-2-亚基)-5'-苯基-异噁唑啉的合成与表征[J]. 林产化学与工业, 2018, 38(6): 110-116.
[7]	刘建群, 高俊博. 迈克尔加成反应预测冬凌草活性成分及其乙酰化产物抗肿瘤活性[J]. 林产化学与工业, 2016, 36(1): 27-34.
[8]	卢圣楼, 刘红, 陈光英, 韩长日, 臧文霞. 神秘果叶挥发油化学成分分析及抗菌、抗肿瘤活性[J]. 林产化学与工业, 2014, 34(1): 121-127.
[9]	郑光耀;康宏兴;薄采颖;宋强;周维纯. 杨树芽提取物体外抗肿瘤活性的研究[J]. 林产化学与工业, 2009, 29(6): 38-42.
[10]	王红刚;周敏华;路晶晶;余伯阳. 沉香叶抗肿瘤活性化学成分研究[J]. 林产化学与工业, 2008, 28(2): 1-5.
[11]	郑光耀;李若达;王成章;谢衡;叶建中;高彩霞. 马尾松树皮提取物抗肿瘤作用的研究[J]. 林产化学与工业, 2007, 27(04): 16-20.
[12]	石若夫;李大力;田春宇;王关林;方宏筠. 栀子多糖的抗肿瘤活性研究[J]. 林产化学与工业, 2002, 22(04): 67-70.