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

Abstract

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

CLC Number:

TQ35
O621.3

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.

Figures/Tables 7

Fig.1

Table 1

Fig.2

Fig.3

Table 2

Table 3

Table 4

References 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]	Xia ZHANG,Yiming LUO,Jing HUANG,Chenjing LIU,Jinyue LUO. Synthesis and Characterization of Methyl Cedrone O-substituted Oximes [J]. Chemistry and Industry of Forest Products, 2019, 39(6): 37-43.
[2]	Xiaoyu WANG,Wengui DUAN,Guishan LIN,Guoqiang KANG,Minghao SHANG,Fuhou LEI. Synthesis and Antifungal Activity of (Z)-/(E)-Verbenone Oxime Ether Compounds [J]. Chemistry and Industry of Forest Products, 2019, 39(4): 27-34.
[3]	HUANG Jing, BAO Han, ZHANG Xia, MO Yue, LUO Jinyue, LIU Zuguang. 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.

Synthesis and Antitumor Activities of Camphene Aldehyde O-Substituted Oximes

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 7

References 15

Related Articles 3

Recommended Articles

Metrics

Comments