Synthesis and Biological Evaluation of 1,2,7,9-Tetrasubstituted Harmine Derivatives as Potential Antitumor Agents†

doi:10.7503/cjcu20130683

Abstract

Abstract:

In order to search for novel candidate compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were synthesized by modiflcation of position 2, 7 and 9 of β-carboline nucleus through N9-alkylated, C7-demethylated and C7-phenolic hydroxyl alkylated. C7-demethylation compounds could be easily obtained from the N9-alkylated derivatives using acetic acid and hydrobromic acid as reaction solvent, but N9-arylted derivatives couldn’t get the demethylation compounds in the same way. The N2-quaternarized compounds(4a, 4b, 8a and 8b) were prepared from demethylation compounds(3a, 3b, 7a and 7b) by the addition of benzyl bromide in refluxing ethyl acetate. Eleven target compounds were synthesized and characterized by ¹H NMR, ¹³C NMR, IR, MS and elemental analysis. All the target compounds were tested for cytotoxic activity against six cancer cell lines including Bel-7402, 786-0, BGC-823, A375, 769-P and MCF7 by methyl thiazolyl tetrazolium(MTT) method in vitro. Structure-activity relationships studies confirmed that N2-quaternarized compounds(4a, 4b, 8a and 8b) had more remarkable cytotoxic activities in vitro than harmine.

Key words: Harmine, β-Carboline, Antitumor activity, Structure-activity relationship

CLC Number:

O626

TrendMD:

GUO Liang, CAO Rihui, FAN Wenxi, MA Qin. Synthesis and Biological Evaluation of 1,2,7,9-Tetrasubstituted Harmine Derivatives as Potential Antitumor Agents^†[J]. Chem. J. Chinese Universities, 2014, 35(3): 518.

Figures/Tables 2

References 24

[1]	Duan J. A., Zhou R. H., Zhao S. X., Wang M. S., Che Z. T., J. China Pharm. Univ., 1998, 29(1), 21—23
	(段金廒, 周荣汗, 赵守训, 王明时, 车镇涛. 中国药科大学学报, 1998, 29(1), 21—23)
[2]	Cowna M. M., Clin. Microbiol. Rev., 1999, 12(4), 564—582
[3]	Song Z. Y., Liu J. R., Lu X. L., Wang L. J., J. Chin. Med. Mater., 2006, 29(6), 571—574
	(宋震亚, 刘济仁, 陆新良, 王良静. 中药材, 2006, 29(6), 571—574)
[4]	Tian X. L., Sun D. J., Du N. S., J. Xinjiang Med. Univ., 2003, 26(2), 113—115
	(田晓丽, 孙殿甲, 诸年生. 新疆医科大学学报, 2003, 26(2), 113—115)
[5]	Cao J., Pan Q. C., Chin. J. Cancer,1993, 12(3), 214—216
	(曹俊, 潘启超. 癌症, 1993, 12(3), 214—216)
[6]	Yang X. P., Pan Q. C., Xie B. F., Li C. J., Chin. Tradit. Herb. Drugs,1998, 29(9), 609—611
	(杨小平, 潘启超, 谢冰芬, 李春杰. 中草药, 1998, 29(9), 609—611)
[7]	Xinjiang Institute of Biology, Pedology and Desert Research, Xinjiang Medicinal Flora, Xinjiang People’s Publishing House, Urumqi, 1977, 92
	(中科院新疆生物土壤沙漠研究所. 新疆药用植物志, 乌鲁木齐, 新疆人民出版社, 1977, 92)
[8]	Pan Q. C., Yang X. P., Li G. W., Liu D. X., Li C. J., Chin. J. Cancer,1985, 4(4), 192—194
	(潘启超, 杨小平, 利国威, 刘得玺, 李春杰. 癌症, 1985, 4(4), 192—194)
[9]	Pan Q. C., Yang X. P., Li C. J., Hu H. T., Li G. W., Cao J., Xu Z. D., Xie B. F., Pan W. G., J. Sun Yat-sen University(Medical Sciences), 1997, 18(3), 9—11
	(潘启超, 杨小平, 李春杰, 胡海棠, 利国威, 曹俊, 许招懂, 谢冰芬, 潘伟光. 中山医科大学学报, 1997, 18(3), 9—11)
[10]	Li C. J., Liu D. X., Mamat Y. M., Pan Q. C., Yang X. P., Li G. W., J. Xinjiang Med. Univ., 1987, 10(1), 27—31
	(李春杰, 刘得玺, 买买提依明, 潘启超, 杨小平, 利国威. 新疆医科大学学报, 1987, 10(1), 27—31)
[11]	Yang X. P., Pan Q. C., Li C. J., Liu D. X., Chin. J. ancer,1991, 10(6), 463—465
	(杨小平, 潘启超, 李春杰, 刘得玺. 癌症, 1991, 10(6), 463—465)
[12]	Cao R. H., Chen Q., Hou X. R., Chen H. X., Guan H. J., Ma Y., Peng W. L., Xu A. L., Bioorg. Med. Chem., 2004, 12, 4613—4623
[13]	Cao R. H., Guan X. D., Shi B. X., Chen Z. Y., Ren Z. H., Peng W. L., Song H. C., Eur. J. Med. Chem., 2010, 45, 2503—2515
[14]	Cao R.H., Structure Activity Relationships and Preliminary Action Mechanisms of Antitumor β-carboline Alkaloids, Sun Yat-sen University, Guangzhou, 2004
	(曹日晖. β-咔啉类生物碱抗肿瘤构效关系及作用机理的初步研究, 广州: 中山大学, 2004)
[15]	Cao R. H., Peng W. L., Wang Z. H., Xu A. L., Curr. Med. Chem., 2007, 14, 479—500
[16]	Cao R. H., Peng W. L., Chen H. X., Hou X. R., Guan H. J., Ma Y., Xu A. L., Eur. J. Med. Chem., 2005, 40, 249—257
[17]	Cao R. H., Chen H. X., Peng W. L., Ma Y., Hou X. R., Guan H. J., Liu X. D., Xu A. L., Eur. J. Med. Chem., 2005, 40, 991—1001
[18]	Cao R. H., Yi W., Wu Q. F., Guan X. D., Feng M. X., Ma C. M., Chen Z. Y., Song H. C., Peng W. L., Bioorg. Med. Chem. Lett., 2008, 18, 6558—6561
[19]	Ma C. M., Cao R. H., Shi B. X., Zhou X. T., Ma Q., Sun J., Guo L., Yi W., Chen Z. Y., Song H. C., Eur. J. Med. Chem., 2010, 45, 5513—5519
[20]	Chen Z. Y., Cao R. H., Shi B. X., Guo L., Sun J., Ma Q., Fan W. X., Song H. C., Eur. J. Med. Chem., 2011, 46, 5127—5137
[21]	Guo L., Sun J., Fan W. X., Ma Q., Chin. J. Modern Appl. Pharm., 2012, 29(5), 385—388
	(郭亮, 孙洁, 范文玺, 马芹. 中国现代应用药学, 2012, 29(5), 385—388)
[22]	Guo L., Fan W. X., Chen X. M., Ma Q., Cao R. H., Chin. J. Org. Chem., 2013, 33(2), 332—338
	(郭亮, 范文玺, 陈雪梅, 马芹, 曹日晖. 有机化学, 2013, 33(2), 332—338)
[23]	Reniers J., Robert S., Frederick R., Masereel B., Vincent S., Wouters J., Bioorg. Med. Chem., 2011, 19, 134—144
[24]	Hu G. Q., Wang G. Q., Duan N. N., Wen X. Y., Cao T. Y., Xie S. Q., Huang W. L., Chem. Res. Chinese Universities,2012, 28(6), 980—984

Compd.	IC₅₀/(μmol·L^-1)						Compd.	IC₅₀/(μmol·L^-1)
Compd.	Bel-7402		BGC-823	786-0	A375	769-P	MCF7	Bel-7402	BGC-823	786-0	A375	769-P	MCF7
DDP	32.7	21.6	13.1	14.6	18.3	12.4	5	44.2	45.7	18.2	40.9	52.7	60.3
1	54	68	38.3	52.4	43.1	ND	6	29.9	35.1	28.3	75.4	48.3	34.5
2	59.5	62.3	32.5	52.3	32.4	19	7a	34.2	34.5	10.3	39.1	46.7	20.9
3a	76.4	>100	41.7	>100	>100	>100	7b	>100	84.0	32.7	35.7	40.4	33.9
3b	72.5	>100	27.1	>100	>100	ND	8a	5.7	3.9	4.3	4.8	3.9	6.5
4a	<1.4	9.1	1.4	3.4	3.2	9.2	8b	7.5	4.2	2.5	8.6	7.9	9.1
4b	2.2	2.3	<1.3	2.0	3.5	4.7

Compd.	IC₅₀/(μmol·L^-1)						Compd.	IC₅₀/(μmol·L^-1)
Compd.	Bel-7402		BGC-823	786-0	A375	769-P	MCF7	Bel-7402	BGC-823	786-0	A375	769-P	MCF7
DDP	32.7	21.6	13.1	14.6	18.3	12.4	5	44.2	45.7	18.2	40.9	52.7	60.3
1	54	68	38.3	52.4	43.1	ND	6	29.9	35.1	28.3	75.4	48.3	34.5
2	59.5	62.3	32.5	52.3	32.4	19	7a	34.2	34.5	10.3	39.1	46.7	20.9
3a	76.4	>100	41.7	>100	>100	>100	7b	>100	84.0	32.7	35.7	40.4	33.9
3b	72.5	>100	27.1	>100	>100	ND	8a	5.7	3.9	4.3	4.8	3.9	6.5
4a	<1.4	9.1	1.4	3.4	3.2	9.2	8b	7.5	4.2	2.5	8.6	7.9	9.1
4b	2.2	2.3	<1.3	2.0	3.5	4.7