二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮的合成及生物活性研究

doi:10.6023/cjoc202107002

摘要/Abstract

以天然产物脱氧鸭嘴花酮生物碱为基础, 通过生物电子等排手段, 设计并合成了40个二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮类化合物, 其结构经¹H NMR、¹³C NMR和HRMS进行了确证, 并对该类化合物合成方法的关键步骤影响因素和构效关系进行了探讨. 使用噻唑蓝(MTT)法对该系列化合物的3种肿瘤细胞(MCF-7、Hela、A549)的体外抗肿瘤活性进行了研究, 采用琼脂打孔法对该系列化合物的抑菌活性也进行了初步评价. 结果表明, 2-(萘-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E12)和2-(4-(三氟甲氧基)苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E39)对HeLa和MCF-7有较强的抗肿瘤增殖活性, 半抑制浓度(IC₅₀)值分别为(4.59±0.10)和(6.89±1.26) μmol•L^–1; 2-((3R,5R,7R)-金刚烷基-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E6)和2-(3,5-二氯苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E28)对白色念珠菌(C. albicans)、大肠杆菌(E. coli)和金黄色葡萄球菌(S. aureus)有较好的抑菌活性.

关键词: 噁唑并嘧啶酮, 合成, 生物电子等排, 抗肿瘤活性, 抗菌活性, 构效关系

Based on the general framework of natural alkaloid deoxyvasicinone, forty dihydrooxazolo[5,4-d]pyrrolo[1,2-a]- pyrimidinone compounds were designed and synthesized through bioisosterism strategy. The novel compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS spectra. The main factors affecting the reactions of synthesis and the structure-activity relationships (SARs) were investigated. The activities of the target compounds against three cancer cell lines (MCF-7, HeLa and A549) were evaluated by methyl thiazolyl tetrazolium (MTT) in vitro. All the compounds were also evaluated for their antimicrobial activities by agar punch method. The results showed that 2-(naphthalen-1-yl)-6,7-dihydrooxazolo[5,4-d]- pyrrolo[1,2-a]pyrimidin-9(5H)-one (E12) and 2-(4-(trifluoromethoxy)phenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E39) exhibited relatively better anti-proliferative activities against HeLa and MCF-7 cancer cell lines, with the half maximal inhibitory concentration (IC₅₀) values of (4.59±0.10), (6.89±1.26) μmol•L^–1, respectively. 2-((3R,5R,7R)- Adamantan-1-yl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E6) and 2-(3,5-dichlorophenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one (E28) showed good antimicrobial activity to C. albicans, E. coli and S. aureus.

Key words: oxazopyrimidinone, synthesis, bioisosterism, anticancer activity, antimicrobial activity, structure-activity relationships (SARs)

引用此文

曾艳, 聂礼飞, 牛超, 阿依提拉•麦麦提江, Khurshed Bozorov, 赵江瑜, 阿吉艾克拜尔•艾萨. 二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮的合成及生物活性研究[J]. 有机化学, 2022, 42(2): 543-556.

Yan Zeng, Lifei Nie, Chao Niu, Aytilla Mamatjan, Khurshed Bozorov, Jiangyu Zhao, Haji Akber Aisa. Synthesis and Biological Activities of Dihydrooxazolo[5,4-d]-pyrrolo[1,2-a]pyrimidinones[J]. Chinese Journal of Organic Chemistry, 2022, 42(2): 543-556.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 7

参考文献 25

[1]	Alshamma, A.; Drake, S.; Flynn, D. L.; Mitscher, L. A.; Park, Y. H.; Rao, G. S. R.; Simpson, A.; Swayze, J. K.; Veysoglu, T.; Wu, S. T. - S. J. Nat. Prod. 1981, 44, 745. pmid: 7334386
[2]	Mohr, N.; Budzikiewicz, H.; Korth, H.; Pulverer, und. G. Liebigs Ann. Chem. 1981, 1515.
[3]	Okmanov, R. Y.; Tashkhodzhaev, B.; Khakimova, Z. M.; Tulyaganov, T. S.; Shakhidoyatov, K. M. Chem. Nat. Compd. 2010, 46, 59. doi: 10.1007/s10600-010-9524-6
[4]	Wu, X.-Y.; Qin, G.-W.; Cheung, K. K.; Cheng, K. F. Tetrahedron 1997, 53, 13323. doi: 10.1016/S0040-4020(97)00846-6
[5]	Molina, P.; Tárraga, A.; Gonzalez-Tejero, A.; Rioja, I.; Ubeda, A.; Terencio, M. C.; Alcaraz, M. J. J. Nat. Prod. 2001, 64, 1297. pmid: 11678654
[6]	Wang, C.-H.; Zeng, H.; Wang, Y.-H.; Li, C.; Cheng, J.; Ye, Z.-J.; He, X.-J. J. Asian Nat. Prod. Res. 2015, 17, 595. doi: 10.1080/10286020.2015.1042373
[7]	Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. ARKIVOC 2008, 100.
[8]	Nepali, K.; Sharma, S.; Ojha, R.; Dhar, K. L. Med. Chem. Res. 2013, 22, 1. doi: 10.1007/s00044-012-0002-5
[9]	Zhang, H.-Z.; Zhao, Z.-L.; Zhou, C.-H. Eur. J. Med. Chem. 2018, 144, 444. doi: 10.1016/j.ejmech.2017.12.044
[10]	Zhang, H.-Z.; Gan, L.-L.; Wang, H.; Zhou, C.-H. Mini-Rev. Med. Chem. 2017, 17, 122. doi: 10.2174/1389557516666160630120725
[11]	Zhang, L.; Peng, X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou, C.-H. Med. Res. Rev. 2014, 34, 340. doi: 10.1002/med.21290 pmid: 23740514
[12]	Zhou, C.-H.; Wang, Y. Curr. Med. Chem. 2012, 19, 239. pmid: 22320301
[13]	Seenaiah, D.; Reddy, P. R.; Reddy, G. M.; Padmaja, A.; Padmavathi, V.; Krishna, N. S. Eur. J. Med. Chem. 2014, 77, 1. doi: 10.1016/j.ejmech.2014.02.050 pmid: 24607584
[14]	Tropcheva, R.; Lesev, N.; Danova, S.; Stoitsova, S.; Kaloyanova, S. J. Photochem. Photobiol.,B 2015, 143, 120. doi: 10.1016/j.jphotobiol.2015.01.002
[15]	Zhang, Y.; Bao, J.; Deng, X.-X.; He, W.; Fan, J.-J.; Jiang, F.-Q.; Fu, L. Bioorg. Med. Chem. Lett. 2016, 26, 4081. doi: 10.1016/j.bmcl.2016.06.074 pmid: 27400889
[16]	Li, Z.; Gever, J. R.; Rao, S.; Widjaja, K.; Prusiner, S. B.; Silber, B. M. ACS Med. Chem. Lett. 2013, 4, 397. doi: 10.1021/ml300472n
[17]	Bernard, A. M.; Cabiddu, M. G.; De Montis, S.; Mura, R.; Pompei, R. Biorg. Med. Chem. 2014, 22, 4061. doi: 10.1016/j.bmc.2014.05.066
[18]	Henderson, J. A.; Bilimoria, D.; Bubenik, M.; Cadilhac, C.; Cottrell, K. M.; Denis, F.; Dietrich, E.; Ewing, N.; Falardeau, G.; Giroux, S.; L'Heureux, L.; Liu, B.; Mani, N.; Morris, M.; Nicolas, O.; Pereira, O. Z.; Poisson, C.; Reddy, T. J.; Selliah, S.; Shawgo, R. S.; Vaillancourt, L.; Wang, J.; Xu, J.; Chauret, N.; Berlioz-Seux, F.; Chan, L. C.; Das, S. K.; Grillot, A.-L.; Bennani, Y. L.; Maxwell, J. P. Biorg. Med. Chem. Lett. 2015, 25, 948. doi: 10.1016/j.bmcl.2014.12.042
[19]	Lu, X.-Y.; Hu, X.-L.; Liu, Z.-Y.; Zhang, T.-Y.; Wang, R.-B.; Wan, B.-J.; Franzblau, S. G.; You, Q.-D. MedChemComm 2017, 8, 1303. doi: 10.1039/C7MD00146K
[20]	Costales, A.; Mathur, M.; Ramurthy, S.; Lan, J.; Subramanian, S.; Jain, R.; Atallah, G.; Setti, L.; Lindvall, M.; Appleton, B. A.; Ornelas, E.; Feucht, P.; Warne, B.; Doyle, L.; Basham, S. E.; Aronchik, I.; Jefferson, A. B.; Shafer, C. M. Bioorg. Med. Chem. Lett. 2014, 24, 1592. doi: 10.1016/j.bmcl.2014.01.058 pmid: 24534486
[21]	An, Y.; Lee, E.; Yu, Y.; Yun, J.; Lee, M. Y.; Kang, J. S.; Kim, W.-Y.; Jeon, R. Bioorg. Med. Chem. Lett. 2016, 26, 3067. doi: 10.1016/j.bmcl.2016.05.017
[22]	Zhang, J.; Yao, D.-H.; Jiang, Y.-N.; Huang, J.; Yang, S.-L.; Wang, J.-H. Bioorg. Chem. 2017, 72, 168. doi: S0045-2068(17)30063-9 pmid: 28460359
[23]	Seth, K.; Garg, S. K.; Kumar, R.; Purohit, P.; Meena, V. S.; Goyal, R.; Banerjee, U. C.; Chakraborti, A. K. ACS Med. Chem. Lett. 2014, 5, 512. doi: 10.1021/ml400500e
[24]	Salomé, C.; Ribeiro, N.; Chavagnan, T.; Thuaud, F.; Serova, M.; de Gramont, A.; Faivre, S.; Raymond, E.; Désaubry, L. Eur. J. Med. Chem. 2014, 81, 181. doi: 10.1016/j.ejmech.2014.05.014
[25]	Lu, X.-Y.; Liu, X.-B.; Wan, B.-J.; Franzblau, S. G.; Chen, L.-L.; Zhou, C.-L.; You, Q.-D. Eur. J. Med. Chem. 2012, 49, 164. doi: 10.1016/j.ejmech.2012.01.007

Entry	POCl₃/equiv.	Solvent (dry)	Temp./℃	Yield/%
1	2	DCM	Reflux	—
2	2	DCE	Reflux	54
3	2	THF	Reflux	—
4	2	CH₃CN	Reflux	—
5	2	CH₃OH	Reflux	—
6	2	PhCH₃	Reflux	51
7	2	1,4-Dioxane	Reflux	67
8	1	1,4-Dioxane	Reflux	48
9	3	1,4-Dioxane	Reflux	73
10	5	1,4-Dioxane	Reflux	71
11	3	1,4-Dioxane	20	34
12	3	1,4-Dioxane	40	38
13	3	1,4-Dioxane	60	56
14	3	1,4-Dioxane	80	82
15	3	1,4-Dioxane	100	79

Entry	POCl₃/equiv.	Solvent (dry)	Temp./℃	Yield/%
1	2	DCM	Reflux	—
2	2	DCE	Reflux	54
3	2	THF	Reflux	—
4	2	CH₃CN	Reflux	—
5	2	CH₃OH	Reflux	—
6	2	PhCH₃	Reflux	51
7	2	1,4-Dioxane	Reflux	67
8	1	1,4-Dioxane	Reflux	48
9	3	1,4-Dioxane	Reflux	73
10	5	1,4-Dioxane	Reflux	71
11	3	1,4-Dioxane	20	34
12	3	1,4-Dioxane	40	38
13	3	1,4-Dioxane	60	56
14	3	1,4-Dioxane	80	82
15	3	1,4-Dioxane	100	79

Compd.	R		IC₅₀/(μmol•L^–1)						Diameter of antibacterial cycle/mm
Compd.	R		Hela		MCF-7		A549		C.a.^a		E.c.^b		S.a.^c
E1	C₂H₅		>50		>50		>50		—		—		—
E2	C₃H₇		>50		>50		>50		—		—		—
E3	C₄H₉		>50		>50		>50		—		—		—
E4	C₁₂H₂₅		43.61±7.34		>50		>50		—		—		—
E5	C(CH₃)₃		>50		>50		>50		—		—		—
E6	AdH		>50		>50		>50		9		10.5		10
E7	CH₂Ph		>50		>50		>50		9		—		—
E8	C₂H₄Ph		31.44±0.1		>50		>50		10		—		—
E9	Cp		30.94±0.7		>50		>50		—		—		—
E10	Cy		>50		>50		>50		—		—		—
E11	Thiophen-2		48.7±0.1		>50		>50		—		—		—
E12	Naphth-1		4.59±0.10		>50		18.66±0.1		—		—		—
E13	Naphth-2		34.82±0.2		>50		>50		—		—		—
E14	Biphenyl-4		>50		>50		18.40±0.1		—		—		—
E15	Furan-2		>50		>50		>50		—		—		—
E16	THP-4		>50		>50		>50		—		—		—
E17	2-CH₃C₆H₄		>50		43.42±4.99		>50		—		—		—
E18	3-CH₃C₆H₄		>50		>50		>50		8.5		—		—
E19	4-CH₃C₆H₄		13.46±0.41		19.34±3.84		>50		—		—		—
E20	2-ClC₆H₄		>50		>50		>50		13		—		—
E21	3-ClC₆H₄		>50		>50		>50		8.5		—		—
Compd.		R		IC₅₀/(μmol•L^–1)						Diameter of antibacterial cycle/mm
Compd.		R		Hela		MCF-7		A549		C.a.^a		E.c.^b		S.a.^c
E22		4-ClC₆H₄		>50		>50		>50		8.5		—		—
E23		2-BrC₆H₄		>50		>50		>50		—		—		—
E24		3-BrC₆H₄		>50		>50		>50		—		—		—
E25		4-BrC₆H₄		>50		>50		>50		—		—		9
E26		3,5-Me₂C₆H₃		>50		>50		>50		—		11		—
E27		3,4-Cl₂C₆H₃		>50		>50		>50		9		14		—
E28		3,5-Cl₂C₆H₃		>50		>50		>50		10		10		9.5
E29		2,6-Cl₂C₆H₃		>50		>50		>50		—		—		—
E30		2-FC₆H₄		>50		>50		>50		—		11		—
E31		3-FC₆H₄		>50		>50		>50		—		—		—
E32		4-F C₆H₄		>50		>50		>50		—		—		—
E33		3,5-F₂C₆H₃		>50		>50		>50		—		—		8
E34		2,6-F₂C₆H₃		>50		>50		>50		—		10		—
E35		3-CF₃C₆H₄		36.86±4.48		>50		>50		—		—		—
E36		4-CF₃C₆H₄		42.17±0.85		>50		>50		—		—		—
E37		3,5-(CF₃)₂C₆H₃		>50		>50		>50		—		10		9.5
E38		3-CF₃OC₆H₄		>50		>50		>50		—		10		—
E39		4-CF₃OC₆H₄		>50		6.89±1.26		>50		—		10		—
E40		4-(CH₃)₃CC₆H₄		>50		30.28±9.66		>50		—		10		—
DMSO^d				ND^e		ND		ND
调零^f				ND		ND		ND
DOX				0.23±0.15		0.15±0.01		0.34±0.03
CPT				1.32±0.08		3.47±0.11		0.81±0.14
氨苄青霉素												11.5^g
氨苄青霉素														10^h
两性霉素B										14ⁱ

Compd.	R		IC₅₀/(μmol•L^–1)						Diameter of antibacterial cycle/mm
Compd.	R		Hela		MCF-7		A549		C.a.^a		E.c.^b		S.a.^c
E1	C₂H₅		>50		>50		>50		—		—		—
E2	C₃H₇		>50		>50		>50		—		—		—
E3	C₄H₉		>50		>50		>50		—		—		—
E4	C₁₂H₂₅		43.61±7.34		>50		>50		—		—		—
E5	C(CH₃)₃		>50		>50		>50		—		—		—
E6	AdH		>50		>50		>50		9		10.5		10
E7	CH₂Ph		>50		>50		>50		9		—		—
E8	C₂H₄Ph		31.44±0.1		>50		>50		10		—		—
E9	Cp		30.94±0.7		>50		>50		—		—		—
E10	Cy		>50		>50		>50		—		—		—
E11	Thiophen-2		48.7±0.1		>50		>50		—		—		—
E12	Naphth-1		4.59±0.10		>50		18.66±0.1		—		—		—
E13	Naphth-2		34.82±0.2		>50		>50		—		—		—
E14	Biphenyl-4		>50		>50		18.40±0.1		—		—		—
E15	Furan-2		>50		>50		>50		—		—		—
E16	THP-4		>50		>50		>50		—		—		—
E17	2-CH₃C₆H₄		>50		43.42±4.99		>50		—		—		—
E18	3-CH₃C₆H₄		>50		>50		>50		8.5		—		—
E19	4-CH₃C₆H₄		13.46±0.41		19.34±3.84		>50		—		—		—
E20	2-ClC₆H₄		>50		>50		>50		13		—		—
E21	3-ClC₆H₄		>50		>50		>50		8.5		—		—
Compd.		R		IC₅₀/(μmol•L^–1)						Diameter of antibacterial cycle/mm
Compd.		R		Hela		MCF-7		A549		C.a.^a		E.c.^b		S.a.^c
E22		4-ClC₆H₄		>50		>50		>50		8.5		—		—
E23		2-BrC₆H₄		>50		>50		>50		—		—		—
E24		3-BrC₆H₄		>50		>50		>50		—		—		—
E25		4-BrC₆H₄		>50		>50		>50		—		—		9
E26		3,5-Me₂C₆H₃		>50		>50		>50		—		11		—
E27		3,4-Cl₂C₆H₃		>50		>50		>50		9		14		—
E28		3,5-Cl₂C₆H₃		>50		>50		>50		10		10		9.5
E29		2,6-Cl₂C₆H₃		>50		>50		>50		—		—		—
E30		2-FC₆H₄		>50		>50		>50		—		11		—
E31		3-FC₆H₄		>50		>50		>50		—		—		—
E32		4-F C₆H₄		>50		>50		>50		—		—		—
E33		3,5-F₂C₆H₃		>50		>50		>50		—		—		8
E34		2,6-F₂C₆H₃		>50		>50		>50		—		10		—
E35		3-CF₃C₆H₄		36.86±4.48		>50		>50		—		—		—
E36		4-CF₃C₆H₄		42.17±0.85		>50		>50		—		—		—
E37		3,5-(CF₃)₂C₆H₃		>50		>50		>50		—		10		9.5
E38		3-CF₃OC₆H₄		>50		>50		>50		—		10		—
E39		4-CF₃OC₆H₄		>50		6.89±1.26		>50		—		10		—
E40		4-(CH₃)₃CC₆H₄		>50		30.28±9.66		>50		—		10		—
DMSO^d				ND^e		ND		ND
调零^f				ND		ND		ND
DOX				0.23±0.15		0.15±0.01		0.34±0.03
CPT				1.32±0.08		3.47±0.11		0.81±0.14
氨苄青霉素												11.5^g
氨苄青霉素														10^h
两性霉素B										14ⁱ