新型1,2-二取代肼的设计合成及抗癌活性初步研究

doi:10.6023/cjoc202401013

有机化学 ›› 2024, Vol. 44 ›› Issue (6): 1870-1883.DOI: 10.6023/cjoc202401013 上一篇下一篇

研究论文

新型1,2-二取代肼的设计合成及抗癌活性初步研究

胡健灵^a, 张超^a, 朱文达^a, 何业谱^a, 彭姝羚^a, 陈振强^a, 李明月^a, 刘志军^a^,^b, 陈河如^a^,^c^,^d^,^*()

a 暨南大学药学院中药及天然药物研究所中药现代化与创新药物研究国际合作联合实验室广州 510632
b 广州药本君安医药科技股份有限公司广州 510663
c 暨南大学广东省中药药效物质基础及创新药物研究重点实验室广州 510632
d 暨南大学生物活性分子与成药性优化全国重点实验室广州 510632

收稿日期:2024-01-13 修回日期:2024-02-21 发布日期:2024-03-20
基金资助:
广东省自然科学基金(2021A1515011238)

Design, Synthesis, and Preliminary Anti-tumor Activity Studies of Novel 1,2-Disubstituted Hydrazines

Jianling Hu^a, Chao Zhang^a, Wenda Zhu^a, Yepu He^a, Shuling Peng^a, Zhenqiang Chen^a, Mingyue Li^a, Zhiju Liu^a^,^b, Heru Chen^a^,^c^,^d,*()

a Institute of Traditional Chinese Medicine and Natural Products, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou 510632
b Guangzhou PharmCherub Medical Science and Technology Incorporated Corporation, Guangzhou 510663
c Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632
d State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632

Received:2024-01-13 Revised:2024-02-21 Published:2024-03-20
Contact: * E-mail: thrchen@jnu.edu.cn
Supported by:
Natural Science Foundation of Guangdong Province(2021A1515011238)

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摘要/Abstract

设计合成了13个新型1,2-二取代肼, 其中包括10个2-芳基-1-(4-(N-异丙基)氨甲酰基)苄肼(9a~9j)、2个2-芳甲基-1-(4-(N-异丙基)氨甲酰基)苄肼(13a~13b)以及2-对甲基苯甲酰基-1-(4-(N-异丙基)氨甲酰基)苄肼(14). 噻唑蓝法(MTT)检测发现, 目标化合物对大鼠脑胶质瘤细胞(C6)、小鼠黑色素瘤复苏细胞(K1735)、人肝癌细胞(HepG-2)、人结肠癌细胞(SW620)、人乳腺癌细胞(MDA-MB-231)和人恶性黑色素瘤(A357)共六株肿瘤细胞大致显示出比阳性对照药丙卡巴肼(Pcb)更好的抗肿瘤活性. Pcb对小鼠黑色素瘤细胞(B16)敏感, 在孵育48 h条件下, 2-(4-甲氧基)苯基-1-(4-(N-异丙基)氨甲酰基)苄肼(9a)、2-(6-甲氧基-2-基)萘基-1-(4-(N-异丙基)氨甲酰基)苄肼(9b)和2-(3-溴)苯基-1-(4-(N-异丙基)氨甲酰基)苄肼(9i)均表现出比Pcb更强的抗癌活性; 9a对除C6和SW620外的其它五株肿瘤细胞展现出最强的抗癌活性, 其中, 对MDA-MB-231细胞的IC₅₀值为(10.8±0.9) μmol/L; 13b对C6的抑制活性最强, IC₅₀值为(15.9±3.1) μmol/L; 9e则对SW620的抑制活性最高, IC₅₀值为(62.7±1.4) μmol/L. 对于化合物9a~9j, 当芳基Ar上的取代基为吸电子效应基团时, 通常处于间位比处于对位的抗癌活性要高(9g>9f, 9i>9h); 而当取代基为供电子效应的基团时, 就没有这样的规律性; 对于SW620而言, 芳环上有弱的供电子诱导效应取代基对提高增殖抑制活性有利. 化合物9a、9b、13a和13b对小鼠胚胎成纤维细胞(3T3)的增殖抑制活性较高, 尤其是化合物9a和13a, 在孵育48 h条件下IC₅₀值分别为(24.9±1.2)和(13.9±1.7) μmol/L.

关键词: 1,2-二取代肼, 抗肿瘤, 烷化剂, 前药, 药物设计合成

Thirteen 1,2-disubstituted hydrazines, including ten 2-aryl-1-(4-(N-isopropyl) aminoformyl)benzyl hydrazines (9a~9j), two 2-aryl methylene-1-(4-(N-isopropyl)aminoformyl)benzyl hydrazines (13a~13b), and 2-(4-methyl)benzoyl- 1-(4-(N-isopropyl)aminoformyl)benzyl hydrazine (14) have been designed and synthesized. By employing methyl thiazolyl tetrazolium (MTT) assay, generally all the title compounds were shown with better anti-cancer activity against rat glioma cells against the five cancer cell lines except both C6 and SW620 cell lines among the 13 title compounds, its IC₅₀ value against MDA-MB-231 cells was (10.8±0.9) μmol/L, whilst 13b was the most active against C6 cells with IC₅₀ value of (15.9±3.1) μmol/L, and 9e was the most active against SW620 cells with IC₅₀ value of (62.7±1.4) μmol/L. It was found that when the substituent in aryl group of 9a~9j was electron-withdrawal, the anti-cancer activity of compound with substituent at meta-position was better that at para-position (9g>9f, 9i>9h). Intriguingly, when the substituent was an electron-donor group, this law was lost. It was also identified that the anti-cancer activity against SW620 cells will be enhanced with the existence of a weak electron-donor inductive group. Mouse embryonic fibroblasts (3T3) were applied here. Compounds 9a, 9b, 13a, and 13b were displayed sensitive to this cell line. IC₅₀ values of 9a, and 13a were (24.9±1.2), and (13.9±1.7) μmol/L, respectively.

Key words: 1,2-disubstituted hydrazines, anti-cancer, alkylation agent, prodrug, drug design-synthesis

引用此文

胡健灵, 张超, 朱文达, 何业谱, 彭姝羚, 陈振强, 李明月, 刘志军, 陈河如. 新型1,2-二取代肼的设计合成及抗癌活性初步研究[J]. 有机化学, 2024, 44(6): 1870-1883.

Jianling Hu, Chao Zhang, Wenda Zhu, Yepu He, Shuling Peng, Zhenqiang Chen, Mingyue Li, Zhiju Liu, Heru Chen. Design, Synthesis, and Preliminary Anti-tumor Activity Studies of Novel 1,2-Disubstituted Hydrazines[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 1870-1883.

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[1]	Zeller, P.; Gutmann, H.; Hegedüs, B.; Kaiser, A.; Langemann, A.; Müller, M. Experientia 1963, 19, 129.
[2]	Samuel, D.; Spivack, M. D. Ann. Intern. Med. 1974, 81, 795. doi: 10.7326/0003-4819-81-6-795 pmid: 4611297
[3]	Sieber, S. M.; Correa, P.; Dalgard, D. W.; Adamson, R. H. Cancer Res. 1978, 38, 2125. pmid: 418874
[4]	Herman, E. H.; Lee, I. Toxicol. Appl. Pharmacol. 1972, 22, 484.
[5]	Chabner, B. A.; Sponzo, R.; Hubbard, S.; Canellos, C. P.; Young, R. C.; Schein, P. S.; DeVita, V. T. Cancer Chemother. Rep. 1973, 57, 361. pmid: 4584487
[6]	Parvinen, L. Exp. Mol. Pathol. 1979, 30, 1. pmid: 421860
[7]	Brule, G.; Schlumberger, J. R.; Griscelli, C. Cancer Chemother. Rep. 1963, 44, 31.
[8]	DeVita, V. T.; Hahn, M. A.; Oliverio, V. T. Proc. Soc. Exp. Biol. Med. 1965, 120, 561. doi: 10.3181/00379727-120-30590 pmid: 4379192
[9]	Green, A. L. Biochem. Pharmacol. 1964, 13, 249.
[10]	Swaffar, D. S.; Horstman, M. G.; Jaw, J.-Y.; Thrall, B. D.; Meadows, G. G.; Harker, W. G.; Yost, G. S. Cancer Res. 1989, 49, 2442. pmid: 2706632
[11]	Dunn, D. L.; Lubet, R. A.; Prough, R. A. Cancer Res. 1979, 39, 4555. pmid: 498087
[12]	Prough, R. A.; Brown, M. I.; Dannan, G. A.; Guengerich, F. P. Cancer Res. 1984, 44, 543. pmid: 6692359
[13]	Fiala, E. S. Cancer (Phila.) 1977, 40, 2436. pmid: 200341
[14]	Weinstock, L. T.; Cheng, C. C. J. Med. Chem. 1979, 22, 595.
[15]	Chen, Z. X.; Riggs, A. D. J. Biol. Chem. 2011, 286, 18347.
[16]	Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. pmid: 11700143
[17]	Meyer, K. G. Synlett 2004, 2355.
[18]	Garcia-Ramos, Y.; Proulx, C.; Lubell, W. D. Can. J. Chem. 2012, 90, 985.
[19]	Kupcsik, L. Methods Mol. Biol. 2011, 740, 13. doi: 10.1007/978-1-61779-108-6_3 pmid: 21468963
[20]	Yao, M.; Walker, G.; Gamcsik, M. P. Cytotechnology 2023, 75, 381.
[21]	Chalouni, C.; Doll, S. J. Exp. Clin. Cancer Res. 2018, 37, 20. doi: 10.1186/s13046-017-0667-1 pmid: 29409507
[22]	Mamantov, A. Prog. React. Kinet. Mech. 2013, 38(1), 1.
[23]	Orvos, J.; Pancik, F.; Fischer, R. Eur. J. Org. Chem. 2023, 26, e202300049.
[24]	Rozengurt, E.; Po, C. C. Nature 1976, 261, 701.
[25]	Spano, A.; Sciola, L. Cell Div. 2023, 18, 18.
[26]	Lawley, P. D.; Brookes, P. Biochem. J. 1968, 109, 433. pmid: 4879534
[27]	Hargreaves, R. H. J.; Hartley, J. A.; Butler, J. Front. Biosci.- Landmark 2000, 5, E172.
[28]	Wang, R.; Zhang, C.; Zheng, C.; Li, H.; Xie, X.; Jin, Y.; Liu, Z.; Chen, H. Bioorg. Chem. 2019, 83, 461.
[29]	Lam, M. S.; Lee, H. W.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2008, 49, 6192.
[30]	Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543.

Compd. Ar		6→7 yield/%	Compd. Ar		6→7 yield/%
a	4-MeOC₆H₄	71.4	f	4-ClC₆H₄	73.6
b	6-MeO-2-Naphth	75.2	g	3-ClC₆H₄	72.8
c	Ph	96.1	h	4-BrC₆H₄	71.2
d	4-MeC₆H₄	87.3	i	3-BrC₆H₄	70.3
e	3-MeC₆H₄	91.2	j	4-CF₃OC₆H₄	83.3

Compd. Ar		6→7 yield/%	Compd. Ar		6→7 yield/%
a	4-MeOC₆H₄	71.4	f	4-ClC₆H₄	73.6
b	6-MeO-2-Naphth	75.2	g	3-ClC₆H₄	72.8
c	Ph	96.1	h	4-BrC₆H₄	71.2
d	4-MeC₆H₄	87.3	i	3-BrC₆H₄	70.3
e	3-MeC₆H₄	91.2	j	4-CF₃OC₆H₄	83.3

Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	C6	K1735	HepG-2	SW620	MDA-MB-231	B16	A375
Pcb	>500*	>500*	>500*	>500*	>500*	326.8±2.4	>500*
9a	42.7±0.6	119.4±2.1	45.7±0.2	>500*	98.8±1.0	37.0±1.0	95.4±2.9
9b	—	—	—	—	—	—	—
9c	316.1±0.3	>500*	438.5±2.3	83.6±3.6	105.8±2.2	299.4±1.3	217.9±3.1
9d	30.3±0.2	>500*	>500*	86.0±2.5	278.4±2.2	>500*	164.6±2.5
9e	79.0±0.9	>500*	293.7±2.9	171.6±2.2	196.7±3.4	>500*	>500*
9f	>500*	>500*	230.6±1.3	>500*	>500*	200.0±0.2	>500*
9g	89.2±0.4	99.7±2.2	380.4±3.5	148.0±2.4	289.7±2.4	93.0±1.1	>500*
9h	>500*	>500*	>500*	>500*	>500*	325.9±2.2	214.4±0.2
9i	296.4±0.8	45.5±0.2	349.5±2.5	>500*	>500*	103.0±1.3	149.1±1.3
9j	>500*	214.8±1.7	>500*	>500*	208.3±3.4	279.1±1.2	210.9±1.7
13a	—	—	—	—	—	—	—
13b	—	—	—	—	—	—	—
14	35.5±1.2	>500*	377.8±3.3	>500*	297.9±4.2	>500*	>500*

Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	C6	K1735	HepG-2	SW620	MDA-MB-231	B16	A375
Pcb	>500*	>500*	>500*	>500*	>500*	326.8±2.4	>500*
9a	42.7±0.6	119.4±2.1	45.7±0.2	>500*	98.8±1.0	37.0±1.0	95.4±2.9
9b	—	—	—	—	—	—	—
9c	316.1±0.3	>500*	438.5±2.3	83.6±3.6	105.8±2.2	299.4±1.3	217.9±3.1
9d	30.3±0.2	>500*	>500*	86.0±2.5	278.4±2.2	>500*	164.6±2.5
9e	79.0±0.9	>500*	293.7±2.9	171.6±2.2	196.7±3.4	>500*	>500*
9f	>500*	>500*	230.6±1.3	>500*	>500*	200.0±0.2	>500*
9g	89.2±0.4	99.7±2.2	380.4±3.5	148.0±2.4	289.7±2.4	93.0±1.1	>500*
9h	>500*	>500*	>500*	>500*	>500*	325.9±2.2	214.4±0.2
9i	296.4±0.8	45.5±0.2	349.5±2.5	>500*	>500*	103.0±1.3	149.1±1.3
9j	>500*	214.8±1.7	>500*	>500*	208.3±3.4	279.1±1.2	210.9±1.7
13a	—	—	—	—	—	—	—
13b	—	—	—	—	—	—	—
14	35.5±1.2	>500*	377.8±3.3	>500*	297.9±4.2	>500*	>500*

Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	C6	K1735	HepG-2	SW620	MDA-MB-231	B16	A375
Pcb	>500*	>500*	>500*	>500*	>500*	65.4±1.1	>500*
9a	19.6±0.9	16.0±1.5	21.3±0.9	>500*	10.8±0.9	24.1±1.0	71.1±1.1
9b	63.2±2.3	—	—	—	70.2±2.1	30.6±2.1	—
9c	356.2±2.4	363.9±3.3	224.0±1.3	140.2±1.9	11.6±0.9	418.6±2.6	207.4±1.3
9d	373.7±3.1	326.9±2.8	53.1±1.3	206.3±2.6	316.5±2.1	479.3±3.5	311.8±2.8
9e	97.9±1.6	*>500	218.5±2.4	62.7±1.4	56.8±0.9	389.6±2.9	411.4±2.5
9f	372.6±0.4	456.2±4.2	224.1±1.4	>500*	>500*	497.3±3.3	>500*
9g	191.8±2.4	33.4±0.8	208.3±2.2	152.4±1.6	86.0±1.9	65.2±1.1	>500*
9h	280.5±0.8	112.4±1.0	262.6±1.3	>500*	>500*	159.1±2.4	141.5±1.3
9i	169.2±1.3	50.0±1.3	130.6±1.9	>500*	>500*	59.3±1.3	117.4±1.5
9j	238.3±3.9	153.4±3.1	121.0±1.1	*>500	101.1±1.0	241.9±0.9	148.4±2.2
13a	19.2±1.5	—	—	—	53.5±2.8	—	—
13b	15.9±3.1	—	41.9±1.1	—	—	—	74.9±2.3
14	149.1±0.1	463.2±2.6	40.1±1.0	91.8±1.2	210.0±1.6	>500*	423.3±3.3

新型1,2-二取代肼的设计合成及抗癌活性初步研究

Design, Synthesis, and Preliminary Anti-tumor Activity Studies of Novel 1,2-Disubstituted Hydrazines

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