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

doi:10.6023/cjoc202401013

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (6): 1870-1883.DOI: 10.6023/cjoc202401013 Previous Articles Next Articles

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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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Abstract

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

Cite this article

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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Fig. & Tab. 8

References 30

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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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