Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities

doi:10.6023/cjoc202311020

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (5): 1606-1619.DOI: 10.6023/cjoc202311020 Previous Articles Next Articles

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具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究

许芹芳^a, 胡健灵^a, 刘园林^a, 张超^a, 李明月^a, 彭姝羚^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 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:2023-11-22 修回日期:2023-12-20 发布日期:2024-01-18
基金资助:
广东省自然科学基金(2021A1515011238)

Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities

Qinfang Xu^a, Jianling Hu^a, Yuanlin Liu^a, Chao Zhang^a, Mingyue Li^a, Shuling Peng^a, Zhijun Liu^a^,^b, Heru Chen^a^,^c^,^d()

a International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632
b Guangzhou PharmCherub Medical Sci. & Tech. 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:2023-11-22 Revised:2023-12-20 Published:2024-01-18
Contact: *E-mail: thrchen@jnu.edu.cn
Supported by:
Natural Science Foundation of Guangdong Province(2021A1515011238)

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Abstract

Eleven novel 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-alkyl (R²) triazenes have been designed and synthesized. Firstly, 4-aminobenzoic acid, as starting material, underwent diazo reaction following the reaction with methyl alkylamine to build the triazene scaffold. Condensation of carboxylic group with 2-diethylaminoethylamine resulted in all the title compounds. The overall yield of these 3-step reactions was between 46.5% and 68.3%. By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl- 3-methyl-3-cyclohexyltriazene (6a), 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-phenyltriazene (6e)~1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)benzyltriazene (6j) were confirmed as good broad-spectrum anti-cancer agents again/st human liver cancer cells (HepG-2), rat glioma cells (C6), human colon cancer cells (SW620), human prostate cancer cells (PC-3), murine melanoma cells (B16), and human non-small-cell lung cancer cells (A549). Among them, 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene (6g) show- ed as the most active agent, where IC₅₀ values of 6g against C6, SW620, PC-3, and B16 cell lines are less than 10 μmol/L, which is far better than the positive dacarbazine. It was found that when R² is aryl group with propriate electron-withdrawal intensity, the triazene will have good even excellent anti-cancer activity. Through drug safety evaluation, the safety indexes (SI) of 6e, 6g, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene (6h) against C6, SW620, and PC-3 cell lines, respectively; 6g, 6h, and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4- methoxyl)phenyltriazene (6i) against B16 cell line respectively; 6e, 6h, and 6i against HepG-2 cell line respectively; 6i against C6, and SW620 cell lines, respectively; were identified more than 2.0, implied better drug safety than dacarbazine. The partition coefficient (lg P) of 6e, 6g~6i lied between 3.0 and 4.0, meaning good membrane permeability. All the data support that the novel triazenes 6e, 6g~6i have better druggability.

Key words: triazenes, anti-cancer, drug safety evaluation, druggability, drug design-synthesis

Cite this article

Qinfang Xu, Jianling Hu, Yuanlin Liu, Chao Zhang, Mingyue Li, Shuling Peng, Zhijun Liu, Heru Chen. Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities[J]. Chinese Journal of Organic Chemistry, 2024, 44(5): 1606-1619.

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References 33

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Cell line	Inhibition rate/%
Cell line	4a	4b	4c	4d	4e	4f	4g	4h	4i	4j	4k
HepG-2	50.8 36.2	27.3 13.4	63.4 50.3	18.6 5.3	45.1 22.7	32.2 23.8	28.2 8.6	37.7 8.9	－8.2 －2.4	1.8 7.1	－8.3 －2.5
MDA-MB-231	－22.5 －47.5	15.8 －1.1	17.8 1.2	－0.4 －8.3	14.1 23.5	28.1 17.5	16.1 9.6	26.4 5.3	14.8 －19.3	14.5 －7.2	1.2 －11.6
PC-3	36.9 32.1	5.5 9.3	－16.2 2.3	7.1 －1.4	－18.8 11.5	－17.1 －10.0	－16.5 －21.0	17.4 6.5	1.9 －8.8	18.7 2.4	19.7 －2.0
SW620	－20.7 －17.5	13.0 6.5	5.4 －5.0	0.9 0.0	6.5 2.2	－13.8 －6.8	－9.3 5.0	15.1 17.8	11.1 －3.3	3.4 －3.3	21.8 2.9
U87	42.4 16.9	17.9 7.7	39.0 28.4	16.2 －15.4	19.1 13.2	17.1 1.5	－43.6 －29.0	19.2 －16.6	8.4 6.0	17.9 －9.1	17.1 －12.1
A375	14.3 －7.3	28.2 2.6	9.9 5.8	8.1 0.0	18.3 －3.9	11.5 －8.2	39.1 15.6	36.8 14.3	29.4 16.7	3.7 －18.4	6.4 2.8

Cell line	Inhibition rate/%
Cell line	4a	4b	4c	4d	4e	4f	4g	4h	4i	4j	4k
HepG-2	50.8 36.2	27.3 13.4	63.4 50.3	18.6 5.3	45.1 22.7	32.2 23.8	28.2 8.6	37.7 8.9	－8.2 －2.4	1.8 7.1	－8.3 －2.5
MDA-MB-231	－22.5 －47.5	15.8 －1.1	17.8 1.2	－0.4 －8.3	14.1 23.5	28.1 17.5	16.1 9.6	26.4 5.3	14.8 －19.3	14.5 －7.2	1.2 －11.6
PC-3	36.9 32.1	5.5 9.3	－16.2 2.3	7.1 －1.4	－18.8 11.5	－17.1 －10.0	－16.5 －21.0	17.4 6.5	1.9 －8.8	18.7 2.4	19.7 －2.0
SW620	－20.7 －17.5	13.0 6.5	5.4 －5.0	0.9 0.0	6.5 2.2	－13.8 －6.8	－9.3 5.0	15.1 17.8	11.1 －3.3	3.4 －3.3	21.8 2.9
U87	42.4 16.9	17.9 7.7	39.0 28.4	16.2 －15.4	19.1 13.2	17.1 1.5	－43.6 －29.0	19.2 －16.6	8.4 6.0	17.9 －9.1	17.1 －12.1
A375	14.3 －7.3	28.2 2.6	9.9 5.8	8.1 0.0	18.3 －3.9	11.5 －8.2	39.1 15.6	36.8 14.3	29.4 16.7	3.7 －18.4	6.4 2.8

细胞株	IC₅₀ ^a/(μmol•L^－1)
细胞株	DTIC	6a	6b	6c	6d	6e	6f	6g	6h	6i	6j	6k
HepG-2	>200^b	86.7±1.5	>200^b	>200^b	>200^b	45.4±2.9	100~200	21.6±2.9	45.1±1.6	100~200	100~200	>200^b
C6	>200^b	31.4±1.2	>200^b	>200^b	>200^b	4.2±1.5	28.2±0.9	3.6±2.1	20.5±1.5	31.9±7.1	27.1±2.3	>200^b
SW620	>200^b	20.4±0.4	>200^b	>200^b	>200^b	12.1±0.4	23.0±2.6	5.8±0.6	13.4±3.8	35.1±8.5	42.9±0.9	>200^b
PC-3	>200^b	32.2±7.5	>200^b	>200^b	>200^b	5.8±0.9	60.6±2.2	7.0±0.3	36.4±0.8	100~200	90.8±1.3	>200^b
B16	>200^b	64.4±6.2	>200^b	>200^b	>200^b	100~200	53.6±3.6	9.4±0.1	13.8±3.1	10.5±0.4	16.8±0.4	>200^b
A549	>200^b	100~200	>200^b	>200^b	>200^b	33.8±4.6	100~200	13.7±1.6	39.5±1.4	74.4±2.1	>200^b	>200^b

细胞株	IC₅₀ ^a/(μmol•L^－1)
细胞株	DTIC	6a	6b	6c	6d	6e	6f	6g	6h	6i	6j	6k
HepG-2	>200^b	86.7±1.5	>200^b	>200^b	>200^b	45.4±2.9	100~200	21.6±2.9	45.1±1.6	100~200	100~200	>200^b
C6	>200^b	31.4±1.2	>200^b	>200^b	>200^b	4.2±1.5	28.2±0.9	3.6±2.1	20.5±1.5	31.9±7.1	27.1±2.3	>200^b
SW620	>200^b	20.4±0.4	>200^b	>200^b	>200^b	12.1±0.4	23.0±2.6	5.8±0.6	13.4±3.8	35.1±8.5	42.9±0.9	>200^b
PC-3	>200^b	32.2±7.5	>200^b	>200^b	>200^b	5.8±0.9	60.6±2.2	7.0±0.3	36.4±0.8	100~200	90.8±1.3	>200^b
B16	>200^b	64.4±6.2	>200^b	>200^b	>200^b	100~200	53.6±3.6	9.4±0.1	13.8±3.1	10.5±0.4	16.8±0.4	>200^b
A549	>200^b	100~200	>200^b	>200^b	>200^b	33.8±4.6	100~200	13.7±1.6	39.5±1.4	74.4±2.1	>200^b	>200^b

细胞株	IC₅₀^a/(μmol•L^－1)
细胞株	DTIC	6a	6b	6c	6d	6e	6f	6g	6h	6i	6j	6k
HepG-2	>200^b	22.6±3.4	>200^b	>200^b	>200^b	20.3±4.1	31.1±1.0	14.1±2.5	23.1±3.7	41.4±5.3	53.8±1.1	>200^b
C6	>200^b	22.7±0.1	>200^b	>200^b	>200^b	4.0±0.4	30.1±0.8	9.1±0.3	21.7±0.6	35.7±5.9	18.7±1.3	>200^b
SW620	>200^b	16.5±1.8	>200^b	>200^b	>200^b	16.4±2.0	24.9±4.2	4.8±0.2	11.6±0.5	42.9±4.6	36.7±0.4	>200^b
PC-3	>200^b	100~200	>200^b	>200^b	>200^b	4.5±0.6	29.3±1.1	5.7±0.4	28.1±1.9	100~200	49.2±1.0	>200^b
B16	>200^b	20.6±2.4	>200^b	>200^b	>200^b	100~200	28.1±1.2	5.8±0.2	16.5±6.8	18.4±5.7	18.3±0.2	>200^b
A549	>200^b	57.0±4.0	>200^b	>200^b	>200^b	19.3±2.0	64.5±0.4	18.7±1.2	30.4±1.0	44.4±1.7	>200^b	>200^b

具更佳成药性的新型三氮烯化合物的设计、合成及抗癌活性研究

Design, Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities

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Fig. & Tab. 11

References 33

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t/h	TC₅₀/(μmol•L^－1)
t/h	DTIC	6e	6g	6h	6i
24	382.4±2.7	54.4±1.1	21.5±0.3	77.4±1.5	159.8±0.3
48	366.9±2.7	34.1±1.2	15.4±3.2	62.9±2.5	156.6±3.2

Compd.	Safety index
Compd.	HepG-2	C6	SW620	PC-3	B16
DTIC	<1.5	<1.5	<1.5	<1.5	1.5^a
6e	1.2	12.8	4.5	9.4	<0.2
6g	1.0	5.9	3.7	3.1	2.3
6h	1.7	3.8	5.8	2.1	5.6
6i	<0.2	5.0	4.6	<0.2	15.2

Compd.	c_{oil phase}/(μg•mL^－1)	c_{aqueous phase}/(μg•mL^－1)	P	lg P
DTIC	205.4	112.4	1.8	0.3
6e	845.4	0.3	2633.8	3.4
6g	1539.3	0.2	7975.8	3.9
6h	1784.3	0.2	7965.7	3.9
6i	732.9	0.4	1720.4	3.2

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