N-异海松酰基-N'-芳酰氨基硫脲的设计、合成、抗肿瘤活性及分子对接

doi:10.6023/cjoc202503022

摘要/Abstract

以天然产物异海松酸为原料, 通过官能团拼合策略, 设计并合成了9种N-异海松酰基-N'-芳基酰氨基硫脲衍生物. 采用四甲基偶氮唑盐(MTT)法测试了这些化合物对4种人源癌细胞HepG2、K562、MCF-7和PC-3的抗癌活性. 结果表明, 这些化合物对4种肿瘤细胞均表现出中等至显著的抑制作用, 其中N-异海松酰基-N'-(4-羟基苯甲酰氨基)硫脲(3d)的活性最为突出, 对MCF-7和PC-3细胞的IC₅₀值分别为(8.3±2.2)和(9.1±1.5) μmol/L; 构效关系分析显示, 苯基间位引入甲基和溴不利于活性的提升, 而对位引入羟基则有助于活性的增强; 当苯基被杂环芳基取代时, 化合物对MCF-7和PC-3的抗增殖活性下降. 进一步的分子对接分析表明, 除N-异海松酰基-N'-(2-呋喃甲酰氨基)硫脲(3i)外, 其余化合物与靶蛋白PARP-1之间通过氢键和疏水作用形成了稳定的蛋白-配体复合物; 化合物3d与PARP-1间形成了多种相互作用, 其中与TYR907残基形成的氢键可能是其抗肿瘤活性显著的重要原因.

关键词: 异海松酸, 酰氨基硫脲, 抗肿瘤活性, 分子对接

Using the natural product isopimaric acid as a starting material, nine N-isopimaroyl-N'-aryl acylamino thiourea derivatives were designed and synthesized through functional group assembly strategy. The tetrazolium salt (MTT) assay was used to evaluate the inhibitory activity of these compounds against four human cancer cells of HepG-2, K562, MCF-7 and PC-3. The results showed that these compounds exhibited moderate to significant inhibitory effects on four tumor cell lines. Among them N-isopimaroyl-N'-(4-hydroxybenzamido)thiourea (3d) demonstrated the strongest activity with IC₅₀ values of (8.3±2.2) and (9.1±1.5) μmol/L for MCF-7 and PC-3 cells, respectively. Structure-activity relationship analysis revealed that the introduction of methyl and bromine atom in the meta-position of phenyl was not conducive to the enhancement of anticancer activity, while the introduction of hydroxyl group in the para position was helpful to enhance the activity. When the phenyl was replaced by heterocyclic aromatic group, the anti-proliferative activity of the compound against MCF-7 and PC-3 decreased. Further molecular docking studies indicated that, except for N-isopimaroyl-N'-(2-furanylamino)thiourea (3i), all other compounds formed stable protein-ligand complexes with the target protein PARP-1 through hydrogen bonding and hydrophobic interactions. Compound 3d exhibited multiple interactions with PARP-1, and the hydrogen bond formed with the TYR907 residue was likely a key factor contributing to its significant antitumor activity.

Key words: isopimaric acid, aroyl thiosemicarbazide, antitumor activity, molecular docking

引用此文

刘娟娟, 高娅, 罗国勇, 杨韶平. N-异海松酰基-N'-芳酰氨基硫脲的设计、合成、抗肿瘤活性及分子对接[J]. 有机化学, 2025, 45(12): 4497-4504.

Juanjuan Liu, Ya Gao, Guoyong Luo, Shaoping Yang. Design, Synthesis, Antitumor Activities and Molecular Docking of N-Isopimaroyl-N'-aroyl Thiosemicarbazide Derivatives[J]. Chinese Journal of Organic Chemistry, 2025, 45(12): 4497-4504.

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Compound	IC₅₀/(μmol•L^－1)
Compound	HepG2	K562	MCF-7	PC-3	LO2
3a	34.5±2.7	67.3±2.6	10.4±2.1	16.2±1.6	63.37±2.3
3b	54.4±1.6	42.1±2.2	38.8±2.5	36.4±2.3	109.24±1.2
3c	62.3±1.3	54.2 ±1.7	20.1±1.6	17.5±2.4	80.84±3.1
3d	26.1±2.2	40.5±1.2	8.3±2.2	9.1±1.5	73.48±1.7
3e	30.7±1.8	76.7±2.6	41.5±2.4	38.3±1.8	93.86±1.4
3f	43.5±2.3	33.4±2.4	23.2±3.0	23.2±3.4	39.46 ±2.8
3g	36.4±1.5	27.2±1.5	26.4±1.9	32.6±1.2	71.51±1.3
3h	35.2±1.2	43.7±3.2	23.5±2.4	27.3±1.4	102.38±2.2
3i	32.8±2.7	35.3±3.4	44.2±1.7	37.8±3.4	86.43±2.7
P1	NT	NT	NT	67.65±2.5	48.73±2.3
P2	NT	NT	NT	33.67±1.9	96.82±1.7
5-FU	31.4±1.3	26.3±2.1	32.2±1.4	36.3±1.7	68.01±1.4

Compound	IC₅₀/(μmol•L^－1)
Compound	HepG2	K562	MCF-7	PC-3	LO2
3a	34.5±2.7	67.3±2.6	10.4±2.1	16.2±1.6	63.37±2.3
3b	54.4±1.6	42.1±2.2	38.8±2.5	36.4±2.3	109.24±1.2
3c	62.3±1.3	54.2 ±1.7	20.1±1.6	17.5±2.4	80.84±3.1
3d	26.1±2.2	40.5±1.2	8.3±2.2	9.1±1.5	73.48±1.7
3e	30.7±1.8	76.7±2.6	41.5±2.4	38.3±1.8	93.86±1.4
3f	43.5±2.3	33.4±2.4	23.2±3.0	23.2±3.4	39.46 ±2.8
3g	36.4±1.5	27.2±1.5	26.4±1.9	32.6±1.2	71.51±1.3
3h	35.2±1.2	43.7±3.2	23.5±2.4	27.3±1.4	102.38±2.2
3i	32.8±2.7	35.3±3.4	44.2±1.7	37.8±3.4	86.43±2.7
P1	NT	NT	NT	67.65±2.5	48.73±2.3
P2	NT	NT	NT	33.67±1.9	96.82±1.7
5-FU	31.4±1.3	26.3±2.1	32.2±1.4	36.3±1.7	68.01±1.4

Compd.	Docking score	Hydrogen bond	Hydrophobic interaction	Π-stacking
3a	－43.5	GLY863	LEU877, TYR889, ILE895, TYR896, TYR907	—
3b	－40.6	—	LEU877, ALA880, TYR896, ALA898, TYR907	TYR907
3c	－39.7	GLY863	LEU877, ALA880, TYR889, TYR896, TYR907, GLU988	—
3d	－39.3	GLY863, TYR907	ALA880, TYR889, TYR896, TYR907	TYR907
3e	－37.2	—	LEU877, ALA880, TYR896, TYR907	—
3f	－33.9	ALA880, TYR889	TYR896, TYR907	—
3g	－37.7	GLY863	TYR896, TYR896, TYR907	TYR907
3h	－33.1	HIS862, SER864, ASN868	LEU877, TYR889, TYR896, TYR907	—
3i	－32.2	ASN868	LEU877, ALA880, TYR889, ILE895, TYR896, TYR907	—
P1	－32.6	GLY888	TYR889, TYR896, TYR907	—
P2	－34.3	GLY888, TYP889	LEU877, TYR889, MET890, TYR896	—

Compd.	Docking score	Hydrogen bond	Hydrophobic interaction	Π-stacking
3a	－43.5	GLY863	LEU877, TYR889, ILE895, TYR896, TYR907	—
3b	－40.6	—	LEU877, ALA880, TYR896, ALA898, TYR907	TYR907
3c	－39.7	GLY863	LEU877, ALA880, TYR889, TYR896, TYR907, GLU988	—
3d	－39.3	GLY863, TYR907	ALA880, TYR889, TYR896, TYR907	TYR907
3e	－37.2	—	LEU877, ALA880, TYR896, TYR907	—
3f	－33.9	ALA880, TYR889	TYR896, TYR907	—
3g	－37.7	GLY863	TYR896, TYR896, TYR907	TYR907
3h	－33.1	HIS862, SER864, ASN868	LEU877, TYR889, TYR896, TYR907	—
3i	－32.2	ASN868	LEU877, ALA880, TYR889, ILE895, TYR896, TYR907	—
P1	－32.6	GLY888	TYR889, TYR896, TYR907	—
P2	－34.3	GLY888, TYP889	LEU877, TYR889, MET890, TYR896	—