新型选择性半胱氨酰白三烯受体1 (CysLT1R)拮抗剂的设计合成及构效关系研究

doi:10.6023/cjoc202306001

摘要/Abstract

半胱氨酰白三烯(CysLTs)是炎症脂介质, 其受体(CysLTsR)在哮喘、过敏性鼻炎和癌症等疾病的发生发展中发挥重要作用. 已发现3-取代1H-吲哚-2-羧酸衍生物具有半胱氨酰白三烯受体1 (CysLT₁R)拮抗活性, 但较差的溶解度限制了其进一步研究. 基于已有研究基础继续进行结构优化, 设计合成了多个系列化合物, 其中3-{2-[(1E)-3-({3-[(1E)-2- (7-氯喹啉-2-基)乙烯基]苯基}氨基)-3-氧亚基丙-1-烯基]苯基}丙酸(T9)展现出良好的选择性CysLT₁受体拮抗活性和改善的溶解度, 其IC₅₀值为(0.0066±0.0023) μmol/L, 在水中溶解度为4.16×10^－5 g/mL.

关键词: 半胱氨酰白三烯, 半胱氨酰白三烯受体1 (CysLT₁R), 选择性拮抗剂

Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation, and their receptors (CysLTsR) play an essential role in asthma, allergic rhinitis, cancer, and other diseases. According to earlier studies, 3-substituted 1H-indole-2-car- boxylic acid derivatives displayed selective cysteinyl leukotriene receptor 1 (CysLT₁R) antagonistic activity, while their poor water solubility restricted their further evaluation. Hence, structural optimization was continued and multiple series of compounds were designed and synthesized based on existing research foundations. Among them, 3-(2-((E)-3-((3-((E)-2-(7-chloro- quinolin-2-yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)phenyl)propanoic acid (T9) exhibits good selective CysLT₁ receptor antagonistic activity and improved solubility, with IC₅₀ value of (0.0066±0.0023) μmol/L and water solubility of 4.16×10^－5 g/mL.

Key words: cysteinyl leukotriene, cysteinyl leukotriene receptor 1 (CysLT₁R), selective antagonists

引用此文

王婧怡, 刘金羽, 陈东升, 陈华燕, 谢欣, 南发俊. 新型选择性半胱氨酰白三烯受体1 (CysLT₁R)拮抗剂的设计合成及构效关系研究[J]. 有机化学, 2024, 44(1): 259-276.

Jingyi Wang, Jinyu Liu, Dongsheng Chen, Huayan Chen, Xin Xie, Fajun Nan. Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT₁R) Antagonists[J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 259-276.

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图/表 16

图1. 已上市的选择性CysLT1受体拮抗剂

Figure 1. Launched drugs of selective CysLT1 receptor antagonists

图式1. 结构改造策略

Scheme 1. Structure modification strategies

图式2. 化合物T1~T6的合成

Scheme 2. Syntheses of compounds T1~T6 Reagents and conditions: (a) R/R1=CHO, tert-butyl(triphenylphosphoranylidene)acetate, toluene, reflux, overnight; (b) R/R1=Br, tert-butyl acrylate, Pd(OAc)2, PPh3, TEA, DMA, 100 ℃, 24 h; (c) TFA, DCM, 0 ℃~r.t., 4 h; (d) M2, HATU, DIPEA, DMF, r.t., overnight; (e) NaOH, EtOH, 50 ℃, overnight or NaOH, EtOH/THF/H2O, 50 ℃, overnight.

Compd.	IC₅₀^a/(μmol•L^－1)	Compd.	IC₅₀^a/(μmol•L^－1)
17g	0.13±0.023	T4	0.94±0.098
T1	0.35±0.12	T5	0.20±0.10
T2	0.85±0.14	T6	0.10±0.014
T3	2.77±0.50	Montelukast	0.057±0.029

表1. 吲哚环替换对CysLT1R拮抗活性的影响

Table 1. Effects of indole ring replacement on CysLT1R antagonistic activity

图式3. 化合物T7~T10的合成

Scheme 3. Syntheses of compounds T7~T10 Reagents and conditions: (a) ethyl bromoacetate, Pd(OAc)2, P(Nap-1)3, K2CO3, THF, H2O, r.t., overnight; (b) tert-butyl(triphenylphospho- ranylidene)acetate, toluene, reflux, overnight; (c) TFA, DCM, 0 ℃~r.t., 4 h; (d) M2, HATU, DIPEA, DMF, r.t., overnight; (e) NaOH, EtOH, 50 ℃, overnight; (f) acryloyl chloride, DMAP, TEA, DCM, r.t., 1 h; (g) M3, Pd(OAc)2, P(o-tol)3, DIPEA, DMF, 100 ℃, 5 h; (h) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h.

Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T7		0.24±0.098	T9		0.0066±0.0023
T8		0.038±0.0060	T10		0.037±0.0090

表2. 羧酸侧链对CysLT1R拮抗活性的影响

Table 2. Effects of carboxyl side chain on CysLT1R antagonistic activity

图式4. 化合物T11~T16的合成

Scheme 4. Syntheses of compounds T11~T16 Reagents and conditions: (a) methyl bromoacetate, K2CO3, DMF, 80 ℃, overnight; (b) M3, Pd(OAc)2, P(o-tol)3, DIPEA, DMF, 100 ℃, 5 h; (c) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h.

Compd.	IC₅₀^a/(μmol•L^－1)	Compd.	IC₅₀^a/(μmol•L^－1)
T11	0.068±0.013	T14	0.059±0.022
T12	0.13±0.032	T15	0.045±0.012
T13	0.075±0.00078	T16	0.039±0.0097

表3. 杂原子引入对CysLT1R拮抗活性的影响

Table 3. Effects of heteroatom introduction on CysLT1R antagonistic activity

图式5. 骨架跃迁策略

Scheme 5. Scaffold hopping strategy

图式6. 化合物T17~T20的合成

Scheme 6. Syntheses of compounds T17~T20 Reagents and conditions: (a) PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (b) tert-butyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (c) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (d) HCl/dioxane, 0 ℃~r.t., 4 h.

图式7. 化合物T21~T23的合成

Scheme 7. Syntheses of compounds T21~T23 Reagents and conditions: (a) 2-chloro-4-pyridylboronic acid, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (b) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (c) HCl/dioxane, 0 ℃~r.t., 4 h.

图式8. 化合物T24~T28的合成

Scheme 8. Syntheses of compounds T24~T28 Reagents and conditions: (a) trimethyl borate, n-BuLi, THF, －78 ℃~r.t., 12 h; (b) 2-chloro-4-iodopyridine, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (c) 2-chloro-4-pyridylboronic acid, PdCl2dppf?CH2Cl2, K2CO3, dioxane/H2O, 60 ℃, overnight; (d) BBr3, DCM, －78 ℃~r.t., overnight; (e) tert-butyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (f) M2, PdCl2dppf?CH2Cl2, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (g) HCl/dioxane, 0 ℃~r.t., 4 h.

图式9. 化合物T29和T30的合成

Scheme 9. Syntheses of compounds T29 and T30 Reagents and conditions: (a) methyl bromoacetate, NaH, THF, 0 ℃~r.t., overnight; (b) M2, Pd2dba3, Xantphos, CsCO3, dioxane, 80 ℃, overnight; (c) LiOH?H2O, MeOH/THF/H2O, r.t., 2 h; (d) Pd(OAc)2, TEA, DMF, 80 ℃, overnight; (e) NaOH, EtOH, 60 ℃, overnight.

Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T17		0.27±0.038	T24		0.075±0.0055
T18		0.070±0.0082	T25		0.60±0.024
T19		0.24±0.012	T26		1.37±0.037
T20		0.59±0.25	T27		0.0081±0.002
Compd.	R	IC₅₀^a/(μmol•L^－1)	Compd.	R	IC₅₀^a/(μmol•L^－1)
T21		0.13±0.041	T28		0.0025±0.0004
T22		0.39±0.070	T29		0.0057±0.001
T23		0.10±0.026	T30		0.010±0.0024

表4. 骨架跃迁对CysLT1R拮抗活性的影响

Table 4. Effects of scaffold hopping on CysLT1R antagonistic activity

Compd.	IC₅₀^a/(μmol•L^－1)
Compd.	CysLT₁R	CysLT₂R
17g	0.13±0.023	>100
T9	0.0066±0.0023	>100
T27	0.0081±0.002	8.75±1.14
T28	0.0025±0.0004	>100
T29	0.0057±0.001	>100
T30	0.010±0.0024	>100
Montelukast	0.057±0.029	>100

表5. CysLTs受体亚型选择性测试

Table 5. Selectivity of CysLTs receptor subtypes

Compd.	Water solubility/(g•mL^－1)
17g	5×10^－6
T9	4.16×10^－5
T9 sodium salt	3.253×10^－2
T28	6.2×10^－7
T29	2.99×10^－5

表6. 化合物溶解度测试

Table 6. Water solubility of compounds

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新型选择性半胱氨酰白三烯受体1 (CysLT₁R)拮抗剂的设计合成及构效关系研究

Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT₁R) Antagonists

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