含咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物的合成及其抗急性髓系白血病活性研究

doi:10.6023/cjoc202403053

摘要/Abstract

合成了一系列含有咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物, 评估了这些化合物对FLT3-ITD激酶的抑制作用和对表达FLT3-ITD的两种急性髓系白血病细胞株的抗增殖作用. 基于咪唑并[1,2-a]吡啶的不同取代基, 对22种化合物进行了初步的构效关系探索. 结果表明, 大多数化合物对FLT3-ITD激酶具有一定的抑制作用, IC₅₀值均低于0.5 μmol•L^－1. 其中, N-(4-氟苯基)-N-(4-(7-((2-吗啉代乙基)氨酰基)咪唑并[1,2-a]吡啶-3-羰基)苯基)环丙烷-1,1-二甲酰胺(12a)具有最佳的FLT3-ITD激酶抑制活性, 且对表达FLT3-ITD的细胞系MV4-11和MOLM-13抗增殖作用最强, IC₅₀值分别为0.06和0.2 μmol•L^－1. 此外, 12a对非FLT3突变的细胞系, 如THP-1、HCT-116、A549、HepG2、K562和MCF-7细胞无抗增殖作用, 且对正常人肾小管上皮细胞(HK-2)、人肝祖细胞(HepaRG)和人胚胎肾细胞(HEK293)无细胞毒性. 化合物12a虽然对FLT3-ITD激酶的抑制活性和抗肿瘤细胞增值活性弱于阳性药Cabozantinib, 但为FLT3-ITD抑制剂的进一步研究提供一定的参考.

关键词: 咪唑并[1,2-a]吡啶, 抗增殖活性, 抑制作用, FLT3激酶, 急性髓系白血病

A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized. The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated. With focused on the different substitutions of imidazo[1,2- a]pyridine, a preliminary exploration of the structure-activity relationship was conducted for 22 compounds. The results revealed that most compounds exhibited certain inhibitory effects on FLT3-ITD kinase with IC₅₀ values below 0.5 μmol•L^－1. Among them, N-(4-fluorophenyl)-N-(4-(7-((2-morpholinoethyl)carbamoyl)imidazo[1,2-a]pyridine-3-carbonyl)phenyl)cyclo- propane-1,1-dicarboxamide (12a) demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD with IC₅₀ values of 0.06 and 0.2 μmol•L^－1, respectively. Moreover, compound 12a did not exhibit anti-proliferative activity against cell lines without FLT3 muta- tions, such as THP-1, HCT-116, A549, HepG2, K562, and MCF-7, and it displayed non-cytotoxicity towards normal human renal tubular epithelial cells (HK-2), human liver progenitor cells (HepaRG), and HEK293 (human embryonic kidney cells). Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to Cabozantinib in this study, it can provide a reference for further research into FLT3-ITD inhibitors.

Key words: imidazole[1,2-a]pyridine, antiproliferative activity, inhibition, FLT3 kinase, acute myeloid leukemia

引用此文

吴律嘉, 黎江东, 石忠花, 金鑫, 王先恒, 赵长阔, 黄强. 含咪唑并[1,2-a]吡啶的环丙烷二甲酰胺衍生物的合成及其抗急性髓系白血病活性研究[J]. 有机化学, 2025, 45(1): 286-296.

Lüjia Wu, Jiangdong Li, Zhonghua Shi, Xin Jin, Xianheng Wang, Changkuo Zhao, Qiang Huang. Synthesis and Anti-acute Myeloid Leukemia Activity of Cyclopropane-1,1-diamide Derivatives Containing Imidazo[1,2-a]pyridine[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 286-296.

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图/表 11

Figure 1. Structures of representative FLT3 inhibitors

Scheme 1. Our previous work and rational design of three novel series of FLT3 inhibitors

Scheme 2. Synthesis of type I series Reagents and conditions: (a) EtOH, 80 ℃, 6 h; (b) 20 mol% I2, DTBP, chlorobenzene, 120 ℃, 12 h; (c) NH3·H2O, 150 ℃, 16 h; (d) 4-fluoroaniline, HATU, DIPEA, DMF, 25 ℃, 4 h; (e) LiOH, MeOH/H2O (V∶V=1∶1), 60 ℃, 2 h; (f) HATU, DIPEA, DMF, 25 ℃, 4 h.

Scheme 3. Synthesis of type II series Reagents and conditions: (a) DMF-DMA, MeOH, reflux, 12 h; (b) 2-bromo-1-(4-nitrophenyl)ethan-1-one, EtOH, reflux, 6 h; (c) H2, Pd/C, EtOH, 40 ℃, 5 h; (d) SOCl2, 60 ℃, 2 h; (e) Et3N, DCM, 6 h.

Scheme 4. Synthesis of type III series Reagents and conditions: (a) chloroacetaldehyde, EtOH, reflux, 12 h; (b) substituted 1-fluoro-4-nitrobenzene, K2CO3, DMF, 80 ℃, 6 h; (c) Pd/C, H2 balloon, MeOH, 25 ℃, 4 h; (d) compound 6, HATU, DIPEA, DMF, 25 ℃, 6 h.

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
7a	>1.0	>100	>100
7b	>1.0	60.3	93.3
Cabozantinib	0.005	0.003	0.045

Table 1. Structure-activity relationship of compounds 7a and 7b

Figure 2. Docking analysis (PDB ID: 4XUF)

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
11a	>1.0	5.4	6.2
11b	.0642	0.6	2.0
11c	>1.0	56.1	>100
11d	0.506	4.2	>100
11e	0.369	2.2	1.6
11f	0.232	0.7	0.7
11g	0.246	5.9	0.7
11h	0.228	0.06	2.0
11i	>1.0	9.4	4.2
11j	0.284	37.5	26.1
11k	>1.0	68.51	44.1
11l	>1.0	72	>100
Cabozantinib	0.005	0.006	0.051

Table 2. Structure-activity relationship of compounds 11a~11l

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
12a	0.127	0.06	0.2
12b	0.322	2.40	8.0
12c	0.0425	0.11	1.3
Cabozantinib	0.005	0.001	0.038

Table 3. Structure-activity relationship of compounds 12a~12c

Compd.	IC₅₀/(μmol•L^－1)
Compd.	FLT3-ITD	MV4-11^a	MOLM-13^a
16a	>1.0	11.36	21.5
16b	>1.0	51.21	50.5
16c	>1.0	41.11	>100
16d	>1.0	78.41	>100
16e	>1.0	>100	>100
Cabozantinib	0.005	0.008	0.041

Table 4. Structure-activity relationship of compounds 16a~16e

Cell line	IC₅₀/(μmol•L^－1)
Cell line	12a	Cabozantinib
MV4-11	0.06	0.003
MOLM-13	0.2	0.045
THP-1	>100	20.3^[19]
HCT-116	>100	15.35^[20]
A549	>100	0.76^[18a]
HepG2	>100	8.48^[21]
K562	>100	2.2^[19]
MCF-7	>100	0.45^[18a]
HEK-293	>100	>100
HepaRG	>100	—
HK-2	>100	1.9

Table 5. Cytotoxicity of 12a on different cell lines

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