PI3K/mTOR抑制剂的合成及生物活性

doi:10.7503/cjcu20170136

摘要/Abstract

摘要：

以NVP-BEZ235为先导化合物, 设计合成了10个磷脂酰肌醇3-激酶/哺乳动物雷帕霉素靶蛋白(PI3K/mTOR)抑制剂; 目标化合物的结构经核磁共振波谱(NMR)和液相色谱-质谱(LC-MS)分析确证. 采用噻唑蓝(MTT)比色法在人急性单核细胞白血病细胞株(MV4-11)、人乳腺癌细胞株(BT474)和人前列腺癌细胞株(PC-3)中测定了目标化合物的抗肿瘤活性, 并对其构效关系进行了初步的讨论. 结果表明, 化合物11(FP-189)对MV4-11细胞株表现出较强的抑制活性(IC₅₀=22.5 nmol/L), 且具有良好的溶解性, 可以作为白血病治疗的候选药物进行下一步开发.

关键词: 磷脂酰肌醇3-激酶/哺乳动物雷帕霉素靶蛋白抑制剂, 抗肿瘤活性, 构效关系

Abstract:

A series of new phosphatidylinositol 3-kinase/mammalian target of rapamycin(PI3K/mTOR) inhibitors with optimized synthetic process was designed and synthesized, the correctness of the structure was determined by ¹H NMR and LC-MS and the antitumor activities of these compounds were evaluated in 3 tumor celllines by MTT colorimetric method. Compound 11 showed very strong inhibition of MV4-11 cell growth, and was selected as a leading compound for further development of anti-leukemia drug candidate.

Key words: Phosphatidylinositol 3-kinase/mammalian target of rapamycin(PI3K/mTOR) inhibitor, Antitumor viability, Structure-activity relationship

中图分类号:

O626.32

TrendMD:

王磊, 郑国钧, 季奇, 陈博, 巩龙龙, 高聪敏, 杜镇建, 张兴民. PI3K/mTOR抑制剂的合成及生物活性. 高等学校化学学报, 2017, 38(9): 1590.

WANG Lei, ZHENG Guojun, JI Qi, CHEN Bo, GONG Longlong, GAO Congmin, DU Zhenjian, ZHANG Xingmin. Synthesis and Biological Activity of Novel PI3K/mTOR Inhibitors^†. Chem. J. Chinese Universities, 2017, 38(9): 1590.

图/表 6

参考文献 29

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Compd.	Appearance	Yield(%)	LC-MS(ESI), m/z, [M+H]⁺	Compd.	Appearance	Yield(%)	LC-MS(ESI), m/z, [M+H]⁺
5a	Yellow solid	93.3	528.4	10b	White solid	98.5	516.7
5b	Brown solid	81.2	528.4	10c	White solid	95.4
6a	Brown solid	77.4		11	White solid	71.8	594.7
6b	Yellow solid	93.3	498.4	12	White solid	37.8	594.7
7a	Brown solid	72.3	524.4	13	White solid	29.7	608.7
7b	Brown solid	44.8	524.4	14	White solid	21.2	611.3
8a	Yellow solid	98.4		15	White solid	38.3	611.3
8b	Yellow solid	88.4	538.5	16	Yellow solid	21.2	625.3
8c	Yellow solid	92.4	552.5	17	White solid	43.8	574.1
9a	White solid	93.3	616.7	18	White solid	31.2	574.1
9b	White solid	78.5	616.7	19	Yellow solid	41.0	588.7
9c	White solid	82.4	630.8	20	Yellow solid	66.8	588.1
10a	White solid	95.3	516.7

Compd.	Appearance	Yield(%)	LC-MS(ESI), m/z, [M+H]⁺	Compd.	Appearance	Yield(%)	LC-MS(ESI), m/z, [M+H]⁺
5a	Yellow solid	93.3	528.4	10b	White solid	98.5	516.7
5b	Brown solid	81.2	528.4	10c	White solid	95.4
6a	Brown solid	77.4		11	White solid	71.8	594.7
6b	Yellow solid	93.3	498.4	12	White solid	37.8	594.7
7a	Brown solid	72.3	524.4	13	White solid	29.7	608.7
7b	Brown solid	44.8	524.4	14	White solid	21.2	611.3
8a	Yellow solid	98.4		15	White solid	38.3	611.3
8b	Yellow solid	88.4	538.5	16	Yellow solid	21.2	625.3
8c	Yellow solid	92.4	552.5	17	White solid	43.8	574.1
9a	White solid	93.3	616.7	18	White solid	31.2	574.1
9b	White solid	78.5	616.7	19	Yellow solid	41.0	588.7
9c	White solid	82.4	630.8	20	Yellow solid	66.8	588.1
10a	White solid	95.3	516.7

Compd.	¹H NMR(400 MHz), δ
11	8.81(s, 1H), 8.54(s, 1H), 8.31(d, J=9.6 Hz, 1H), 8.07(s, 1H), 7.85(d, J=8.4 Hz, 1H), 7.69—7.46(m, 6H), 7.26(s, 1H), 3.97(s, 4H), 3.89(d, J=11.1 Hz, 1H), 3.70(s, 3H), 3.14—3.04(m, 1H), 2.93—2.70(m, 5H), 2.18—2.10(m, 1H), 2.05—1.96(m, 1H), 1.92—1.78(m, 1H), 1.78—1.62(m, 1H)
12	8.82(s, 1H), 8.39(s, 1H), 8.19(d, J=8.7 Hz, 1H), 8.04(s, 1H), 7.97(s, 1H), 7.86(d, J=8.8 Hz, 1H), 7.69—7.66(m, 1H), 7.59—7.52(m, 4H, Ar), 7.50(d, J=8.4 Hz, 1H), 7.21(s, 1H), 4.00(s, 5H), 3.74(s, 3H), 2.99—2.78(m, 6H), 2.15—1.94(m, 4H, —CH₂—)
13	8.86(s, 1H), 8.49—8.39(m, 1H), 8.37(s, 1H), 7.99(s, 1H), 7.94—7.81(m, 1H), 7.79—7.67(m, 1H), 7.64—7.53(m, 6H), 4.31—4.28(m, 2H), 4.03(s, 5H), 2.89—2.85(m, 6H), 2.26—2.10(m, 4H, —CH₂—), 2.02(s, 3H, )
14	9.45(s, 1H), 8.65(d, J=11.9 Hz, 1H), 8.57(s, 1H), 8.47—8.40(m, 2H), 8.40—8.30(m, 1H), 8.19(s, 1H), 8.12—8.01(m, 1H), 7.86—7.65(m, 5H), 7.21—7.05(m, 1H), 3.90(d, J=17.4 Hz, 3H), 3.44—3.34(m, 1H), 3.49—3.21(m, 2H), 2.98—2.86(m, 1H), 2.18—2.06(m, 1H), 2.02—1.82(m, 3H), 1.77—1.38(m, 2H)
15	8.81(s, 1H), 8.45—8.39(m, 1H), 8.26—8.22(m, 1H), 8.19—8.13(m, 1H), 8.08(s, 1H), 7.81(d, J=8.8 Hz, 1H), 7.63(s, 1H), 7.58—7.49(m, 5H), 7.45(s, 1H), 7.24(s, 1H), 4.03(s, 3H), 3.71(s, 4H), 3.40—3.28(m, 1H), 3.14—2.93(m, 2H), 2.30—1.85(m, 5H)
16	8.89(s, 1H), 8.48—8.41(m, 1H), 8.22(d, J=8.8 Hz, 1H), 8.09(s, 1H), 8.00(s, 1H), 7.90(d, J=8.2 Hz, 1H), 7.68—7.63(m, 1H), 7.63—7.53(m, 5H), 7.52—7.49(m, 1H), 7.26(s, 1H), 5.06—4.84(m, 1H), 4.01(s, 5H), 3.19—2.99(m, 3H), 2.23—1.60(m, 6H), 1.56(t, J=7.2 Hz, 3H)
17	8.83(d, J=4.1 Hz, 1H), 8.31—8.65(m, 1H), 8.24(d, J=8.8 Hz, 1H), 8.15—8.05(m, 1H), 7.98—7.90(m, 1H), 7.90—7.80(m, 1H), 7.77—7.63(m, 1H), 7.60—7.50(m, 4H), 7.48—7.43(m, 1H), 7.23(s, 1H), 4.35—4.20(m, 2H), 3.98(s, 3H), 3.84—3.65(m, 4H), 3.64—3.58(m, 1H), 3.24—3.04(m, 1H), 3.02—2.76(m, 2H), 2.30—2.19(m, 1H), 2.13—1.80(m, 3H)
18	9.51(s, 1H), 8.93—8.80(m, 1H), 8.67—8.43(m, 3H), 8.43—8.35(m, 1H), 8.21—8.05(m, 2H), 7.82—7.63(m, 4H), 7.16(d, J=22.8 Hz, 1H), 4.62—4.47(m, 1H), 43.99(d, J=6.0 Hz, 3H), 3.95—3.78(m, 2H), 3.70(s, 3H), 3.42(d, J=11.2 Hz, 1H), 3.29—3.00(m, 2H), 2.94—2.67(m, 1H), 2.18—1.47(m, 4H)
19	8.85(s, 1H), 8.44—8.34(m, 1H), 8.24(d, J=8.8 Hz, 1H), 8.02—7.98(m, 2H), 7.81(d, J=8.8 Hz, 1H), 7.70(d, J=7.8 Hz, 1H), 7.61—7.48(m, 4H), 7.45(d, J=8.0 Hz, 1H), 7.24(s, 1H), 4.85(d, J=12.9 Hz, 1H), 4.29—4.14(m, 4H), 4.04(s, 3H), 3.73—3.68(m, 2H), 3.24—3.18(m, 1H), 3.08—2.95(m, 1H), 2.95—2.81(m, 1H), 2.09—1.71(m, 4H), 1.56(t, J=7.2 Hz, 3H)
20	9.39(s, 1H), 8.67(d, J=10.6 Hz, 1H), 8.48(d, J=10.6 Hz, 1H), 8.46—8.35(m, 1H), 8.35—8.25(m, 1H), 8.05—7.91(m, 1H), 7.88—7.48(m, 5H), 7.18(d, J=12.3 Hz, 1H), 4.70—4.41(m, 2H), 3.91(s, 3H), 3.67(s, 4H), 3.34—3.21(m, 1H), 3.21—3.16(m, 1H), 3.02—2.60(m, 3H), 2.20—1.80(m, 4H), 1.40—1.23(m, 3H)

Compd.	¹H NMR(400 MHz), δ
11	8.81(s, 1H), 8.54(s, 1H), 8.31(d, J=9.6 Hz, 1H), 8.07(s, 1H), 7.85(d, J=8.4 Hz, 1H), 7.69—7.46(m, 6H), 7.26(s, 1H), 3.97(s, 4H), 3.89(d, J=11.1 Hz, 1H), 3.70(s, 3H), 3.14—3.04(m, 1H), 2.93—2.70(m, 5H), 2.18—2.10(m, 1H), 2.05—1.96(m, 1H), 1.92—1.78(m, 1H), 1.78—1.62(m, 1H)
12	8.82(s, 1H), 8.39(s, 1H), 8.19(d, J=8.7 Hz, 1H), 8.04(s, 1H), 7.97(s, 1H), 7.86(d, J=8.8 Hz, 1H), 7.69—7.66(m, 1H), 7.59—7.52(m, 4H, Ar), 7.50(d, J=8.4 Hz, 1H), 7.21(s, 1H), 4.00(s, 5H), 3.74(s, 3H), 2.99—2.78(m, 6H), 2.15—1.94(m, 4H, —CH₂—)
13	8.86(s, 1H), 8.49—8.39(m, 1H), 8.37(s, 1H), 7.99(s, 1H), 7.94—7.81(m, 1H), 7.79—7.67(m, 1H), 7.64—7.53(m, 6H), 4.31—4.28(m, 2H), 4.03(s, 5H), 2.89—2.85(m, 6H), 2.26—2.10(m, 4H, —CH₂—), 2.02(s, 3H, )
14	9.45(s, 1H), 8.65(d, J=11.9 Hz, 1H), 8.57(s, 1H), 8.47—8.40(m, 2H), 8.40—8.30(m, 1H), 8.19(s, 1H), 8.12—8.01(m, 1H), 7.86—7.65(m, 5H), 7.21—7.05(m, 1H), 3.90(d, J=17.4 Hz, 3H), 3.44—3.34(m, 1H), 3.49—3.21(m, 2H), 2.98—2.86(m, 1H), 2.18—2.06(m, 1H), 2.02—1.82(m, 3H), 1.77—1.38(m, 2H)
15	8.81(s, 1H), 8.45—8.39(m, 1H), 8.26—8.22(m, 1H), 8.19—8.13(m, 1H), 8.08(s, 1H), 7.81(d, J=8.8 Hz, 1H), 7.63(s, 1H), 7.58—7.49(m, 5H), 7.45(s, 1H), 7.24(s, 1H), 4.03(s, 3H), 3.71(s, 4H), 3.40—3.28(m, 1H), 3.14—2.93(m, 2H), 2.30—1.85(m, 5H)
16	8.89(s, 1H), 8.48—8.41(m, 1H), 8.22(d, J=8.8 Hz, 1H), 8.09(s, 1H), 8.00(s, 1H), 7.90(d, J=8.2 Hz, 1H), 7.68—7.63(m, 1H), 7.63—7.53(m, 5H), 7.52—7.49(m, 1H), 7.26(s, 1H), 5.06—4.84(m, 1H), 4.01(s, 5H), 3.19—2.99(m, 3H), 2.23—1.60(m, 6H), 1.56(t, J=7.2 Hz, 3H)
17	8.83(d, J=4.1 Hz, 1H), 8.31—8.65(m, 1H), 8.24(d, J=8.8 Hz, 1H), 8.15—8.05(m, 1H), 7.98—7.90(m, 1H), 7.90—7.80(m, 1H), 7.77—7.63(m, 1H), 7.60—7.50(m, 4H), 7.48—7.43(m, 1H), 7.23(s, 1H), 4.35—4.20(m, 2H), 3.98(s, 3H), 3.84—3.65(m, 4H), 3.64—3.58(m, 1H), 3.24—3.04(m, 1H), 3.02—2.76(m, 2H), 2.30—2.19(m, 1H), 2.13—1.80(m, 3H)
18	9.51(s, 1H), 8.93—8.80(m, 1H), 8.67—8.43(m, 3H), 8.43—8.35(m, 1H), 8.21—8.05(m, 2H), 7.82—7.63(m, 4H), 7.16(d, J=22.8 Hz, 1H), 4.62—4.47(m, 1H), 43.99(d, J=6.0 Hz, 3H), 3.95—3.78(m, 2H), 3.70(s, 3H), 3.42(d, J=11.2 Hz, 1H), 3.29—3.00(m, 2H), 2.94—2.67(m, 1H), 2.18—1.47(m, 4H)
19	8.85(s, 1H), 8.44—8.34(m, 1H), 8.24(d, J=8.8 Hz, 1H), 8.02—7.98(m, 2H), 7.81(d, J=8.8 Hz, 1H), 7.70(d, J=7.8 Hz, 1H), 7.61—7.48(m, 4H), 7.45(d, J=8.0 Hz, 1H), 7.24(s, 1H), 4.85(d, J=12.9 Hz, 1H), 4.29—4.14(m, 4H), 4.04(s, 3H), 3.73—3.68(m, 2H), 3.24—3.18(m, 1H), 3.08—2.95(m, 1H), 2.95—2.81(m, 1H), 2.09—1.71(m, 4H), 1.56(t, J=7.2 Hz, 3H)
20	9.39(s, 1H), 8.67(d, J=10.6 Hz, 1H), 8.48(d, J=10.6 Hz, 1H), 8.46—8.35(m, 1H), 8.35—8.25(m, 1H), 8.05—7.91(m, 1H), 7.88—7.48(m, 5H), 7.18(d, J=12.3 Hz, 1H), 4.70—4.41(m, 2H), 3.91(s, 3H), 3.67(s, 4H), 3.34—3.21(m, 1H), 3.21—3.16(m, 1H), 3.02—2.60(m, 3H), 2.20—1.80(m, 4H), 1.40—1.23(m, 3H)

Compd.	IC₅₀/(nmol·L^-1)			Compd.	IC₅₀/(nmol·L^-1)
Compd.	MV4-11		PC-3	BT-474	MV4-11	PC-3	BT-474
11	22.5	15.41	40.9	16	>1000	>1000	>1000
12	225	30.2	171	17	112.3	67.95	141.2
13	>1000	>1000	>1000	18	248	73.59	142
14	70.8	83.95	349	19	357	477	489
15	132.9	127.8	422	20	>1000	107.2	115.5
NVP-BEZ235	35.1	14.36	35.6