Synthesis and Biological Activity of Novel PI3K/mTOR Inhibitors†

doi:10.7503/cjcu20170136

Abstract

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

CLC Number:

O626.32

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2017, 38(9): 1590.

Figures/Tables 6

References 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