Synthesis and Biological Activity of N-substituted Carnosine Amide Derivatives†

doi:10.7503/cjcu20140395

Abstract

Abstract:

A series of carnosine derivatives were synthesized by modification of primary amino groups of carnosine, eleven target compounds were obtained and characterized by NMR, UV-Vis and HR-MS. Acrolein scavenging activity test results showed that most compounds exhibited some acrolein scavenging activities, especially compound 4k showed the highest acrolein scavenging activity which was stronger than carnosine. Spleen cell proliferation test results showed that most compounds exhibited some spleen cell proliferation activities, compounds 4b, 4d and 4k showed stronger spleen cell proliferation activities than the positive control conA. Hydrogen peroxide injury pre-protection results showed that most compounds exhibited some pre-protection effects, especially compounds 4a, 4j and 4k showed stronger ECV-304 cell pre-protection effects than carnosine. Plasma stability assay results showed that compared with carnosine, eleven compounds had good plasma stability.

Key words: Carnosine derivative, Acrolein scavenging, Spleen cell proliferation, Hydrogen peroxide injury protection, Plasma stability

CLC Number:

O629.72

TrendMD:

ZANG Hao, SUN Jiaming, HUANG Xiaoguang, JI Yang, DAI Tingting, GAO Xiaochen, LI Xiaodong, ZHANG Hui. Synthesis and Biological Activity of N-substituted Carnosine Amide Derivatives^†[J]. Chem. J. Chinese Universities, 2014, 35(12): 2567.

Figures/Tables 7

References 22

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Compd.	Appearance	Yield(%)	m.p./℃	UV-Vis, λ_max/nm	HR-MS([M+H]⁺), m/z
4a	White solid	70.2	188—190	201	297.1503
4c	White solid	58.5	219—220	213	367.2246
4e	White solid	73.4	258—259	205, 239	345.1475
4f	White solid	94.2	156—158	205, 239	387.1927
4g	White solid	86.6	264—265	206, 238	365.0960
4h	White solid	52.3	263—265	206, 269	407.1637
4i	White solid	55.7	239—241	215, 258	345.1479
4j	White solid	56.9	243—245	216, 258	359.1643
4k	White solid	81.2	190—191	207	415.1373

Compd.	Appearance	Yield(%)	m.p./℃	UV-Vis, λ_max/nm	HR-MS([M+H]⁺), m/z
4a	White solid	70.2	188—190	201	297.1503
4c	White solid	58.5	219—220	213	367.2246
4e	White solid	73.4	258—259	205, 239	345.1475
4f	White solid	94.2	156—158	205, 239	387.1927
4g	White solid	86.6	264—265	206, 238	365.0960
4h	White solid	52.3	263—265	206, 269	407.1637
4i	White solid	55.7	239—241	215, 258	345.1479
4j	White solid	56.9	243—245	216, 258	359.1643
4k	White solid	81.2	190—191	207	415.1373

Compd.	¹H NMR(D₂O, 600 MHz), δ	¹³C NMR(D₂O, 150 MHz), δ
4a	8.45(s, 1H), 7.16(s, 1H), 4.41(dd, J=7.8, 4.8 Hz, 1H), 3.32(q, J=6.6 Hz, 2H), 3.16(q, J=4.8 Hz, 1H), 3.00(q, J=8.4 Hz, 1H), 2.40(t, J=6.6 Hz, 2H), 2.09(t, J=7.2 Hz, 2H), 1.47(q, J=7.2 Hz, 2H), 0.78(t, J=7.2 Hz, 3H)	176.3, 175.6, 172.5, 132.5, 129.2, 115.9, 53.3, 36.8, 34.9, 34.3, 26.7, 18.1, 11.8
4c	8.47(s, 1H), 7.17(s, 1H), 4.42(t, J=7.8, 5.4 Hz, 1H), 3.33(q, J=6.6 Hz, 2H), 3.17(q, J=5.4 Hz, 1H), 3.01(q, J=7.8 Hz, 1H), 2.41(t, J=6.6 Hz, 2H), 2.12(t, J=7.2 Hz, 2H), 1.47(s, 2H), 1.19(s, 10H), 0.78(t, J=7.2 Hz, 3H)	176.5, 175.5, 172.4, 132.5, 129.2, 115.9, 53.3, 34.9, 34.9, 34.3, 30.2, 27.5, 27.4, 27.3, 26.7, 24.5, 21.2, 12.6
4e	8.17(s, 1H), 7.52(d, J=7.8 Hz, 2H), 7.28(d, J=8.4 Hz, 2H), 7.05(s, 1H), 4.44(s, 1H), 3.54(q, J=6.0 Hz, 2H), 3.13(t, J=4.2 Hz, 1H), 2.98(q, J=8.4 Hz, 1H), 2.56(d, J=6.6 Hz, 1H), 2.50(d, J=6.6 Hz, 1H), 2.34(s, 1H)	175.6, 172.7, 169.7, 142.5, 132.2, 129.6, 129.1, 128.6, 128.6, 126.2, 126.2, 115.5, 53.0, 35.5, 34.5, 26.5, 19.7
4f	8.15(s, 1H), 7.59(d, J=8.4 Hz, 2H), 7.53(d, J=8.4 Hz, 2H), 7.06(s, 1H), 4.45(dd, J=8.4, 4.8 Hz, 1H), 3.52—3.58(m, 2H), 3.14(q, J=4.8 Hz, 1H), 2.97(q, J=8.4 Hz, 1H), 2.51—2.57(m, 2H), 1.26(s, 9H)	175.6, 172.7, 169.5, 155.5, 132.1, 129.6, 129.1, 126.1, 126.1, 125.0, 125.0, 115.6, 53.0, 35.5, 34.5, 33.6, 29.5, 29.5, 29.5, 26.6
4g	8.32(d, 1H), 7.57(d, J=8.4 Hz, 2H), 7.44(d, J=8.4 Hz, 2H), 7.09(s, 1H), 4.44(dd, J=8.4, 4.8 Hz, 1H), 3.51—3.56(m, 2H), 3.15(q, J=4.8 Hz, 1H), 2.99(q, J=8.4 Hz, 1H), 2.50—2.55(m, 2H)	175.5, 172.6, 168.8, 136.8, 132.2, 131.1, 129.0, 128.0, 128.0, 127.7, 127.7, 115.6, 53.0, 35.6, 34.5, 26.5
4h	8.53(s, 1H, —COOH),8.20(d, J=7.8 Hz, 1H, imidazole NH)7.91(d, J=8.4Hz, 2H), 7.75(d, J=8.4 Hz, 2H), 7.73(s, 1H, —CONH), 7.72(s, 1H, —CONH), 7.55(s, 1H), 7.49(t, J=7.8 Hz, 2H), 7.41(d, J=7.8 Hz, 1H), 6.81(s, 1H), 4.44(d, J=5.4 Hz, 1H), 3.45(d, J=6.0 Hz, 2H), 2.95(q, J=5.4 Hz, 1H), 2.84(q, J=5.4 Hz, 1H), 2.41(q, J=7.2 Hz, 2H)	173.1, 170.3, 165.8, 142.6, 142.6, 139.2, 134.7, 133.3, 133.3, 129.0, 129.0, 128.0, 127.8, 127.8, 126.8, 126.8, 126.4, 126.4, 52.3, 36.0, 35.2, 28.9
4i	8.34(s, 1H), 7.31(t, J=7.2 Hz, 2H), 7.26(t, J=7.2 Hz, 1H), 7.21(d, J=7.2 Hz, 2H), 7.09(s, 1H), 4.36(q, J=5.4 Hz, 1H), 3.49(s, 2H), 3.34(t, J=6.0 Hz, 2H), 3.07(d, J=4.8 Hz, 1H), 2.94(d, J=7.8 Hz, 1H), 2.40(t, J=6.0 Hz, 2H)	175.7, 173.8, 172.4, 134.1, 132.6, 129.4, 128.3, 128.3, 128.1, 128.1, 126.5, 116.0, 53.4, 41.5, 35.1, 34.3, 26.8
4j	8.45(s, 1H), 7.27(t, J=7.2 Hz, 2H), 7.15—7.20(m, 4H), 4.38(q, J=5.4 Hz, 1H), 3.22(t, J=6.6 Hz, 2H), 3.17(q, J=5.4 Hz, 1H), 3.14(q, J=5.4 Hz, 1H), 2.98(q, J=7.8 Hz, 1H), 2.82(t, J=7.2 Hz, 2H), 2.44(t, J=7.2 Hz, 2H), 2.26(t, J=6.6 Hz, 2H)	175.5, 174.9, 172.3, 139.7, 132.3, 129.0, 127.9, 127.9, 127.6, 127.6, 125.6, 115.8, 53.2, 36.5, 34.7, 34.1, 30.5, 26.6
4k	8.49(d, J=1.2 Hz, 1H), 7.18(s, 1H), 4.43(dd, J=7.8, 5.4 Hz, 1H), 3.62(s, 1H), 3.34(q, J=6.6 Hz, 2H), 3.15—3.19(m, 2H), 3.12(d, J=6.6 Hz, 1H), 3.01(t, J=7.2 Hz, 1H), 2.41(q, 3H), 2.15(t, J=7.2 Hz, 2H), 1.92(t, J=7.2 Hz, 1H), 1.66(s, 1H), 1.50—1.56(m, 3H), 1.32(t, J=7.8 Hz, 2H)	176.1, 175.5, 172.4, 132.4, 129.1, 115.9, 55.7, 53.3, 39.5, 37.3, 34.9, 34.6, 34.3, 32.9, 26.9, 26.7, 24.2

Compd.	¹H NMR(D₂O, 600 MHz), δ	¹³C NMR(D₂O, 150 MHz), δ
4a	8.45(s, 1H), 7.16(s, 1H), 4.41(dd, J=7.8, 4.8 Hz, 1H), 3.32(q, J=6.6 Hz, 2H), 3.16(q, J=4.8 Hz, 1H), 3.00(q, J=8.4 Hz, 1H), 2.40(t, J=6.6 Hz, 2H), 2.09(t, J=7.2 Hz, 2H), 1.47(q, J=7.2 Hz, 2H), 0.78(t, J=7.2 Hz, 3H)	176.3, 175.6, 172.5, 132.5, 129.2, 115.9, 53.3, 36.8, 34.9, 34.3, 26.7, 18.1, 11.8
4c	8.47(s, 1H), 7.17(s, 1H), 4.42(t, J=7.8, 5.4 Hz, 1H), 3.33(q, J=6.6 Hz, 2H), 3.17(q, J=5.4 Hz, 1H), 3.01(q, J=7.8 Hz, 1H), 2.41(t, J=6.6 Hz, 2H), 2.12(t, J=7.2 Hz, 2H), 1.47(s, 2H), 1.19(s, 10H), 0.78(t, J=7.2 Hz, 3H)	176.5, 175.5, 172.4, 132.5, 129.2, 115.9, 53.3, 34.9, 34.9, 34.3, 30.2, 27.5, 27.4, 27.3, 26.7, 24.5, 21.2, 12.6
4e	8.17(s, 1H), 7.52(d, J=7.8 Hz, 2H), 7.28(d, J=8.4 Hz, 2H), 7.05(s, 1H), 4.44(s, 1H), 3.54(q, J=6.0 Hz, 2H), 3.13(t, J=4.2 Hz, 1H), 2.98(q, J=8.4 Hz, 1H), 2.56(d, J=6.6 Hz, 1H), 2.50(d, J=6.6 Hz, 1H), 2.34(s, 1H)	175.6, 172.7, 169.7, 142.5, 132.2, 129.6, 129.1, 128.6, 128.6, 126.2, 126.2, 115.5, 53.0, 35.5, 34.5, 26.5, 19.7
4f	8.15(s, 1H), 7.59(d, J=8.4 Hz, 2H), 7.53(d, J=8.4 Hz, 2H), 7.06(s, 1H), 4.45(dd, J=8.4, 4.8 Hz, 1H), 3.52—3.58(m, 2H), 3.14(q, J=4.8 Hz, 1H), 2.97(q, J=8.4 Hz, 1H), 2.51—2.57(m, 2H), 1.26(s, 9H)	175.6, 172.7, 169.5, 155.5, 132.1, 129.6, 129.1, 126.1, 126.1, 125.0, 125.0, 115.6, 53.0, 35.5, 34.5, 33.6, 29.5, 29.5, 29.5, 26.6
4g	8.32(d, 1H), 7.57(d, J=8.4 Hz, 2H), 7.44(d, J=8.4 Hz, 2H), 7.09(s, 1H), 4.44(dd, J=8.4, 4.8 Hz, 1H), 3.51—3.56(m, 2H), 3.15(q, J=4.8 Hz, 1H), 2.99(q, J=8.4 Hz, 1H), 2.50—2.55(m, 2H)	175.5, 172.6, 168.8, 136.8, 132.2, 131.1, 129.0, 128.0, 128.0, 127.7, 127.7, 115.6, 53.0, 35.6, 34.5, 26.5
4h	8.53(s, 1H, —COOH),8.20(d, J=7.8 Hz, 1H, imidazole NH)7.91(d, J=8.4Hz, 2H), 7.75(d, J=8.4 Hz, 2H), 7.73(s, 1H, —CONH), 7.72(s, 1H, —CONH), 7.55(s, 1H), 7.49(t, J=7.8 Hz, 2H), 7.41(d, J=7.8 Hz, 1H), 6.81(s, 1H), 4.44(d, J=5.4 Hz, 1H), 3.45(d, J=6.0 Hz, 2H), 2.95(q, J=5.4 Hz, 1H), 2.84(q, J=5.4 Hz, 1H), 2.41(q, J=7.2 Hz, 2H)	173.1, 170.3, 165.8, 142.6, 142.6, 139.2, 134.7, 133.3, 133.3, 129.0, 129.0, 128.0, 127.8, 127.8, 126.8, 126.8, 126.4, 126.4, 52.3, 36.0, 35.2, 28.9
4i	8.34(s, 1H), 7.31(t, J=7.2 Hz, 2H), 7.26(t, J=7.2 Hz, 1H), 7.21(d, J=7.2 Hz, 2H), 7.09(s, 1H), 4.36(q, J=5.4 Hz, 1H), 3.49(s, 2H), 3.34(t, J=6.0 Hz, 2H), 3.07(d, J=4.8 Hz, 1H), 2.94(d, J=7.8 Hz, 1H), 2.40(t, J=6.0 Hz, 2H)	175.7, 173.8, 172.4, 134.1, 132.6, 129.4, 128.3, 128.3, 128.1, 128.1, 126.5, 116.0, 53.4, 41.5, 35.1, 34.3, 26.8
4j	8.45(s, 1H), 7.27(t, J=7.2 Hz, 2H), 7.15—7.20(m, 4H), 4.38(q, J=5.4 Hz, 1H), 3.22(t, J=6.6 Hz, 2H), 3.17(q, J=5.4 Hz, 1H), 3.14(q, J=5.4 Hz, 1H), 2.98(q, J=7.8 Hz, 1H), 2.82(t, J=7.2 Hz, 2H), 2.44(t, J=7.2 Hz, 2H), 2.26(t, J=6.6 Hz, 2H)	175.5, 174.9, 172.3, 139.7, 132.3, 129.0, 127.9, 127.9, 127.6, 127.6, 125.6, 115.8, 53.2, 36.5, 34.7, 34.1, 30.5, 26.6
4k	8.49(d, J=1.2 Hz, 1H), 7.18(s, 1H), 4.43(dd, J=7.8, 5.4 Hz, 1H), 3.62(s, 1H), 3.34(q, J=6.6 Hz, 2H), 3.15—3.19(m, 2H), 3.12(d, J=6.6 Hz, 1H), 3.01(t, J=7.2 Hz, 1H), 2.41(q, 3H), 2.15(t, J=7.2 Hz, 2H), 1.92(t, J=7.2 Hz, 1H), 1.66(s, 1H), 1.50—1.56(m, 3H), 1.32(t, J=7.8 Hz, 2H)	176.1, 175.5, 172.4, 132.4, 129.1, 115.9, 55.7, 53.3, 39.5, 37.3, 34.9, 34.6, 34.3, 32.9, 26.9, 26.7, 24.2

Compd.	Scavenging ratio(%)			Compd.	Scavenging ratio(%)
Compd.	1 h	2 h	3 h	Compd.	1 h	2 h	3 h
4a	25.6±0.9	30.4±0.4	37.0±0.5	4h	38.7±0.6	51.5±1.6	60.5±0.5
4b	22.0±0.6	32.9±2.3	40.3±1.2	4i	21.0±0.6	26.5±1.2	40.7±1.2
4c	21.9±0.4	42.6±0.8	55.5±1.2	4j	14.9±0.4	28.6±0.8	43.6±1.1
4d	22.2±1.4	31.7±1.8	40.5±1.6	4k	56.0±2.1	75.2±1.0	92.1±1.1
4e	28.0±1.1	39.1±1.5	55.8±2.0	Carnosine	46.6±1.8	74.7±2.0	88.0±2.3
4f	21.3±0.7	38.5±0.5	58.4±0.5	β-Alanine	12.3±1.5	27.6±1.7	41.1±2.0
4g	22.9±1.4	39.7±1.2	58.2±0.4	GABA	10.4±0.8	23.4±0.4	39.0±2.3