Synthesis and Antitumor Activities of Rhein-Valine Adducts†

doi:10.7503/cjcu20160568

Abstract

Abstract:

In order to search for novel leading compounds endowed with better antitumor activities, twelve novel rhein-valine derivatives were designed and synthesized by modification of position-1, 3 and 8 of rhein nucleus, and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. All the target compounds were tested for cytotoxic activity against five cancer cell lines including Hela, MCF-7, HepG2, KB and HEK293T by methyl thiazolyl tetrazolium(MTT) method in vitro. The results demonstrate that compound 5l displayed a broad spectrum of cytotoxic activities with IC₅₀ value of lower than 10 μmol/L against all tumor cell lines, compounds 5e, 5i and 5j only demonstrated moderate cytotoxic activities(IC₅₀<50 μmol/L). Primary structure-activity relationships(SARs) analysis indicated that the 3-phenylpropoxyl substituents in position-1,8 of rhein nucleus were the suitable pharmacophoric group giving rise to significant antitumor agents. In addition, compound 5l was found to exhibit remarkable DNA intercalating effects.

Key words: Rhein, Valine, Adduct, Antitumor activity, Structure-activity relationship

CLC Number:

O626

TrendMD:

ZHANG Jie, ZHOU Changjian, XIE Jianwei, DAI Bin. Synthesis and Antitumor Activities of Rhein-Valine Adducts^†[J]. Chem. J. Chinese Universities, 2016, 37(12): 2159.

Figures/Tables 9

References 24

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Compd.	Appearance	Yield(%)	m. p./℃	Compd.	Appearance	Yield(%)	m. p./℃
3a	Yellow solid	85	301.0—301.7	3g	Yellow solid	90	230.1—230.7
3b	Yellow solid	72	249.9—250.9	3h	Yellow solid	92	199.7—200.4
3c	Yellow solid	54	181.9—182.8	3i	Yellow solid	93	222.9—223.7
3d	Yellow solid	46	231.1—232.1	3j	Yellow solid	95	194.3—195.2
3e	Yellow solid	86	181.1—181.9	3k	Yellow solid	92	166.6—167.5
3f	Yellow solid	95	231.4—232.2	3l	Yellow solid	95	179.5—180.3

Compd.	Appearance	Yield(%)	m. p./℃	Compd.	Appearance	Yield(%)	m. p./℃
3a	Yellow solid	85	301.0—301.7	3g	Yellow solid	90	230.1—230.7
3b	Yellow solid	72	249.9—250.9	3h	Yellow solid	92	199.7—200.4
3c	Yellow solid	54	181.9—182.8	3i	Yellow solid	93	222.9—223.7
3d	Yellow solid	46	231.1—232.1	3j	Yellow solid	95	194.3—195.2
3e	Yellow solid	86	181.1—181.9	3k	Yellow solid	92	166.6—167.5
3f	Yellow solid	95	231.4—232.2	3l	Yellow solid	95	179.5—180.3

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ
3a	13.73(s, 1H), 8.17(d, J=1.6 Hz, 1H), 7.90(d, J=1.6 Hz, 1H), 7.78(t, J=8.0 Hz, 1H), 7.70(dd, J=1.2, 7.6 Hz, 1H), 7.56(dd, J=0.8, 8.4 Hz, 1H), 3.98(s, 3H), 3.93(s, 3H)
3b	13.70(s, 1H), 8.16(d, J=1.2 Hz, 1H), 7.87(d, J=1.2 Hz, 1H), 7.74(t, J=7.6 Hz, 1H), 7.69(dd, J=1.2, 7.6 Hz, 1H), 7.55(dd, J=1.2, 8.0 Hz, 1H), 4.28(q, J=7.2 Hz, 2H), 4.23(q, J=7.2 Hz, 2H), 1.43(t, J=7.2 Hz, 3H), 1.42(t, J=7.2 Hz, 3H)
3c	8.17(d, J=1.6 Hz, 1H), 7.88(d, J=1.6 Hz, 1H), 7.74(t, J=8.0 Hz, 1H), 7.69(dd, J=1.6, 7.6 Hz, 1H), 7.54(dd, J=1.2, 8.4 Hz, 1H), 4.16(t, J=6.4 Hz, 2H), 4.11(t, J=6.4 Hz, 2H), 1.78—1.84(m, 4H), 1.05—1.10(m, 6H)
3d	8.15(d, J=1.2 Hz, 1H), 7.86(s, 1H), 7.72(t, J=7.6 Hz, 1H), 7.67(d, J=6.8 Hz, 1H), 7.52(d, J=8.4 Hz, 1H), 4.18(t, J=6.0 Hz, 2H), 4.12(t, J=6.0 Hz, 2H), 1.72—1.80(m, 4H), 1.52—1.59(m, 4H), 0.96(t, J=7.6 Hz, 6H)
3e	8.25(d, J=1.2 Hz, 1H), 8.05(d, J=1.2 Hz, 1H), 7.73—7.79(m, 2H), 7.63—7.67(m, 5H), 7.35—7.43(m, 6H), 5.37(s, 2H), 5.33(s, 2H)
3f	8.27(d, J=1.2 Hz, 1H), 8.06(d, J=1.2 Hz, 1H), 7.79(d, J=1.2 Hz, 1H), 7.78(s, 1H), 7.69(t, J=4.8 Hz, 1H), 7.42—7.50(m, 6H), 5.36(s, 2H), 5.33(s, 2H)
3g	8.24(d, J=1.6 Hz, 1H), 8.02(d, J=1.6 Hz, 1H), 7.75—7.80(m, 2H), 7.62—7.69(m, 5H), 7.17—7.23(m, 4H), 5.36(s, 2H), 5.30(s, 2H)
3h	8.23(s, 1H), 8.01(s, 1H), 7.50—7.69(m, 7H), 7.36—7.44(m, 4H), 5.24(s, 4H)
3i	8.24(d, J=1.6 Hz, 1H), 8.02(d, J=1.2 Hz, 1H), 7.76—7.83(m, 2H), 7.65(dd, J=1.6, 8.0 Hz, 1H), 7.42—7.56(m, 6H), 7.16—7.21(m, 2H), 5.43(s, 2H), 5.37(s, 2H)
3j	8.22(d, J=1.2 Hz, 1H), 8.03(d, J=1.2 Hz, 1H), 7.73—7.80(m, 2H), 7.64(dd, J=1.2, 7.6 Hz, 1H), 7.57(t, J=8.4 Hz, 4H), 7.29(d, J=7.2 Hz, 4H), 5.34(s, 2H), 5.28(s, 2H), 2.89—2.95(m, 2H), 1.25(s, 6H), 1.23(s, 6H)
3k	8.17(d, J=1.6 Hz, 1H), 7.89(d, J=1.2 Hz, 1H), 7.68—7.75(m, 2H), 7.50(dd, J=1.6, 8.0 Hz, 4H), 7.29—7.34(m, 5H), 7.20—7.24(m, 2H), 4.41(t, J=6.8 Hz, 2H), 4.35(t, J=6.8 Hz, 2H), 3.16(q, J=6.4 Hz, 4H)
3l	8.19(d, J=1.6 Hz, 1H), 7.87(d, J=1.6 Hz, 1H), 7.71—7.77(m, 2H), 7.53(dd, J=2.0, 7.6 Hz, 1H), 7.12—7.28(m, 10H), 4.18(t, J=6.0 Hz, 2H), 4.12(t, J=6.0 Hz, 2H), 2.91(t, J=7.2 Hz, 4H), 2.04—2.13(m, 4H)

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ
3a	13.73(s, 1H), 8.17(d, J=1.6 Hz, 1H), 7.90(d, J=1.6 Hz, 1H), 7.78(t, J=8.0 Hz, 1H), 7.70(dd, J=1.2, 7.6 Hz, 1H), 7.56(dd, J=0.8, 8.4 Hz, 1H), 3.98(s, 3H), 3.93(s, 3H)
3b	13.70(s, 1H), 8.16(d, J=1.2 Hz, 1H), 7.87(d, J=1.2 Hz, 1H), 7.74(t, J=7.6 Hz, 1H), 7.69(dd, J=1.2, 7.6 Hz, 1H), 7.55(dd, J=1.2, 8.0 Hz, 1H), 4.28(q, J=7.2 Hz, 2H), 4.23(q, J=7.2 Hz, 2H), 1.43(t, J=7.2 Hz, 3H), 1.42(t, J=7.2 Hz, 3H)
3c	8.17(d, J=1.6 Hz, 1H), 7.88(d, J=1.6 Hz, 1H), 7.74(t, J=8.0 Hz, 1H), 7.69(dd, J=1.6, 7.6 Hz, 1H), 7.54(dd, J=1.2, 8.4 Hz, 1H), 4.16(t, J=6.4 Hz, 2H), 4.11(t, J=6.4 Hz, 2H), 1.78—1.84(m, 4H), 1.05—1.10(m, 6H)
3d	8.15(d, J=1.2 Hz, 1H), 7.86(s, 1H), 7.72(t, J=7.6 Hz, 1H), 7.67(d, J=6.8 Hz, 1H), 7.52(d, J=8.4 Hz, 1H), 4.18(t, J=6.0 Hz, 2H), 4.12(t, J=6.0 Hz, 2H), 1.72—1.80(m, 4H), 1.52—1.59(m, 4H), 0.96(t, J=7.6 Hz, 6H)
3e	8.25(d, J=1.2 Hz, 1H), 8.05(d, J=1.2 Hz, 1H), 7.73—7.79(m, 2H), 7.63—7.67(m, 5H), 7.35—7.43(m, 6H), 5.37(s, 2H), 5.33(s, 2H)
3f	8.27(d, J=1.2 Hz, 1H), 8.06(d, J=1.2 Hz, 1H), 7.79(d, J=1.2 Hz, 1H), 7.78(s, 1H), 7.69(t, J=4.8 Hz, 1H), 7.42—7.50(m, 6H), 5.36(s, 2H), 5.33(s, 2H)
3g	8.24(d, J=1.6 Hz, 1H), 8.02(d, J=1.6 Hz, 1H), 7.75—7.80(m, 2H), 7.62—7.69(m, 5H), 7.17—7.23(m, 4H), 5.36(s, 2H), 5.30(s, 2H)
3h	8.23(s, 1H), 8.01(s, 1H), 7.50—7.69(m, 7H), 7.36—7.44(m, 4H), 5.24(s, 4H)
3i	8.24(d, J=1.6 Hz, 1H), 8.02(d, J=1.2 Hz, 1H), 7.76—7.83(m, 2H), 7.65(dd, J=1.6, 8.0 Hz, 1H), 7.42—7.56(m, 6H), 7.16—7.21(m, 2H), 5.43(s, 2H), 5.37(s, 2H)
3j	8.22(d, J=1.2 Hz, 1H), 8.03(d, J=1.2 Hz, 1H), 7.73—7.80(m, 2H), 7.64(dd, J=1.2, 7.6 Hz, 1H), 7.57(t, J=8.4 Hz, 4H), 7.29(d, J=7.2 Hz, 4H), 5.34(s, 2H), 5.28(s, 2H), 2.89—2.95(m, 2H), 1.25(s, 6H), 1.23(s, 6H)
3k	8.17(d, J=1.6 Hz, 1H), 7.89(d, J=1.2 Hz, 1H), 7.68—7.75(m, 2H), 7.50(dd, J=1.6, 8.0 Hz, 4H), 7.29—7.34(m, 5H), 7.20—7.24(m, 2H), 4.41(t, J=6.8 Hz, 2H), 4.35(t, J=6.8 Hz, 2H), 3.16(q, J=6.4 Hz, 4H)
3l	8.19(d, J=1.6 Hz, 1H), 7.87(d, J=1.6 Hz, 1H), 7.71—7.77(m, 2H), 7.53(dd, J=2.0, 7.6 Hz, 1H), 7.12—7.28(m, 10H), 4.18(t, J=6.0 Hz, 2H), 4.12(t, J=6.0 Hz, 2H), 2.91(t, J=7.2 Hz, 4H), 2.04—2.13(m, 4H)

Compd.	Appearance	Yield(%)	m. p./℃	Compd.	Appearance	Yield(%)	m. p./℃
4a	Yellow solid	68	223.5—224.3	4g	Yellow solid	70	216.8—217.6
4b	Yellow solid	96	184.5—185.1	4h	Yellow solid	44	221.8—222.6
4c	Yellow solid	89	151.9—152.8	4i	Yellow solid	49	193.7—194.6
4d	Yellow solid	79	161.2—162.4	4j	Yellow solid	39	98.7—99.4
4e	Yellow solid	97	172.3—173.1	4k	Yellow solid	72	72.3—73.1
4f	Yellow solid	51	100.2—101.1	4l	Yellow solid	81	125.5—126.4