Citation: Jia-Hua Cui, Dagula Hu, Xu Zhang, Zheng Jing, Jing Ding, Ru-Bing Wang, Shao-Shun Li. Design and synthesis of new 7, 8-dimethoxy-α-naphthoflavones as CYP1A1 inhibitors[J]. Chinese Chemical Letters, ;2013, 24(3): 215-218. shu

Design and synthesis of new 7, 8-dimethoxy-α-naphthoflavones as CYP1A1 inhibitors

1.
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China

Corresponding author: Shao-Shun Li,
Received Date: 19 November 2012
Available Online: 27 December 2012

The flavonoids as inhibitors of CYP1A1 exhibit chemopreventive effects against certain procarcinogens and have been considered as the promising cancer preventive agents. A series of novel 7,8-dimethoxy-α-naphthoflavones as the substrate analogs were designed and prepared. The enzyme assay suggested that all of these new flavones were stronger inhibitors of CYP1A1 than the lead compound a-naphthoflavone. Among the tested ones, 3h showed the most potent inhibitory effects.
- α-Naphthoflavone,
- CYP1A1 inhibitors,
- 7, 8-Dimethoxy-α-naphthoflavone,
- Flavonoids
1. [1]
  [1] J.B. Harborne, C.A. Williams, Advances in flavonoid research since 1992, Phytochemistry 55 (2000) 481-504.
2. [2]
  [2] B.H. Havsteen, The biochemistry and medical significance of the flavonoids, Pharmacol. Ther. 96 (2002) 67-202.
3. [3]
  [3] A.A. Franke, R.V. Cooney, L.J. Custer, et al., Inhibition of neoplastic transformation and bioavailability of dietary flavonoid agents, Adv. Exp. Med. Biol. 439 (1998) 237-248.
4. [4]
  [4] F.V. So, N. Guthrie, A.F. Chambers, et al., Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices, Nutr. Cancer 26 (1996) 167-181.
5. [5]
  [5] T. Tanaka, K. Kawabata, M. Kakumoto, et al., Chemoprevention of 4-nitroquinoline-1-oxide-induced oral carcinogenesis by citrus auraptene in rats, Carcinogenesis 19 (1998) 425-431.
6. [6]
  [6] H.J. Kim, B.L. Sang, S.K. Park, et al., Effects of hydroxyl group numbers on the B-ring of 5, 7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes, Arch. Pharm. Res. 28 (2005) 1114-1121.
7. [7]
  [7] V.P. Androutsopoulos, A. Papakyriakou, D. Vourloumis, et al., Dietary flavonoids in cancer therapy and prevention: substrates and inhibitors of cytochrome P450 CYP1 enzymes, Pharmacol. Ther. 126 (2010) 9-20.
8. [8]
  [8] T. Shimada, Y. Fujii-Kuriyama, Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1, Cancer Sci. 95 (2004) 1-6.
9. [9]
  [9] V.P. Androutsopoulos, A.M. Tsatsakis, D.A. Spandidos, Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention, BMC Cancer 9 (2009) 187-204.
10. [10]
  [10] A. Pastrakuljic, B.K. Tang, E.A. Roberts, et al., Distinction of CYP1A1 and CYP1A2 activity by selective inhibition using fluvoxamine and isosafrole, Biochem. Pharmacol. 53 (1997) 531-538.
11. [11]
  [11] A.P. Koley, J.T.M. Buters, R.C. Robinson, et al., Differential mechanisms of cytochrome P450 inhibition and activation by a-naphthoflavone, J. Biol. Chem. 272 (1997) 3149-3152.
12. [12]
  [12] S.S. Li, Medicinal Chemistry, 1st ed., Science Publication, Beijing, 2009.
13. [13]
  [13] R. Livingstone, Rodd's Chemistry of Carbon Compounds, vol. IV, Elsevier Publishing Co., Amsterdam, 1977.
14. [14]
  [14] W. Baker, Molecular rearrangement of some o-acyloxyaceto phenones and the mechanism of the production of 3-acylchromones, J. Chem. Soc. (1933) 1381-1389.
15. [15]
  [15] H.S. Mahal, K. Venkataraman, Synthetical experiments in the chromone group. Part XIV. The action of sodamide on 1-acyloxy-2-acetonaphthones, J. Chem. Soc. (1934) 1767-1769.
16. [16]
  [16] D.C. Bhalla, H.S. Mahal, K. Venkataraman, Synthetical experiments in the chromone group. Part XVⅡ. Further observations on the action of sodamide on oacyloxyacetophenous, J. Chem. Soc. (1935) 868-870.
17. [17]
  [17] F.A. Carey, Organic Chemistry, 7th ed., McGraw-Hill Inc., New York, 2008.
18. [18]
  [18] R.G.F. Giles, A.B. Hughes, M.V. Sargent, Regioselectivity in the reactions of methoxydehydrobenzenes with furans. Part 2. 2-methoxyfuran and methoxydehydrobenzenes, J. Chem. Soc. Perkin Trans. I (1991) 1581-1587.
19. [19]
  [19] K.S. Huang, E.C. Wang, H.M. Chen, Syntheses of substituted naphthalenes and naphthols, J. Chin. Chem. Soc. 51 (2004) 585-605.
20. [20]
  [20] The spectroscopic data of compound 9 and 10. 9: White crystals; mp 89-91℃; IR (KBr, cm^-1): v 2965, 2933, 1761vs (C=O), 1369, 1274, 1212, 1079, 1007; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, 1H, J = 9.0 Hz, H-C(4)), 7.61 (d, 1H, J = 9.0 Hz, H-C(8)), 7.45 (dd, 1H, J = 7.2, 9.0 Hz, H-C(3)), 7.31 (d, 1H, J = 9.0 Hz, H-C(7)), 7.11 (d, 1H, J = 7.2 Hz, H-C(2)), 3.99 (s, 6H, CH₃O), 2.45 (s, 3H, CH₃CO); ¹³C NMR (100 MHz, CDCl₃): δ 169.4 (quat., C=O), 148.8, 146.7, 143.1, 130.6, 122.9 (quat., 5 C_Ar,), 125.7, 119.5, 117.5, 116.2, 115.6 (5 C_ArH), 61.1 (OCH₃), 56.8 (OCH₃), 20.9 (CH₃); ESIHRMS: Calcd. for C₁₄H₁₅O₄ 247.0970; found 247.0958 [M+H]⁺. 10: Light yellow plates; mp 136-138℃; IR (KBr, cm^-1): v 2980, 2950, 1622vs (C=O), 1497, 1488, 1394, 1281, 1085; ¹H NMR (CDCl₃, 300 MHz): δ 14.15 (s, 1H, OH), 8.23 (d, 1H, J = 9.3 Hz, H-C(4)), 7.61 (d, 1H, J = 9.0 Hz, H-C(8)), 7.51 (d, 1H, J = 9.0 Hz, H-C(7)), 7.28 (d, 1H, J = 9.3 Hz, H-C(3)), 4.02 (s, 3H, CH₃O), 3.96 (s, 3H, CH₃O), 2.67 (s, 3H, CH₃CO). ¹³C NMR (100 MHz, CDCl₃): δ 203.8 (quat., C=O), 162.9, 152.3, 142.4,133.0, 120.4, 111.8 (quat., 6 C_Ar), 125.2, 121.4, 113.4, 111.6 (4 C_ArH), 61.1 (OCH₃), 56.3 (OCH₃), 26.6 (CH₃); ESI-HRMS: Calcd. for C₁₄H₁₅O₄ 247.0970; found 247.0964 [M+H]⁺.
21. [21]
  [21] S. Yamaori, M. Kushihara, I. Yamamoto, et al., Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes, Biochem. Pharmacol. 79 (2010) 1691-1698.
22. [22]
  [22] The spectroscopic data of compounds 3a-3j. 3a: Pale yellow crystals; mp 175-176℃; ¹H NMR (300 MHz, CDCl₃): δ 8.38 (d, 1H, J = 9.0 Hz), 8.15 (d, 1H, J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz), 8.02 (m, 2H, H-C(2'), H-C(6')), 7.58 (m, 3H, H-C(3'), H-C(4'), H-C(5')), 7.46 (d, 1H, J = 9.0 Hz), 6.96 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₇O₄ 333.1127; found 333.1119 [M+H]⁺. 3b: Pale-yellow needles; mp 207-209℃; ¹H NMR (300 MHz, CDCl₃): δ 8.33 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.04 (d, 1H, J = 9.0 Hz), 7.95 (d, 2H, J = 9.0 Hz, H-C(2'), H-C(6')), 7.44 (d, 1H, J = 9.0 Hz), 7.07 (d, 2H, J = 9.0 Hz, H-C(30), H-C(50)), 6.85 (s, 1H, H-C(3)), 4.06 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O), 3.91 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₂H₁₉O₅ 363.1233; found 363.1217 [M+H]⁺. 3c: While needles; mp 190-191℃; ¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, 1H, J = 9.0 Hz), 8.14 (d, 1H, J = 9.0 Hz), 8.02 (m, 2H), 7.51 (m, 1H), 7.42 (d, 1H, J = 9.0 Hz), 7.25 (s, 1H), 7.17 (m, 1H), 7.08 (d, 1H, J = 8.4 Hz, H-C(3')), 4.05 (s, 3H, CH₃O), 4.02 (s, 3H, CH₃O), 3.96 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₂H₁₉O₅ 363.1233; found 363.1221 [M+H]⁺. 3d: Pale yellow crystals; mp 220-222℃; ¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.05 (d, 1H, J = 9.0 Hz), 7.65 (d, 1H, J = 8.4 Hz, H-C(6')), 7.45 (m, 2H, H-C(2'), H-C(5')), 7.04 (d, 1H, J = 9.0 Hz), 6.86 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O), 4.02 (s, 3H, CH₃O), 3.99 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₃H₂₁O₆ 393.1338; found 393.1345 [M+H]⁺. 3e: Pale yellow needles; mp 204-206℃; ¹H NMR (300 MHz, CDCl₃): δ 8.32 (d, 1H, J = 9.3 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz), 7.94 (d, 2H, J = 8.4 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.46 (d, 1H, J = 9.3 Hz), 6.91 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₆O₄ 367.0737; found 367.0728 [M+H]⁺. 3f: Light yellow needles; mp 193-195℃; ¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, 1H, J = 9.0 Hz), 8.16 (d, 1H, J = 9.0 Hz), 8.08 (d, 1H, J = 9.0 Hz), 7.70 (m, 1H, H-C(6')), 7.59 (d, 1H, J = 7.2 Hz, H-C(3')), 7.48 (m, 2H, H-C(40), H-C(5')), 7.41 (d, 1H, J = 9.0 Hz), 6.79 (s, 1H, H-C(3)), 4.05 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₆O₄ 367.0737; found 367.0733 [M+H]⁺. 3g: Light yellow needles; mp 194-195℃; ¹H NMR (300 MHz, CDCl₃): δ 8.32 (d, 1H, J = 9.0 Hz), 8.12 (d, 1H, J = 9.0 Hz), 8.06 (d, 1H, J = 9.0 Hz), 7.98 (s, 1H, H-C(2')), 7.85 (d, 1H, J = 6.6 Hz), 7.53 (m, 2H), 7.47 (d, 1H, J = 9.0 Hz), 6.91 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₆O₄ 367.0737; found 367.0726 [M+H]⁺. 3 h: Pale yellow needles; mp 206-208℃; ¹H NMR (300 MHz, CDCl₃): δ 8.33 (d, 1H, J = 9.0 Hz), 8.13 (d, 1H, J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz), 8.01 (m, 2H), 7.46 (d, 1H, J = 9.0 Hz), 7.27 (m, 2H), 6.88 (s, 1H, HC(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₆FO₄ 351.1033; found 351.1024 [M+H]⁺. 3i: Pale yellow crystals; mp 192-193℃; ¹H NMR (300 MHz, CDCl₃): δ 8.33 (d, 1H, J = 9.0 Hz), 8.14 (d, 1H, J = 9.0 Hz), 8.07 (d, 1H, J = 9.0 Hz), 8.00 (m, 1H, H-C(6')), 7.55 (m, 1H), 7.45 (d, 1H, J = 9.0 Hz), 7.38 (m, 1H), 7.28 (m, 1H), 7.04 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESIHRMS: Calcd. for C₂₁H₁₆FO₄ 351.1033; found 351.1045 [M+H]⁺. 3j: Light yellow crystals; mp 192-194℃; ¹H NMR (300 MHz, CDCl₃): δ 8.33 (d, 1H, J = 9.0 Hz), 8.12 (d, 1H, J = 9.0 Hz), 8.06 (d, 1H, J = 9.0 Hz), 7.76 (d, 1H, J = 7.5 Hz, H-C(60)), 7.73 (m, 1H), 7.55 (m, 1H), 7.47 (d, 1H, J = 9.0 Hz), 7.27 (m, 1H), 6.93 (s, 1H, H-C(3)), 4.07 (s, 3H, CH₃O), 4.03 (s, 3H, CH₃O); ESI-HRMS: Calcd. for C₂₁H₁₆FO₄ 351.1033; found 351.1020 [M+H]⁺.
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