N, n-dipentane substituted quinacridone compounds, preparation method and application thereof

Abstract

The invention discloses an N, N-dipentane substituted quinacridone compound specifically combined with a nucleic acid as well as a preparation method and an application in anti-tumor. The structure formula is shown in formula I. The N, N-dipentane substituted quinacridone compound shown in formula I can rapidly judge whether the sample to be tested is a nucleic acid through a fluorescence spectrum. Under a light condition, the N, N-dipentane substituted quinacridone compound shown in formula I has a high activity for killing the tumor cell or causing the tumor cell apoptosis and has a potential as a photochemical anti-tumor therapeutic agent. The compound in formula I is easy to synthesize, stable and convenient to store.

Description

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to N,N-dipentane-substituted quinacridone compounds specifically binding to nucleic acids, a preparation method thereof, and an antitumor application thereof. Background technique

[0002] Small molecules that bind to nucleic acids are widely used in nucleic acid analysis, fluorescence imaging of nucleic acids in cells, and treatment of cancer and viral infections [K.Cheung-Ong, G.Giaever and C.Nislow, Chem.Biol., 2013, 20, 648-659; K. Gurova, Future Oncology, 2009, 5, 1685-1704; L.J. Kricka, Ann. Clin. Biochem., 2002, 39, 114-129; R. Palchaudhuri and P.J. Hergenrother, Curr. Opin. Biotechnol., 2007 , 18, 497-503.]. Today, most chemotherapeutic agents are DNA-binding drugs [B. Maji and S. Bhattacharya, Chem. Commun., 2014, 50, 6422-6438.]. The binding methods of ligands and DNA include planar stacking of conjugated aromatic macrocycles, hydrogen bonds, electrostatic interaction...

Examples

Embodiment 1

[0065] Embodiment 1, the synthesis of compound E1 (QAB)

[0066] Dissolve NaH (200mg, 60%) and quinacridone (624mg, 2mmol) in dry THF (10mL), heat to reflux for 1h, add 5mg of tetrabutylammonium bromide, 1,5 di Pentyl bromide (2.04 g, 10 mmol) was refluxed overnight. Post-treatment: After the reaction solution was allowed to cool, 5 mL of methanol was added to quench the reaction. After the solvent was evaporated, solid column chromatography was used for separation (washing away impurities with dichloromethane of 2 times the column volume, and then using dichloromethane with a volume ratio of 1:1) Eluted with methanol and collected the eluate) to obtain compound E1. The yield was 41%.

[0067] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.72 (d, J = 9.0Hz, 2H), 8.55 (dd, J = 1.8Hz, J = 8.1Hz, 2H), 7.78-7.72 (m, 2H), 7.48 (d, J = 8.7Hz, 2H), 7.27(t, J=7.5Hz, 3H), 4.52(t, J=7.8Hz, 4H), 3.49(t, J=6.6Hz, 4H), 2.10-1.99(m, 8H) ,1.85-1....

Embodiment 2

[0068] Embodiment 2, the synthesis of compound E2 (QAP)

[0069] Basically the same as Example 1, except that 10 mmol of compound 1-(5-bromopentyl)-4-methylpiperazine was used instead of 1,5-dibromopentane, and the reaction was refluxed overnight. After evaporating the solvent, solid column chromatography (first wash away impurities with 2 times column volume of dichloromethane, then elute with dichloromethane and methanol at a volume ratio of 1:1, and collect the eluent) to obtain compound E2, The yield was 71%.

[0070] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.73 (s, 2H), 8.55 (dd, J = 1.2Hz, J = 8.1Hz, 2H), 7.76-7.71 (m, 2H), 7.48 (d, J = 8.7Hz, 2H) ,7.26(t,J=7.5Hz,3H),4.50(t,J=7.8Hz,4H),2.47-2.39(m,18H),2.29(s,7H),2.02(s,7H),1.65( t,J=3.3Hz,8H); 13 C NMR (100MHz, CDCl 3 ):δ(ppm)177.8,142.0,135.4,134.5,127.9,126.0,120.9,120.8,114.6,113.3,58.3,55.0,53.0,46.1,45.9,26.9,26.5,24.9.ESI HRMS exact masscalcd.for C 40 h 53 o 2 ...

Embodiment 3

[0071] Embodiment 3, the synthesis of compound E3 (QAT)

[0072] It is basically the same as Example 1, except that 10 mmol of the compound 5-bromo-N,N-dimethylpentanyl-1-amine is used instead of 1,5 dibromopentane, the reaction is refluxed overnight, and the solvent is evaporated Afterwards, solid column chromatography separation (first wash away impurities with dichloromethane of 2 times of column volume, then elute with volume ratio 1:1 dichloromethane and methanol, collect eluent), obtain compound E3, yield is 42%.

[0073] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.72 (s, 2H), 8.54 (dd, J = 1.2Hz, J = 7.8Hz, 2H), 7.75-7.70 (m, 2H), 7.48 (d, J = 9.0Hz, 2H) ,7.27-7.22(m,3H),4.50(t,J=7.8Hz,4H),2.36(t,J=6.3Hz,4H),2.25(t,J=2.4Hz,15H),2.03(d, J=8.1Hz, 4H), 1.65(s, 8H); 13 C NMR (100MHz, CDCl 3 ): δ (ppm) 178.0, 142.1, 135.5, 134.6, 128.0, 126.1, 121.0, 120.8, 114.6, 113.4, 59.7, 46.3, 45.6, 27.5, 27.1, 24.9.ESI HRMS exact massca...

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to N,N-dipentane-substituted quinacridone compounds specifically binding to nucleic acids, a preparation method thereof, and an antitumor application thereof. Background technique

[0002] Small molecules that bind to nucleic acids are widely used in nucleic acid analysis, fluorescence imaging of nucleic acids in cells, and treatment of cancer and viral infections [K.Cheung-Ong, G.Giaever and C.Nislow, Chem.Biol., 2013, 20, 648-659; K. Gurova, Future Oncology, 2009, 5, 1685-1704; L.J. Kricka, Ann. Clin. Biochem., 2002, 39, 114-129; R. Palchaudhuri and P.J. Hergenrother, Curr. Opin. Biotechnol., 2007 , 18, 497-503.]. Today, most chemotherapeutic agents are DNA-binding drugs [B. Maji and S. Bhattacharya, Chem. Commun., 2014, 50, 6422-6438.]. The binding methods of ligands and DNA include planar stacking of conjugated aromatic macrocycles, hydrogen bonds, electrostatic interaction...

Examples

Embodiment 1

[0065] Embodiment 1, the synthesis of compound E1 (QAB)

[0066] Dissolve NaH (200mg, 60%) and quinacridone (624mg, 2mmol) in dry THF (10mL), heat to reflux for 1h, add 5mg of tetrabutylammonium bromide, 1,5 di Pentyl bromide (2.04 g, 10 mmol) was refluxed overnight. Post-treatment: After the reaction solution was allowed to cool, 5 mL of methanol was added to quench the reaction. After the solvent was evaporated, solid column chromatography was used for separation (washing away impurities with dichloromethane of 2 times the column volume, and then using dichloromethane with a volume ratio of 1:1) Eluted with methanol and collected the eluate) to obtain compound E1. The yield was 41%.

[0067] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.72 (d, J = 9.0Hz, 2H), 8.55 (dd, J = 1.8Hz, J = 8.1Hz, 2H), 7.78-7.72 (m, 2H), 7.48 (d, J = 8.7Hz, 2H), 7.27(t, J=7.5Hz, 3H), 4.52(t, J=7.8Hz, 4H), 3.49(t, J=6.6Hz, 4H), 2.10-1.99(m, 8H) ,1.85-1....

Embodiment 2

[0068] Embodiment 2, the synthesis of compound E2 (QAP)

[0069] Basically the same as Example 1, except that 10 mmol of compound 1-(5-bromopentyl)-4-methylpiperazine was used instead of 1,5-dibromopentane, and the reaction was refluxed overnight. After evaporating the solvent, solid column chromatography (first wash away impurities with 2 times column volume of dichloromethane, then elute with dichloromethane and methanol at a volume ratio of 1:1, and collect the eluent) to obtain compound E2, The yield was 71%.

[0070] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.73 (s, 2H), 8.55 (dd, J = 1.2Hz, J = 8.1Hz, 2H), 7.76-7.71 (m, 2H), 7.48 (d, J = 8.7Hz, 2H) ,7.26(t,J=7.5Hz,3H),4.50(t,J=7.8Hz,4H),2.47-2.39(m,18H),2.29(s,7H),2.02(s,7H),1.65( t,J=3.3Hz,8H); 13 C NMR (100MHz, CDCl 3 ):δ(ppm)177.8,142.0,135.4,134.5,127.9,126.0,120.9,120.8,114.6,113.3,58.3,55.0,53.0,46.1,45.9,26.9,26.5,24.9.ESI HRMS exact masscalcd.for C 40 h 53 o 2 ...

Embodiment 3

[0071] Embodiment 3, the synthesis of compound E3 (QAT)

[0072] It is basically the same as Example 1, except that 10 mmol of the compound 5-bromo-N,N-dimethylpentanyl-1-amine is used instead of 1,5 dibromopentane, the reaction is refluxed overnight, and the solvent is evaporated Afterwards, solid column chromatography separation (first wash away impurities with dichloromethane of 2 times of column volume, then elute with volume ratio 1:1 dichloromethane and methanol, collect eluent), obtain compound E3, yield is 42%.

[0073] The confirmed data of the compound structure are: 1 H NMR (300MHz, CDCl 3 ): δ (ppm) 8.72 (s, 2H), 8.54 (dd, J = 1.2Hz, J = 7.8Hz, 2H), 7.75-7.70 (m, 2H), 7.48 (d, J = 9.0Hz, 2H) ,7.27-7.22(m,3H),4.50(t,J=7.8Hz,4H),2.36(t,J=6.3Hz,4H),2.25(t,J=2.4Hz,15H),2.03(d, J=8.1Hz, 4H), 1.65(s, 8H); 13 C NMR (100MHz, CDCl 3 ): δ (ppm) 178.0, 142.1, 135.5, 134.6, 128.0, 126.1, 121.0, 120.8, 114.6, 113.4, 59.7, 46.3, 45.6, 27.5, 27.1, 24.9.ESI HRMS exact massca...

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