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4-hydroxyquinoline derivative as well as preparation method and application thereof in antitumor drugs

A technology of hydroxyquinolines and derivatives, applied in antitumor drugs, drug combinations, organic chemistry, etc., can solve the problem of lack of P-gp specificity, low affinity of P-gp inhibitors, insufficient to produce obvious inhibitory effect, strong side effects, etc.

Inactive Publication Date: 2021-04-30
林剑雄
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] As an important method to reverse MDR, P-glycoprotein inhibitors have been studied for more than 30 years. According to their selectivity, pharmacological activity and mechanism of action, they can be roughly divided into three generations. Among them, (1) the first generation of P-glycoprotein -gp inhibitors: Verapamil (Verapamil), Cyclosporine A (cyclosporine A), etc. The disadvantage is that they usually lack the specificity of P-gp, and many first-generation P-gp inhibitors are also other transporters And the substrate of the enzyme system, some unpredictable pharmacokinetic reactions occur in the presence of chemotherapy drugs; the ability to combine with P-gp is weak, and the clinical dosage is large, which will cause serious side effects, such as the cardiotoxicity of verapamil , nephrotoxicity and immunosuppressive effect of cyclosporine A; (2) second-generation P-gp inhibitors: Valspodar / PSC 833 (Valspodar), Biricodar / VX-710 (Biricodar), etc. P-gp inhibitors have too low affinity to produce significant inhibition at tolerated doses; they are substrates of CYP3A4, and competition between antineoplastic factors and MDR modulators affecting CYP3A4 activity will affect pharmacokinetics (3) The third-generation P-gp inhibitors: Zosuquidar / LY335979, Tariquidar / XR9576, etc., have unknown toxic and side effects in clinical use, and have no effect on reducing the mortality of cancer patients. obvious effect

Method used

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  • 4-hydroxyquinoline derivative as well as preparation method and application thereof in antitumor drugs
  • 4-hydroxyquinoline derivative as well as preparation method and application thereof in antitumor drugs
  • 4-hydroxyquinoline derivative as well as preparation method and application thereof in antitumor drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Synthesis of Step 1 Intermediate 2

[0031] 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.00g, 21.77mmol), 4-nitrophenethyl bromide (5.51g, 23.94mmol) and Potassium carbonate (7.52g, 54.42mmol) was dissolved in 100mL of acetonitrile, and then heated to reflux for reaction. After 18 hours, TLC detected that the reaction was complete. The heating was stopped, and the temperature was lowered to room temperature. A solid was precipitated, and 6.75 g of a yellow solid product was obtained by filtration, with a yield of 90.57%. The next reaction was carried out directly without purification.

[0032] Synthesis of Step 2 Intermediate 3

[0033] Intermediate 2 (6.0 g, 17.52 mmol) was dissolved in 80 mL of ethanol, palladium-carbon (10%, 0.6 g) was slowly added, and reacted at room temperature for 16 h under hydrogen atmosphere. The completion of the reaction was detected by TLC, the palladium-carbon was filtered off, and the filtrate was concentrat...

Embodiment 2

[0038]

[0039] 1 H-NMR (400MHz, DMSO-d 6 )δ13.30(s,1H),11.02(s,1H),8.74(s,1H),7.70(d,J=8.4Hz,2H),7.34–7.28(m,2H),7.11(d,J =8.4Hz, 2H), 7.01(d, J=8.1Hz, 1H), 6.66(s, 1H), 6.61(s, 1H), 3.69(s, 6H), 3.54(s, 2H), 2.84-2.77 (m,2H),2.66-2.52(m,6H).ESI-MS m / z:502.4[M+H] + .

Embodiment 3

[0041]

[0042] 1 H-NMR (400MHz, DMSO-d 6 )δ13.28(s,1H),11.04(s,1H),8.72(s,1H),7.71(d,J=8.4Hz,2H),7.52(d,J=1.4Hz,1H),7.30( dt,J=8.4,1.5Hz,1H),7.11(d,J=8.4Hz,2H),6.66(s,1H),6.62(s,1H),6.48(d,J=8.0Hz,1H)3.70 (s,6H),3.55(s,2H),2.84-2.76(m,2H),2.66-2.54(m,6H),2.42(s,3H).ESI-MS m / z:498.6[M+H ] + .

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 4-hydroxyquinoline derivative as well as a preparation method and application thereof, the 4-hydroxyquinoline derivative can be used as a P-gp inhibitor to reverse drug resistance of K562 / AO, A549 / ADM, HepG2 / ADM and MCF7 / ADM doxorubicin resistance with high expression of P-gp, and achieves an anti-tumor treatment effect and has prospect.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to 4-hydroxyquinoline derivatives and a preparation method thereof, and their application as a P-gp inhibitor in the preparation of reversing drug resistance of antitumor drugs. Background technique [0002] Tumor multidrug resistance (MDR) refers to the phenomenon that after tumor cells develop resistance to a certain anticancer drug, they will also develop resistance to anticancer drugs with completely different targets, mechanisms and chemical structures. The multidrug resistance of tumors is divided into two categories, namely, intrinsic drug resistance and acquired drug resistance. The former refers to the existence in tumor cells before chemotherapy, that is, the phenomenon of drug resistance to the first chemotherapy; the latter refers to Tumor cells are highly sensitive to anticancer drugs for the first time. During chemotherapy, they not only develop resi...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D491/056A61P35/00
CPCA61P35/00C07D401/12C07D491/056
Inventor 林剑雄
Owner 林剑雄
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