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Albumin binding type camptothecin derivative prodrug as well as preparation method and application thereof

A technology of albumin-binding type and camptothecin, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of low drug loading dose, inability to directly administer drugs, low water solubility, etc., and achieve extended In vivo half-life, excellent anti-tumor activity effect

Pending Publication Date: 2022-05-06
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, SN38 exhibits extremely low water solubility under both physiological and pharmacological conditions, resulting in its inability to be administered directly, thus limiting its clinical application
In recent years, a large number of SN38 drug delivery systems have been reported, such as: PEGylated conjugates, liposomes, antibody-drug conjugates, etc., often show poor tumor penetration and low drug loading dose, limiting its clinical application

Method used

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  • Albumin binding type camptothecin derivative prodrug as well as preparation method and application thereof
  • Albumin binding type camptothecin derivative prodrug as well as preparation method and application thereof
  • Albumin binding type camptothecin derivative prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of Compound Ia

[0045]

[0046] Preparation of compound IIa:

[0047] Under nitrogen protection conditions, 2.47g (5.10mmol) of compound 1, 2g (5.10mmol) of SN38 and 3.85g (15.30mmol) of ADDP were dissolved in 500mL of toluene, and 3mL of n-Bu 3 P (15.30mmol), heated at 80 degrees overnight. Spin dry toluene, dissolve in 500mL ethyl acetate, saturated NaHCO 3 solution (250 mL), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and spin-dried. Add 50 mL of ethyl acetate to make a slurry, filter, and collect the filter cake as compound IIa, 3 g of light yellow solid, with a yield of 69%.

[0048] 1 H-NMR (400MHz, CDCl 3 )δ(ppm): δ8.17(d, J=9.2Hz, 1H), 7.97(d, J=2.1Hz, 1H), 7.69(dd, J=8.7, 2.2Hz, 1H), 7.62(s, 1H), 7.49(dd, J=9.3, 2.7Hz, 1H), 7.44(d, J=8.6Hz, 1H), 7.34(d, J=2.7Hz, 1H), 5.72(d, J=16.3Hz, 1H),5.44–5.14(m,9H),4.24(d,J=8.7Hz,1H),4.00(s,1H),3.74(s,3H),3.12(q,J=7.6Hz,2H), 2.13(s,3H),2.07(s,3H),2.06(s,3H),1.88(ddt,J=...

Embodiment 2

[0066] Synthesis of Compound Ib

[0067]

[0068] The preparation of compound Ib:

[0069] Under nitrogen protection, 0.80 g (1.00 mmol) of compound VIa, 0.31 g (1.20 mmol) of compound VIIb and 0.50 g (0.25 mmol) of sodium ascorbate were dissolved in 50 mL of tetrahydrofuran. 0.63g (0.25mmol) of copper sulfate pentahydrate was dissolved in 50mL of water and added to the reaction system. Stir at room temperature for half an hour. Prepare the liquid phase directly over half. The liquid phase method is the same as above. The effluent with a relative retention time of 9-10 min was collected and freeze-dried to obtain 0.96 g of compound Ib as a light yellow solid, with a yield of 90%. 1 H NMR (400MHz,DMSO)δ9.17(s,1H),8.36–8.20(m,2H),8.06(d,J=9.1Hz,1H),7.93(s,1H),7.59–7.48(m, 2H),7.33–7.21(m,2H),7.13(d,J=8.3Hz,1H),7.01–6.91(m,3H),5.41(s,2H),5.26(d,J=6.7Hz,4H ),4.87(d,J=7.4Hz,1H),4.40(t,J=6.6Hz,2H),4.27(s,2H),3.37–3.29(m,4H),3.17–3.10(m,2H) ,2.46–2.38(m,2H),2.17–2.00(m,5H),...

Embodiment 3

[0072] Compound Ia and plasma protein binding experiment

[0073] The plasma was warmed at 37°C for half an hour, and 6 μl of 10 mM compound Ia stock solution was added to 594 μl of plasma. Sampling time points are: 15s, 2min, 4min, 8min, 15min, 30min. Take 30 μl of the above plasma each time, add 120 μl of iced methanol-acetonitrile (v / v, 1:1) solution, vortex for 1 minute, and centrifuge at 9000 rpm at 4 degrees for half an hour. The supernatant was fed into the liquid phase to determine the compound Ia not bound to the protein. The experimental results are shown in the attached picture figure 1 and figure 2 . Within 2 minutes, 99% of compound Ia combined with plasma albumin, indicating that compound Ia can quickly combine with plasma albumin to form a macromolecule drug-carrying system after intravenous injection.

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Abstract

The invention discloses an albumin binding type camptothecin derivative prodrug, a preparation method of the albumin binding type camptothecin derivative prodrug and application of the albumin binding type camptothecin derivative prodrug in an anti-tumor drug delivery system. According to the prodrug, a series of prodrugs are prepared by connecting a camptothecin derivative and a maleimide group which can be rapidly and specifically combined with albumin through a beta-glucuronidase cleavable connecting chain. After intravenous injection of the prodrug, the maleimide group of the prodrug and sulfydryl of 34-site cysteine of plasma albumin are subjected to Michael addition to form a macromolecular albumin drug-loading system, passive accumulation of tumors is realized under the EPR effect and albumin receptor mediation, camptothecin derivatives are released through a tumor microenvironment, the anti-tumor effect is improved, and the prodrug has a good application prospect. The compound can be applied to preparation of anti-tumor drugs.

Description

technical field [0001] The invention belongs to the field of prodrug design of pharmaceutical preparations, and relates to prodrugs of β-glucuronidase-cleaved albumin-binding camptothecin derivatives and their preparation methods and applications. Background technique [0002] Despite many years of research devoted to discovering new anticancer drugs, chemotherapy is still not fully effective in treating many solid tumors. Most drugs used clinically act through anti-proliferative mechanisms and lack any inherent selectivity, leading to serious adverse reactions due to damage to normal tissues. Therefore, the development of more selective therapeutics has become a major goal of medicinal chemistry. [0003] Over the past two decades, many glucuronide prodrugs have been reported with the aim of efficiently delivering cytotoxic drugs only in the vicinity of the tumor. This enzymatically cleaved prodrug can be selectively activated by high concentrations of β-glucuronidase. T...

Claims

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Application Information

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IPC IPC(8): C07H15/203C07H1/00A61P35/00A61K31/706
CPCC07H15/203C07H1/00A61P35/00
Inventor 余家会黄颖王磊吕伟
Owner EAST CHINA NORMAL UNIVERSITY
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