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7-ethyl-10-hydroxycamptothecin derivative prodrug non-covalently bound with human serum albumin, and preparation and application of 7-ethyl-10-hydroxycamptothecin derivative prodrug

A technology of human serum albumin and hydroxycamptothecin, applied in the field of biomedicine, can solve the problems of no targeting, low solubility of SN38, and limited clinical application, etc., and achieve improved physical and chemical properties, small side effects, and effective anti-tumor effect Effect

Pending Publication Date: 2022-04-12
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the toxicity of SN38 is much lower than that of camptothecin, and its anti-tumor effect is higher. However, SN38 has extremely low solubility and no targeting, which greatly limits clinical application.

Method used

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  • 7-ethyl-10-hydroxycamptothecin derivative prodrug non-covalently bound with human serum albumin, and preparation and application of 7-ethyl-10-hydroxycamptothecin derivative prodrug
  • 7-ethyl-10-hydroxycamptothecin derivative prodrug non-covalently bound with human serum albumin, and preparation and application of 7-ethyl-10-hydroxycamptothecin derivative prodrug
  • 7-ethyl-10-hydroxycamptothecin derivative prodrug non-covalently bound with human serum albumin, and preparation and application of 7-ethyl-10-hydroxycamptothecin derivative prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Synthesis of Compound 10-C18-SN38

[0051]

[0052] Preparation of compound 1:

[0053] Under nitrogen protection conditions, 0.5g (1.27mmol) SN38, 0.59g (1.59mmol) mono-tert-butyl octadecanedioate, 0.66g (3.44mmol) EDCI and 0.04g (0.29mmol) DMAP were dissolved in 15mL of anhydrous di In methyl chloride, react for 4 hours. Diluted by adding 15 mL of dichloromethane, saturated ammonium chloride (NH 4 Cl) solution (15 mL), water (15 mL), saturated brine (15 mL), washed with anhydrous sodium sulfate, and spin-dried. Purify by silica gel column chromatography, the mobile phase is dichloroalane:methanol=200:1-90:1. The collected pure product was compound 1, which was spin-dried to obtain 0.48 g of light yellow solid with a yield of 51.1%.

[0054] 1 H NMR (400MHz, CDCl 3 )δ8.23(d, J=9.1Hz, 1H), 7.79(s, 1H), 7.66(d, J=9.1Hz, 1H), 7.53(s, 1H), 5.74(s, 2H), 5.24( s,2H),3.14(q,J=7.3Hz,2H),2.66(m,2H),2.20(m,2H),1.98–1.87(m,2H),1.85–1.80(m,2H),1.61 –1.53(m,2H),1.44(s,9H...

Embodiment 2

[0060] Synthesis of Compound 20-C18-SN38

[0061]

[0062] Preparation of compound 2-1:

[0063] Under nitrogen protection conditions, 1.51g (3.84mmol) SN38, 1.09g (4.99mmol) Boc 2 O and 9 mL (112.87 mmol) of anhydrous pyridine were dissolved in 22 mL of anhydrous dichloromethane, and stirred overnight at room temperature. With 0.5M dilute hydrochloric acid (HCl) solution (10mL), saturated sodium bicarbonate (NaHCO 3 ) solution (10 mL), saturated brine (10 mL), and dried over anhydrous sodium sulfate. Evaporated to dryness under reduced pressure to obtain 1.85 g of compound 2-1 as a yellow solid, with a yield of 98%.

[0064] 1 H NMR (400MHz, CDCl 3 )δ8.24(d, J=9.2Hz, 1H), 7.89(s, 1H), 7.66(d, J=6.1Hz, 2H), 5.75(d, J=16.3Hz, 1H), 5.34–5.25( m,3H),3.87(s,1H),3.16(q,J=7.5Hz,2H),1.96–1.85(m,2H),1.62(s,9H),1.40(t,J=7.5Hz,3H ), 1.04(t,J=7.3Hz,3H).

[0065] Preparation of Compound 2-2:

[0066] Under nitrogen protection, 0.5g (1.02mmol) compound 2-1, 0.56g (1.52mmol) mon...

Embodiment 3

[0073] Synthesis of compound 20-Gly-C18-SN38:

[0074]

[0075] Preparation of compound 2-1:

[0076] Under nitrogen protection conditions, 1.51g (3.84mmol) SN38, 1.09g (4.99mmol) Boc 2 O and 9 mL (112.87 mmol) of anhydrous pyridine were dissolved in 22 mL of anhydrous dichloromethane, and stirred overnight at room temperature. With 0.5M HCl solution (10mL), saturated NaHCO 3 solution (10 mL), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Evaporated to dryness under reduced pressure to obtain 1.85 g of compound 2-1 as a yellow solid, with a yield of 98%.

[0077] 1 H NMR (400MHz, CDCl 3 )δ8.24(d, J=9.2Hz, 1H), 7.89(s, 1H), 7.66(d, J=6.1Hz, 2H), 5.75(d, J=16.3Hz, 1H), 5.34–5.25( m,3H),3.87(s,1H),3.16(q,J=7.5Hz,2H),1.96–1.85(m,2H),1.62(s,9H),1.40(t,J=7.5Hz,3H ), 1.04(t,J=7.3Hz,3H).

[0078] Preparation of compound 3-1:

[0079] Under nitrogen protection, 0.5g (1.02mmol) of compound 2-1, 0.36g (2.03mmol) of N-Boc-glycine, 0.23g (1.22mmo...

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Abstract

The invention discloses a 7-ethyl-10-hydroxycamptothecin derivative prodrug in non-covalent binding with human serum albumin as well as preparation and application of the 7-ethyl-10-hydroxycamptothecin derivative prodrug. The prodrug has a structure as shown in a formula I, and is prepared by modifying 7-ethyl-10-hydroxycamptothecin with a monocarboxyl group of long-chain fatty diacid or modifying 7-ethyl-10-hydroxycamptothecin with a monocarboxyl glycine derivative of long-chain fatty diacid. The long-chain fatty acid in the prodrug can be subjected to non-covalent binding with human serum albumin to form a supramolecular drug delivery system. Under the tumor EPR effect and mediation of human serum albumin related receptors, the supramolecular prodrug can increase accumulation of drugs in tumors, reduce toxic and side effects and improve the anti-tumor effect.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to the prodrug, preparation and application of human serum albumin non-covalent binding type 7-ethyl-10-hydroxycamptothecin (SN38) derivative. Background technique [0002] Cancer has always been a malignant disease that seriously threatens human health. With the development of science and technology, in addition to traditional therapies such as chemotherapy and radiotherapy, immunotherapy and photodynamic photothermal therapy have also been developed, but they are still in the research stage. Therefore, people still Emphasis will be placed on traditional chemotherapy, which is the most widely used. Traditional chemotherapy has high toxicity, low tumor selectivity, and poor physical and chemical properties of drugs, which limit its clinical application. Therefore, the demand for new chemotherapy drugs with low toxicity and tumor targeting is constantly increasing, and it has become the curr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/4745A61P35/00
CPCY02P20/55
Inventor 余家会韦清瑜吕伟何洋姜星
Owner EAST CHINA NORMAL UNIV
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