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Synthesis and application of four new conjugates of camptothecin-steroid

A camptothecin and conjugate technology, applied in the field of synthesis of new camptothecin-steroid conjugates, can solve the problem of destroying the integrity of the E ring

Inactive Publication Date: 2012-10-24
GUANGXI UNIV FOR NATITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The hydroxyl group at the 20th position of the E ring of the camptothecin molecule and its adjacent ester carbonyl form an intramolecular hydrogen bond, making it easy to open the ring and destroy the integrity of the E ring

Method used

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  • Synthesis and application of four new conjugates of camptothecin-steroid
  • Synthesis and application of four new conjugates of camptothecin-steroid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of 20(S)-O-3β-hydroxy-5-androstene-17β-acylcamptothecin (CPT-1)

[0032] Add 3β-hydroxy-5-androstene-17β-carboxylic acid (280 mg, 0.88 mmol) and anhydrous dichloromethane (30 mL) into a 100 mL reaction flask, stir and dissolve at room temperature, and then add EDC HCl (200 mg, 1.04 mmol), DMAP (213 mg, 1.75 mmol) and camptothecin (100 mg, 0.29 mmol). Stir the reaction at room temperature under the protection of argon, and monitor it by TLC. After the reaction, pour into a separatory funnel and add 50 mL of dichloromethane, then wash with 0.1 mol / L HCl and saturated brine respectively, dry the organic layer with anhydrous magnesium sulfate, and concentrate The organic layer was concentrated and the residue was subjected to pressure column chromatography v (chloroform): v (methanol) = 150:1~50:1 as the eluent to obtain the product (CPT-1).

[0033] The product (CPT-1) is a yellow powdery solid (75 mg, yield 40.2%), mp: 268-271 ℃; 1 H NMR (CDCl 3 , 600 MHz) ...

Embodiment 2

[0035] Preparation of 20(S)-O-3β-acetoxy-5-androstene-17β-acylcamptothecin (CPT-2)

[0036] Add 3β-acetoxy-5-androstene-17β-carboxylic acid (317 mg, 0.88 mmol) and anhydrous dichloromethane (30 mL) into a 100 mL reaction flask, stir to dissolve at room temperature, and then add EDC HCl separately (200 mg, 1.04 mmol), DMAP (213 mg, 1.75 mmol) and camptothecin (100 mg, 0.29 mmol). Stir the reaction at room temperature under the protection of argon, and monitor it by TLC. After the reaction, pour into a separatory funnel and add 50 mL of dichloromethane, then wash with 0.1 mol / L HCl and saturated brine respectively, dry the organic layer with anhydrous magnesium sulfate, and concentrate The organic layer was concentrated and the residue was subjected to pressure column chromatography v (chloroform):v (methanol)=150:1~50:1 as the eluent to obtain the product (CPT-2).

[0037] The product (CPT-2) is a yellow-white powdery solid (85 mg, yield 42.8%), mp: 235-238 ℃, 1 H NMR (CDCl 3 ...

Embodiment 3

[0039] Preparation of 0(S)-O-androst-4-ene-17β-acylcamptothecin (CPT-3)

[0040] Add androst-4-ene-17β-carboxylic acid (278 mg, 0.88 mmol) and anhydrous dichloromethane (30 mL) into a 100 mL reaction flask, stir at room temperature to dissolve, and then add EDC HCl (200 mg, 1.04 mmol), DMAP (213 mg, 1.75 mmol) and camptothecin (100 mg, 0.29 mmol). Stir the reaction at room temperature under the protection of argon, and monitor it by TLC. After the reaction, pour into a separatory funnel and add 50 mL of dichloromethane, then wash with 0.1 mol / L HCl and saturated brine respectively, dry the organic layer with anhydrous magnesium sulfate, and concentrate The organic layer was concentrated and the residue was subjected to pressure column chromatography v (chloroform): v (methanol) = 150:1 ~ 50:1 as the eluent to obtain the product (CPT-3).

[0041] The product (CPT-3) is a yellow-white powdery solid (85 mg, yield 45.8%). mp: 253-256 ℃, 1 H NMR (CDCl 3 , 600 MHz) 8.40 (s, 1H),...

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Abstract

The invention discloses the synthesis and application of four new conjugates of camptothecin-steroid. The four new conjugates of camptothecin-steroid are: 1) the name of the first new conjugate is 20 (S)-O-3 beta-hydroxy-5-androstene-17 beta-acyl camptothecin, CPT-1 for short; 2) the name of the second new conjugate is 20 (S)-O-3 beta-acetoxy-5-androstene-17 beta-acyl camptothecin, CPT-2 for short; 3) the name of the third new conjugate is 20 (S)-O-androst-4-alkene-17 beta-acyl camptothecin, CPT-3 for short; 4) the name of the forth new conjugate is 20 (S)-O-4-aza-5 alpha-androst-3-ketone-17 beta-acyl camptothecin, CPT-4 for short; By employing EDCI-DMAP coupling method, all the four new conjugates of camptothecin-steroid are synthesized based on raw materials of camptothecin and four steroid acids. The compounds of the invention have good antineoplastic activity, and great prospect in pharmaceutical development.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the synthesis and application of four new camptothecin-steroid conjugates. Background technique [0002] Camptothecin (CPT for short)) was an alkaloid isolated from Camptotheca acuminate in China by Wani and Wall in 1966 (J.Am.Chem.Soc., 1966,88, 3888-3890). The molecular formula of camptothecin is a parallel structure of five-membered rings, in which the A and B rings are quinoline rings, the C ring is a pyrrole ring, the D ring is a conjugated pyridine ring, and the E ring is a chiral ring with an S configuration. α-Hydroxylactone with center (C20). Among them, the ABCD ring is a huge conjugated system, forming a planar structure. Animal experiments have shown that camptothecin has antitumor activity, but its application is limited due to its strong bladder toxicity, poor water solubility and low bioavailability. In the late 1980s, it was discovered that the antitumor acti...

Claims

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Application Information

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IPC IPC(8): C07J17/00C07J73/00A61K31/4745A61K47/48A61P35/00
Inventor 申利群黄素玉唐勇吴爱群雷福厚
Owner GUANGXI UNIV FOR NATITIES
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