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Multi-arm targeted anti-cancer conjugate

A technology of drug conjugates and targeting molecules, applied in the field of targeted anti-cancer conjugates, can solve the problems of affecting the performance of normal cells, poor targeting, and high incidence of adverse reactions

Active Publication Date: 2018-11-02
高瑞耀业(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the drug still has disadvantages. For example, it has poor targeting and cannot act on specific cancer cells. While killing cancer cells, it will also affect the performance of normal cells, so that the incidence of adverse reactions is still relatively high.

Method used

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  • Multi-arm targeted anti-cancer conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148]

[0149] Preparation of compound 2

[0150] Add 3.50g of compound 1 (1.0eq) and 52.5ml of DMF to a 250mL round bottom flask, heat to 60°C to dissolve, evaporate the DMF under reduced pressure after 5-10min, add 300ml of n-heptane and distill under reduced pressure, repeat three times, spin dry Add 105ml of DCM, 1.08g of Boc-Gly-OH (1.2eq), 63mg of DMAP (0.1eq), add dropwise a solution of 1.59g of DCC (1.5eq) dissolved in 10ml of DCM, and react at 20°C for 4 hours. After the reaction is monitored by TLC, filter and concentrate When the remaining 25% volume was reached, 120ml of IPA was added, 75% of the solvent was evaporated, 150ml of n-heptane was added, stirred at room temperature for 1 hour, filtered, washed twice with n-heptane, and dried to obtain 4.02g of compound 2 as a pale yellow solid.

[0151] Preparation of compound 3

[0152] Add 4.02g of compound 2 and 50ml of DCM to a 100mL three-neck flask, stir and dissolve, then add 11.6ml of TFA dropwise, react at...

Embodiment 2

[0154]

[0155] Preparation of compound 5

[0156] Add 6.9g of compound 4 and 30ml of EA into a 250mL three-neck flask, stir to dissolve and cool down to 0°C, add 40ml of 0.3M HCl / EA, keep the reaction for 2h, monitor the reaction by TLC and concentrate to dryness to obtain compound 5, directly proceed to the following One step reaction.

[0157] Preparation of compound 6

[0158] Dissolve compound 5 (1.0eq) with 50ml of purified water, add 3.96g of sodium bicarbonate (2.0eq), dissolve 5.30g of Fmoc-OSU (1.0eq) with 50ml of DME, add it to the reaction flask of compound 5, and add 25ml of THF , stirred at room temperature for 2 hours, after the reaction was monitored by TLC, evaporated the organic solvent, extracted impurities with EA, adjusted the pH of the aqueous phase to 3-4 with dilute hydrochloric acid, extracted twice with EA, combined the organic phases, washed once with water, and washed with saturated saline It was dried over anhydrous sodium sulfate and concentr...

Embodiment 3

[0164] Preparation of Targeting Molecule cRGD (Compound 11) Linked with Protecting Group

[0165]

[0166] Preparation of compound 9

[0167] Using 2Cl-Trt Resin, Fmoc protection method, HOBT / DIC as the coupling reagent, DMF as the reaction solvent, and ninhydrin detection as the reaction monitoring, the following protected amino acids are connected to the resin in sequence: Fmoc-Gly-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Glu(OBzl)-OH, Fmoc-D-Phe-OH, Fmoc-Asp(OtBu)OH, remove Fmoc, wash with DMF, DCM, wash with methanol and dry, then add lysis reagent: Acetic acid / TFE / DCM=1 / 2 / 7, reacted for 2 hours, precipitated with ice MTBE, washed, and dried to obtain compound 9 as an off-white solid.

[0168] Preparation of compound 10

[0169] Add 14.0g of compound 9 (1.0eq) to a 2L three-necked flask, add 1L of DMF, cool to 0°C, add 9.2g of sodium bicarbonate (8.0eq), add 15.1g of DPPA (4.0eq) after dissolving, and keep warm overnight. After the TLC reaction was completed, it was poured into 5...

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Abstract

The invention discloses a multi-branch-chain drug conjugate with the following structural formula (I) as shown in description or a pharmacologically acceptable salt thereof, wherein R is an organic center, POLY is polymer, L is a multivalent joint, T is a targeted molecule, D is an activator, q is any integer from 3 to 8, L is as shown in the description, * is a connecting point for the multivalent joint L and the targeted molecule T, # is a connecting point for the multivalent joint L and the activator D, % is a connecting point for the multivalent joint L and POLY, l is any integer from 2 to20, m and n are any integer from 0 to 10, T is iRGD, cRGD, tLyp-1, Lyp-1 or RPARPAR, and D is a camptothecin drug. Compared with a small-molecule anti-cancer compound, the conjugate has stronger inhibiting ability in tumors, and is suitable for solid tumor types which comprise colon cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, glioma as well as sarcoma, cancers and lymphoma of breasts, ovaries, colons, kidneys, bile ducts, lungs and brains.

Description

technical field [0001] The invention relates to a multi-arm polymer modified targeting anticancer conjugate, more specifically, the invention relates to linking a targeting molecule with an anticancer drug through a multi-arm polymer to form a conjugate. Background technique [0002] Over the years, various approaches have been proposed for improving the stability and delivery of bioactive agents. Challenges associated with the formulation and delivery of pharmaceutical agents can include poor aqueous solubility, toxicity, low bioavailability, instability, and rapid in vivo degradation of the pharmaceutical agent. Although many approaches have been devised to improve the delivery of pharmaceutical agents, no single approach is without its drawbacks. For example, commonly used drug delivery methods aim to solve or at least improve one or more of the following problems, including drug encapsulation, covalent attachment, etc., in a liposome, polymer matrix, or unimolecular mic...

Claims

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Application Information

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IPC IPC(8): C08G65/333
CPCC08G65/33396C08G2650/38C08G2650/50
Inventor 袁建栋黄仰青宋云松丁海峰
Owner 高瑞耀业(北京)科技有限公司
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