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Targeted Anticancer Conjugates

A technology of drug conjugates and targeting molecules, applied in the direction of organic active ingredients, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problem of inability to act on cancer cells, poor targeting, and affect normal Cell performance and other issues

Active Publication Date: 2021-11-05
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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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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  • Targeted Anticancer Conjugates
  • Targeted Anticancer Conjugates
  • Targeted Anticancer Conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123]

[0124] Preparation of Compound 2

[0125] 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.

[0126] Preparation of compound 3

[0127] Add 4.02g of compound 2 and 50ml of DCM to a 100mL three-neck flask, stir to dissolve, add 11.6ml of TFA dropwise, react at room ...

Embodiment 2

[0129]

[0130] Preparation of compound 5

[0131] 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.

[0132] Preparation of Compound 6

[0133] 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

[0139] Preparation of Targeting Molecule Angiopep-2 (Compound 50) Linked with Protecting Group

[0140]

[0141] The sequence of Angiopep-2 is TFFYGGSRGKRNNFKTEEY

[0142] Using 2Cl-Trt Resin, using HOBT / DIC as the coupling reagent, DMF as the reaction solvent, and using ninhydrin detection method for reaction monitoring, the following protected amino acids are connected to the resin in sequence: Fmoc-Tyr(tBu)-OH, Fmoc-Glu (OtBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-Asn(Trt)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc -Gly-OH, Fmoc-Gly-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Phe-OH, Boc-Thr(tBu)-OH add cleavage reagent: acetic acid / TFE / DCM= 1 / 2 / 7, reacted for 2 hours, precipitated with ice MTBE, washed, and dried to obtain compound 50 as an off-white solid.

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Abstract

The invention discloses a multi-branched drug conjugate with the following structural formula (I) or a pharmaceutically acceptable salt thereof: R is an organic center, POLY is a polymer, L is a multivalent linker, T is a targeting molecule, D is an active agent, q is any integer between 3-8, wherein L is: the symbol "*" represents the connection point between the multivalent linker L and the targeting molecule T, and "#" represents the multivalent linker L and the active agent D "%" represents the connection point between polyvalent linker L and POLY, wherein l is any integer between 2-20, m and n are any integer between 0-10; T is Angiopep2 ; D is camptothecin drugs. Compared with the small molecule anticancer compound, the conjugate of the present invention has stronger tumor inhibitory ability, and the suitable solid tumor types include colon cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma and breast and ovarian cancer. , malignant sarcomas, carcinomas and lymphomas of the colon, kidney, bile duct, lung and brain.

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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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60
CPCA61K31/4745C08G65/33396C08G2650/38C08G2650/50
Inventor 袁建栋黄仰青宋云松丁海峰
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD