Organic AIE photosensitive probe with mitochondrial targeting and preparation method and application thereof

A mitochondrial and organic technology, applied in the field of anti-tumor drugs, can solve the problems of unknown mechanism, uneven induction effect, immunogenic death, etc., and achieve the effect of improving immunogenicity and good anti-tumor immune response effect

Active Publication Date: 2020-01-03
浙江义氪生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current drugs that induce immunogenic death of tumor cells are very limited, and the mechanism is unknown, and the induction effect is also uneven.

Method used

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  • Organic AIE photosensitive probe with mitochondrial targeting and preparation method and application thereof
  • Organic AIE photosensitive probe with mitochondrial targeting and preparation method and application thereof
  • Organic AIE photosensitive probe with mitochondrial targeting and preparation method and application thereof

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preparation example Construction

[0036] The invention provides the preparation method of the organic AIE photosensitive probe with mitochondrial targeting, comprising the following steps:

[0037] 1) Under the protection of argon, compound 1, 2-bromothiophene, tri-tert-butylphosphine tetrafluoroborate, sodium tert-butoxide, Pd 2 (dba) 3 Mixing, the obtained mixture is mixed with an organic solvent to carry out a substitution reaction to obtain a compound 2 having a structure shown in formula III;

[0038] 2) Under the condition of ice bath, mix the DMF solution containing the compound 2 and phosphorus oxychloride, naturally warm up to 23-27°C, then gradually heat to 80-100°C for substitution reaction for 1-1.5h, to obtain Compound 3 of the structure shown in formula IV;

[0039] 3) Under the condition of ice bath and under the protection of argon, the absolute ethanol solution in which the compound 3 and the compound 4 having the structure shown in formula V are dissolved is mixed with sodium ethoxide, and ...

Embodiment 1

[0064] Compound 1a (1g, 5.92mmol, 1.0eq.), 2-bromothiophene (1.45g, 8.88mmol, 1.5eq.), tri-tert-butylphosphine tetrafluoroborate (70mg, 0.24mmol, 0.04eq.) , sodium tert-butoxide (853mg, 8.88mmol, 1.5eq.) and Pd 2 (dba) 3 (108mg, 0.12mmol, 0.02eq) were mixed under the protection of argon, anhydrous toluene (toluene, tetrahydrofuran, DMF and other solvents) (30mL) was added, and the substitution reaction was carried out at 110°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and 30 mL of water and 200 mL of chloroform were added to the filtrate for liquid separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The crude compound 2a was directly used in the next reaction without further purification.

[0065] To a solution of compound 2a (1.5 g, crude) in DMF (25 mL) was added dropwise phosphorus oxychloride (2.3 g, 14.8 mmol, 2.5 eq.) under ic...

Embodiment 2

[0072] Compound 1b (1g, 2.36mmol, 1.0eq.), 2-bromothiophene (577mg, 3.54mmol, 1.5eq.), tri-tert-butylphosphine tetrafluoroborate (30mg, 0.097mmol, 0.04eq.), Sodium tert-butoxide (340mg, 3.54mmol, 1.5eq.) and Pd 2 (dba) 3 (45mg, 0.049mmol, 0.02eq) were mixed under the protection of argon, 20mL of anhydrous toluene was added, and the reaction was carried out at 110°C for 16h. After cooling to room temperature, the reaction mixture was filtered through celite, and 30 mL of water and 200 mL of chloroform were added to the filtrate for liquid separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The crude product was directly used in the next reaction without purification.

[0073] In an ice bath, phosphorus oxychloride (757 mg, 4.95 mmol, 2.5 eq.) was added dropwise to compound 2b dissolved in DMF (25 mL). After the dropwise addition, it was naturally raised to room temperature, and then gradu...

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Abstract

The invention provides an organic AIE photosensitive probe with mitochondrial targeting and a preparation method and application thereof, and belongs to the technical field of antitumor drugs. The organic AIE photosensitive probe with mitochondrial targeting has a structure as shown in the following formula I in the specification. According to the organic AIE photosensitive probe, mitochondrial ROS oxidative stress is triggered, a large amount of calreticulin translocation is induced to be generated, the immunogenicity of tumor cells is effectively improved, and lasting anti-tumor immune response of an organism is triggered. Therefore, the organic AIE photosensitive probe is applied to preparation of drugs for tumor cell immune response or preparation of reagents for triggering the mitochondrial ROS oxidative stress and inducing generation of calreticulin transposition.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, and in particular relates to an organic AIE photosensitive probe with mitochondrial targeting and its preparation method and application. Background technique [0002] Tumor immunotherapy has revolutionary significance in the treatment of tumors, and immune checkpoint inhibitors won the 2018 Nobel Prize in Physiology or Medicine for this reason. The use of PD-1 / PD-L1 inhibitors can achieve long-lasting remission in a small proportion of advanced cancer patients, such as the treatment of melanoma. However, for the vast majority of advanced solid tumors, especially triple-negative breast cancer tumors, the response rate of PD-1 / PD-L1 inhibitors is extremely low, and the effect is not satisfactory. And the treatment of immune checkpoint inhibitors may trigger a strong cytokine storm in patients, which may leave serious sequelae or even life-threatening after treatment. [0003] In rec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10A61K41/00A61P35/00C09K11/06
CPCA61K41/0057A61P35/00C07D409/10C09K11/06C09K2211/1007C09K2211/1014C09K2211/1029C09K2211/1092
Inventor 丁丹陈超倪翔章经天
Owner 浙江义氪生物科技有限公司
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