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A short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors and its preparation method and application

A nanomaterial and self-assembly technology, which is applied in the preparation methods of peptides, anti-tumor drugs, chemical instruments and methods, etc., can solve the problems of lack of hypoxia in cancer treatment, and achieve high biological safety, simple preparation process, and enhanced anti-cancer properties. The effect of tumor efficacy

Active Publication Date: 2022-06-17
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, until now, self-assembled molecular nanomaterials based on short peptides are lacking in the application of hypoxic cancer therapy.

Method used

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  • A short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors and its preparation method and application
  • A short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors and its preparation method and application
  • A short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] This example is used to illustrate the synthesis of isothiocyanate-benzenesulfonamide.

[0107] 4-(2-Aminoethyl)benzenesulfonamide (0.5 mmol) was dissolved in 1 mL of DMF, and triethylamine (3 mmol) was added to the above solution. 1,1'-thiocarbonyldiimidazole (1 mmol) was dissolved in 1.5 mL of DMF at 50°C and added dropwise to the above solution. The solution was stirred continuously for 30 min at room temperature and then added with dd H 2 O quenched. The product was first extracted with ethyl acetate and then purified by silica gel chromatography (ethyl acetate-hexane). The NMR information is as follows: 1 H NMR (400MHz, DMSO-d 6 ) δ7.79(d, J=7.8Hz, 2H), 7.49(d, J=7.8Hz, 2H), 7.35(s, 2H), 3.96(t, 2H), 3.04(t, 2H).

Embodiment 2

[0109] This example is used to illustrate the synthesis of 2-naphthaleneacetic acid-(D)-Phe-(D)-Phe-(D)-Lys-OH.

[0110] Short peptide hydrogels were prepared by standard solid-phase peptide synthesis (SPPS), namely 2-chlorotrityl chloride resin (1.10 mmol / g) and with side chain amino groups protected by tert-butoxycarbonyl, and Fmoc protected Various types of D-amino acids in the main chain amino groups are prepared by the reaction. The resin was swelled by bubbling nitrogen in dry dichloromethane (DCM) for 30 minutes, then washed three times with 5 mL of dry N,N-dimethylformamide (DMF). Then a mixed solution (1 mL of DMF) of the first Fmoc-protected amino acid (2eqv. Fmoc-D-Lys-Boc-OH) and N,N-diisopropylethylamine (DIPEA) was added, and the solution was bubbled through the solution. The bubble reacts the resin with the amino acid C-terminus for 40 minutes. The resin was then washed three times with DMF 5mL. The blocking solution (16:3:1 DCM / MeOH / DIPEA) was then added to ...

Embodiment 3

[0113] This example is used to illustrate the synthesis of 2-naphthaleneacetic acid-(D)-Phe-(D)-Phe-(D)-Lys-(benzenesulfonamide)-OH.

[0114] 0.3 mmol of the short peptide small molecule prepared in Example 2 above was added to methanol (6 mL) and dd H 2 0 (1 mL), then 1 M NaOH was added to adjust the pH to 8, the activated isothiocyanate-benzenesulfonamide (0.33 mmol) was dissolved in methanol (1 mL) and added to the short peptide small molecule in the mixed solution. The mixture was stirred at room temperature overnight. The obtained crude product was purified by HPLC.

[0115] The NMR information is as follows: 1 H NMR (400MHz, DMSO-d 6 )δ8.25(d,J=8.1Hz,1H), 8.13(d,J=8.3Hz,1H),7.85(d,J=7.4Hz,1H),7.80–7.76(m,1H),7.75( d, J = 2.9Hz, 2H), 7.73 (d, J = 3.5Hz, 2H), 7.58 (s, 1H), 7.50–7.44 (m, 2H), 7.43 (d, 2H), 7.30–7.12 (m ,10H),4.61–4.55(m,2H),4.54–4.46(m,1H),4.20(dd,1H),),3.59(s,2H),3.53(dd,J=35.9,14.0Hz,2H ), 3.08–3.03 (m, 2H), 2.95–2.79 (m, 2H), 2.69 (dd, J=13.4, 10....

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Abstract

The present invention provides a preparation method and application of short peptide small molecule self-assembled nanomaterials targeting tumor hypoxic regions. The nanomaterials are small molecule carbonic anhydrase inhibitors modified by short peptides, wherein the short The N-terminus of the peptide is bound to a substituted or unsubstituted aromatic group. By targeting the highly expressed carbonic anhydrase in the membrane of hypoxic tumor cells, the tumor microenvironment responds to self-assembly in situ, and induces the specific endocytosis of hypoxic tumor cells, thereby regulating and killing hypoxic tumor cells. The preparation process of this material is simple and has high biological safety. It can effectively kill tumor hypoxic cells, significantly improve the effect of conventional clinical chemotherapy, slow down the process of tumor metastasis, and provide more ideas and means for clinical tumor treatment.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a short peptide small molecule self-assembled nanomaterial targeting hypoxic tumors, a preparation method and application thereof. Background technique [0002] As a feature shared by various solid tumors, tumor hypoxic microenvironment has profound clinical significance in tumor multidrug resistance and cancer metastasis. At the same time, the tumor hypoxic microenvironment also suppresses the immune response and recruits tumor-associated macrophages, providing protection for the survival of tumor stem cells. During conventional tumor radiation therapy or chemotherapy treatment, the tumor microenvironment can significantly promote cancer cell survival. Alpha-carbonic anhydrase is a large family with 16 different phenotypes, of which carbonic anhydrase IX (CA IX) is highly dependent on the tumor hypoxic microenvironment and requires transcriptional activation of hypoxia-induci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K31/145A61K45/00A61P35/00C07K5/087C07K1/16C07K1/107
CPCA61K47/542A61K31/145A61K45/00C07K5/0812A61P35/00
Inventor 陈春英李佳阳泽纳布·法哈蒂·沙贝特史可鉴赵宇亮
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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