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CN-122010883-A - Napabucasin derivative with double-target anti-tumor activity and preparation method and application thereof

CN122010883ACN 122010883 ACN122010883 ACN 122010883ACN-122010883-A

Abstract

The invention relates to Napabucasin derivatives with double-target antitumor activity, and a preparation method and application thereof. The invention takes STAT3 inhibitor Napabucasin as a mother nucleus, and active structures such as zinc ion chelating group hydroxamic acid, o-phenylenediamine, alkane hydrazide and the like of the HDAC inhibitor are introduced into the tail end of the mother nucleus through different Linker, so that a series of Napabucasin derivative inhibitors with double-target antitumor activity are successfully obtained, the structural general formula of the inhibitor is shown as (I), and pharmacological experiments show that the inhibitor has stronger in-vitro antitumor activity, so that the inhibitor can be used as an antitumor drug. 。

Inventors

  • WANG YONG
  • LI XIAOCUN
  • ZHU ZEQI

Assignees

  • 中国海洋大学

Dates

Publication Date
20260512
Application Date
20251218

Claims (10)

  1. 1. Napabucasin derivatives or pharmaceutically acceptable salts thereof with double-target antitumor activity are characterized in that the structural general formula of the Napabucasin derivatives is shown as follows: Wherein: a is selected from the group consisting of, ; Wherein R 1 is hydrogen, halogen, heterocycle, R 2 is hydrogen or halogen; Wherein the heterocycle is pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; Wherein R 4 is selected from hydrogen, methyl, alkynyl, halogen, methoxy, trifluoromethyl, cyano; Wherein X is selected from N is an integer from 1 to 10; wherein R 3 is selected from the group consisting of hydroxy, N is an integer from 1 to 6.
  2. 2. The Napabucasin derivative with double-target anti-tumor activity or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt thereof.
  3. 3. The Napabucasin derivative with double-target anti-tumor activity or a pharmaceutically acceptable salt thereof according to claim 2, wherein the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, biphosphoric acid, hydrobromic acid or nitric acid, and the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid, tannic acid, citric acid, trifluoroacetic acid, malic acid or benzenesulfonic acid salt.
  4. 4. The Napabucasin derivative or a pharmaceutically acceptable salt thereof with dual-target antitumor activity according to claim 1, wherein the Napabucasin derivative is any one of the following: The compound XC-1:N- (2-aminophenyl) -4, 9-dioxo-4, 9-dihydronaphthoxy [2,3-b ] furan-2-carboxamide, The compound XC-2:N- (3- ((2-aminophenyl) amino) -3-oxopropyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-3:N- (2-amino-5-fluorophenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-4:N- (2-amino-4, 5-difluorophenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-5N- (4-amino- [1,1' -biphenyl ] -3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-6:N- (4-amino-4 '-fluoro- [1,1' -biphenyl ] -3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-7N- (4-amino-4 '-methyl- [1,1' -biphenyl ] -3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-8:N- (4-amino-4' -chloro-biphenyl-3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-9:N- (4-amino-4' -methoxy-biphenyl-3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-10N- (2-amino-5- (pyridin-4-yl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-11:N- (2-amino-5- (pyridin-3-yl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-12N- (2-amino-5- (furan-2-yl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-13 is N- (2-amino-5- (thiophen-2-yl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-14 is N- (2-amino-5- (thiophen-3-yl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-15 is N- (4-amino-4' - (trifluoromethyl) -biphenyl-3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-16N- (4-amino-4' -cyano-biphenyl-3-yl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-17:N-hydroxy-4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-18:N- (4- (hydroxycarbamoyl) phenyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-19 is N- (3- (hydroxyamino) -3-oxopropyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-20:N- (5- (hydroxyamino) -5-oxopentyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-21:N- (6- (hydroxyamino) -6-oxohexyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-22N- (7- (hydroxyamino) -7-oxoheptyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-23N- (8- (hydroxyamino) -8-oxooctyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-24:N- (9- (hydroxyamino) -9-oxononyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-25:N' -ethyl-4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-26:4, 9-dioxo-N' -propyl-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-27:N' -butyl-4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide, The compound XC-28:4, 9-dioxo-N' -pentyl-4, 9-dihydronaphtho [2,3-b ] furan-2-formylhydrazine, The compound XC-29:N' -isopentyl-4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide.
  5. 5. The preparation method of Napabucasin derivatives or pharmaceutically acceptable salts thereof with double-target antitumor activity as claimed in claim 4, wherein the synthesis method of the compounds XC-1 to XC-16 comprises the following steps: Condensing the compound 5 with the compound 14 to obtain a compound 15, removing tert-butyl from the compound 15 under an acidic condition to obtain a compound 16, condensing the compound 16 with o-phenylenediamine 17 with Boc group protection to obtain a compound 18, removing Boc group from the compound 18 under an acidic condition to obtain a target compound XC-2, or condensing the compound 5 with o-phenylenediamine 19a-o with different substituents to obtain a compound 20a-o, and removing Boc group from the compound 20a-o under an acidic condition to obtain a target compound XC-1 or XC-3-16; The reaction route is as follows: Reagents and conditions (a) HBTU, DIPEA, DMF, room temperature, 4h, 64-74% yield, and (b) TFA, room temperature, 1h, 93-95% yield.
  6. 6. The preparation method of Napabucasin derivatives or pharmaceutically acceptable salts thereof with double-target antitumor activity as claimed in claim 4, which is characterized in that the synthesis method of the compounds XC-17-XC-24 comprises the following steps: The method comprises the steps of directly condensing a compound 5 with ortho-triphenylhydroxylamine 24 to obtain a compound 26, reacting the compound 26 with TFA to remove a protective group to obtain a target compound XC-17, or condensing the compound 5 with the compound 21 to obtain a compound 22, removing tert-butyl from the compound 22 under an acidic condition to obtain a compound 23, condensing the compound 23 with the ortho-triphenylhydroxylamine 24 to obtain a compound 25, reacting the compound 25 with TFA to remove the protective group to obtain a target compound XC-18, or condensing the compound 5 with alkane chains with different lengths to obtain a compound 28a-f, removing tert-butyl from the compound 28a-f under the acidic condition to obtain a compound 29a-f, condensing the compound 29a-f with ortho-triphenylhydroxylamine 24 to obtain a compound 30a-f, and reacting the compound 25 with TFA to remove the protective group to obtain the target compound XC-19-24; The reaction route is as follows: reagents and conditions (a) HBTU, DIPEA, DMF, room temperature, 4: 4h, 64-74% yield, and (b) TFA, room temperature, 1h, 93-95% yield.
  7. 7. The preparation method of Napabucasin derivatives or pharmaceutically acceptable salts thereof with double-target antitumor activity as claimed in claim 4, which is characterized in that the synthesis method of the compound XC-25-XC-29 comprises the following steps: The compound 5 and the hydrazide 31a-d with different chain lengths protected by Boc are subjected to condensation reaction to generate the compound 32a-d, the compound 32a-d is subjected to tert-butyl removal under an acidic condition to obtain a target compound XC-25-28, or the compound 5 and the compound 33 are subjected to condensation reaction to generate a compound 34, and the compound 34 is subjected to tert-butyl removal under the acidic condition to obtain the target compound XC-29; The reaction route is as follows: Reagents and conditions (a) HBTU, DIPEA, DMF, room temperature, 4h, 64-74% yield, and (b) TFA, room temperature, 1h, 93-95% yield.
  8. 8. The use of Napabucasin derivatives or pharmaceutically acceptable salts thereof with dual-target antitumor activity as defined in claim 1 in the preparation of antitumor drugs or differentiation and proliferation related diseases.
  9. 9. The use according to claim 8, wherein the tumour is selected from colorectal cancer, breast cancer, lung cancer, liver cancer, prostate cancer, and the pharmaceutically acceptable salt is free of water of crystallisation or contains one or more than one water of crystallisation.
  10. 10. The use of Napabucasin derivatives or pharmaceutically acceptable salts thereof having dual-target anti-tumor activity as claimed in claim 1 for the preparation of HDAC inhibitors, STAT3 inhibitors or HDAC/STAT3 dual-target inhibitors.

Description

Napabucasin derivative with double-target anti-tumor activity and preparation method and application thereof Technical Field The invention relates to Napabucasin derivatives with double-target antitumor activity, and a preparation method and application thereof, belonging to the technical field of medicines. Background Cancer has become one of the diseases that is severely threatening to human health and life. Clinically, the tumor is mainly treated by adopting modes of single targeted drug treatment, combination of multiple drugs and the like, but the therapies have serious defects of large toxic and side effects, poor patient compliance and the like. The multi-target medicine can act on a plurality of targets in a disease network at the same time, and a synergistic effect is generated on the action of each target, so that the total effect is larger than the sum of the single effects, and the optimal treatment effect is achieved. In addition, multi-target drugs have relatively simple pharmacokinetic properties and can also overcome adverse reactions resulting from drug-drug interactions. Therefore, multi-target drugs have become one of the important directions in the development of new generation antitumor drugs. Epigenetic (epigenetics) corresponds to genetics, which mainly includes changes in gene expression levels due to non-genetic sequence changes, such as conformational changes in chromatin, DNA methylation, etc., and the occurrence of cancer is often closely related to epigenetic deregulation. It is found that abnormal histone acetylation and deacetylation regulation in epigenetic inheritance can cause remodelling and space configuration change of cell chromatin, influence expression of normal genes, cause abnormality of cancer suppressor genes or proteins related to cell cycle regulation, and further promote occurrence and metastasis of tumors. Therefore, the regulation of epigenetic related targets has become a new direction for the development of antitumor drugs, and especially the research of epigenetic target histone deacetylases (histone deacetylases, HDACs) has become a current research hotspot. Histone acetylation and histone deacetylation are two important regulatory modes of gene expression and chromosomal structural changes, which play a key role in biological processes such as cell transcription, translation, apoptosis, and energy metabolism, and are controlled by histone acetylases (histone acetylase, HAT) and histone deacetylases (histone deacetylases, HDACs), respectively. HDACs remove the N-terminal acetyl group on the histone lysine (Lys) side chain by hydrolysis, thereby making nucleosomes more compact, inhibiting gene transcription. And simultaneously, various biological functions and processes of the cells are regulated, including gene expression, proliferation, differentiation, apoptosis and the like of the cells, and the occurrence and development of tumors are closely related to the abnormal expression of HDACs. HDAC inhibitors (HDACi) have been shown to be effective in inducing cell differentiation, inhibiting growth, promoting apoptosis, enhancing chemosensitivity, and inhibiting angiogenesis, among other biological processes. Classical zinc ion-dependent HDAC inhibitors consist mainly of three parts, a hydrophobic group (Cap) that recognizes the enzyme from each other, a zinc ion chelating group (Zinc binding group, ZBG), and a Linker region (Linker) that connects the two. The surface of the HDAC protein is provided with a hydrophobic region capable of being combined with a Cap group, and other anti-tumor active groups are introduced into the Cap end of the HDAC inhibitor to design a multi-target inhibitor, so that the combination effect between the HDAC protein and the inhibitor can be enhanced, and the anti-tumor activity of the compound is improved. Several HDAC multi-target inhibitors have been currently in clinical or preclinical investigation. Signal transduction and transcription activator 3 (STAT 3) is a cell transcription factor, is responsible for extracellular cytokine and growth factor signal transduction and gene transcription activation, and STAT3 signal cascade is triggered by upstream kinase signals, undergoes phosphorylation, homodimerization, is transferred into the nucleus and is combined with DNA, and participates in a series of important physiological processes such as growth, proliferation, differentiation, apoptosis and the like of cells. Under normal physiological conditions, STAT3 is activated rapidly and transiently, however, STAT3 is often activated continuously and expressed at high level in various malignant tumors such as colorectal cancer, lung cancer, breast cancer and renal cancer, plays roles in regulating cell proliferation, angiogenesis, metastasis, apoptosis resistance and the like, and is related to the development of tumors and poor prognosis. Therefore, the targeting STAT3 protein has great development potential as a treatment strateg