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CN-122010944-A - TBC1D 2-targeted aromatic methyl alkenyl matrine derivative and preparation method and application thereof

CN122010944ACN 122010944 ACN122010944 ACN 122010944ACN-122010944-A

Abstract

The invention discloses an aromatic methyl alkenyl matrine derivative targeting TBC1D2, and a preparation method and application thereof, and relates to the technical field of chemical medicines. The invention synthesizes a series of aromatic methyl alkenyl matrine derivatives containing naphthalene ring, indole ring, azaindole ring and benzene ring, and the special structure formed by introducing the aromatic rings can greatly increase the in vitro anti-tumor activity of matrine. The aromatic methyl alkenyl matrine derivative of the target TBC1D2 can be used for preparing antitumor drugs, and has the advantages of easily available raw materials and simple synthesis steps. In vitro biological experiments show that the derivative has brand new action targets and action mechanisms, and in vitro anti-tumor activity researches show that the derivative is an anti-tumor drug with development prospect, and the derivative can be applied to clinical tumor treatment.

Inventors

  • WANG LISHENG
  • HAN KEYAN

Assignees

  • 广西大学

Dates

Publication Date
20260512
Application Date
20260203

Claims (8)

  1. 1. An aromatic methyl matrine derivative of a target TBC1D2, which is characterized by having a structure shown in a general formula I, a general formula II or a general formula III: ; In the general formula I, r=2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3, 4-difluorophenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-di- (trifluoromethyl) phenyl, 3, 5-di-t-butylphenyl or 2-naphthyl; In formula II, r=3-chlorophenyl, 2, 4-difluorophenyl, 4-bromophenyl, 3, 4-difluorophenyl or 4-tert-butylphenyl; in the general formula III, X=C or N, R=allyl, 3-phenoxypropyl, 4-phenoxybutyl or 4- (2-naphthoxy) butyl when X=C, and R=benzyl, 3-fluorobenzyl, 3-chlorobenzyl or 4-bromobenzyl when X=N.
  2. 2. A process for the preparation of an aromatic mevinyl matrine derivative targeted to TBC1D2 according to claim 1 comprising the steps of: Carrying out substitution reaction on one of the compounds shown in the formulas IV-VI and one of the compounds shown in the formulas VII-X as reactants under alkaline conditions to obtain aromatic aldehyde, and carrying out condensation reaction on the aromatic aldehyde and matrine as reactants and NaH as a condensing agent to obtain the aromatic methyl matrine derivative of the targeted TBC1D 2; 、 、 、 、 、 、 ; In formula IV, r=2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3, 4-difluorophenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-di- (trifluoromethyl) phenyl, 3, 5-di-t-butylphenyl or 2-naphthyl; in formula V, r=allyl, 3-phenoxypropyl, 4-phenoxybutyl, benzyl, 3-fluorobenzyl, 3-chlorobenzyl, or 4-bromobenzyl; in formula VI, r=4- (2-naphthoxy) butyl.
  3. 3. The method of preparing an aromatic mehtyl matrine derivative targeting TBC1D2 according to claim 2, wherein the molar ratio of one of the compounds of formulas IV-VI to one of the compounds of formulas VII-X is 2:3.
  4. 4. The method for preparing an aromatic methyl matrine derivative targeting TBC1D2 according to claim 2, wherein the temperature of the substitution reaction is 60 ℃ for 1-4h.
  5. 5. The method of preparing an aromatic methyl matrine derivative targeting TBC1D2 according to claim 2, wherein the molar ratio of aromatic aldehyde to matrine is 2:3.
  6. 6. The method for preparing the aromatic matrine derivative targeting TBC1D2 according to claim 2, wherein the condensation reaction is carried out by reacting for 1h at 23-27 ℃ and then reacting for 20min-1h at 60-100 ℃.
  7. 7. Use of an aromatic mevinyl matrine derivative targeted to TBC1D2 as claimed in claim 1 in the preparation of a TBC1D2 inhibitor.
  8. 8. Use of an aromatic mevinyl matrine derivative targeting TBC1D2 as claimed in claim 1 for the preparation of an anticancer drug.

Description

TBC1D 2-targeted aromatic methyl alkenyl matrine derivative and preparation method and application thereof Technical Field The invention relates to the technical field of chemical medicines, in particular to an aromatic methyl alkenyl matrine derivative targeting TBC1D2, a preparation method and application thereof. Background Cancer is a complex disease characterized by abnormal proliferation and metastasis of cells, and has become one of the major public health problems worldwide. Current treatments for cancer include surgery, radiation therapy, targeted therapy, immunotherapy, antibody Drug Conjugate (ADC) therapy, CAR-T cell therapy. However, cancer research still faces many challenges, including tumor heterogeneity and drug resistance evolution, unclear metastatic mechanisms, maldistribution of medical resources, and quality of life issues for long-term survivors. Developing new mechanisms of action anticancer drugs may provide new opportunities for addressing these challenges. TBC1D2 is a member of the TBC (Tre-2/Bub 2/Cdc 16) domain protein family and is primarily involved in regulating processes such as cell migration, invasion and metabolism. It is abnormally highly expressed in a variety of cancers (e.g., ovarian cancer, breast cancer). TBC1D2 is capable of catalyzing hydrolysis of rab7a-GTP to rab7a-GDP, and the inactive rab7a-GDP is favorable for mitochondrial dissociation from lysosomes, and hinders formation of late autophagy lysosomes. Thus TBC1D2 inhibitors are able to inhibit the progression of cancer by inducing autophagy. At present, no medicine aiming at TBC1D2 exists, so the medicine has great application value and wide application prospect. Disclosure of Invention The invention aims to provide an aromatic methyl matrine derivative targeting TBC1D2, and a preparation method and application thereof, so as to solve the problems in the prior art. In order to achieve the above object, the present invention provides the following solutions: one of the technical schemes of the invention is that an aromatic methyl matrine derivative of a targeted TBC1D2 has a structure shown as a general formula I, a general formula II or a general formula III: ; In the general formula I, r=2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3, 4-difluorophenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-di- (trifluoromethyl) phenyl, 3, 5-di-t-butylphenyl or 2-naphthyl; In formula II, r=3-chlorophenyl, 2, 4-difluorophenyl, 4-bromophenyl, 3, 4-difluorophenyl or 4-tert-butylphenyl; in the general formula III, X=C or N, R=allyl, 3-phenoxypropyl, 4-phenoxybutyl or 4- (2-naphthoxy) butyl when X=C, and R=benzyl, 3-fluorobenzyl, 3-chlorobenzyl or 4-bromobenzyl when X=N. The second technical scheme of the invention is that the preparation method of the aromatic methyl alkenyl matrine derivative targeting TBC1D2 comprises the following steps: Carrying out substitution reaction on one of the compounds shown in the formulas IV-VI and one of the compounds shown in the formulas VII-X as reactants under alkaline conditions to obtain aromatic aldehyde, and carrying out condensation reaction on the aromatic aldehyde and matrine as reactants and NaH as a condensing agent to obtain the aromatic methyl matrine derivative of the targeted TBC1D 2; 、、、、、、; In formula IV, r=2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3, 4-difluorophenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 5-dimethoxyphenyl, 3, 5-di- (trifluoromethyl) phenyl, 3, 5-di-t-butylphenyl or 2-naphthyl; in formula V, r=allyl, 3-phenoxypropyl, 4-phenoxybutyl, benzyl, 3-fluorobenzyl, 3-chlorobenzyl, or 4-bromobenzyl; in formula VI, r=4- (2-naphthoxy) butyl. Further, the molar ratio of one of the compounds of formulae IV-VI to one of the compounds of formulae VII-X is 2:3. Further, the temperature of the substitution reaction is 60 ℃ and the time is 1-4h. Further, the molar ratio of the aromatic aldehyde to the matrine is 2:3. Further, the condensation reaction is carried out by reacting at 23-27 deg.C for 1 hr, and then reacting at 60-100 deg.C for 20min-1 hr. The third technical scheme of the invention is the application of the aromatic methyl alkenyl matrine derivative targeting TBC1D2 in preparation of TBC1D2 inhibitors. The fourth technical scheme of the invention is the application of the aromatic methyl alkenyl matrine derivative of the targeting TBC1D2 in preparing anticancer drugs. In the invention, target spot identification is carried out on the synthesized aromatic methyl matrine derivative by an immunoassay method. The immunoassay is a biochemical detection technology established based on the s