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CN-121990921-A - CA4 dimer prodrug compound and preparation method and application thereof

CN121990921ACN 121990921 ACN121990921 ACN 121990921ACN-121990921-A

Abstract

The invention discloses a CA4 dimer prodrug compound, a preparation method and application thereof, wherein the structural formula of the CA4 dimer prodrug compound is shown in a general formula I. The compound of the invention plays a synergistic anti-tumor role by inhibiting tubulin polymerization and regulating and controlling CYP7A1 related channels, in vitro experiments show that the IC50 value of CA4-dimer1 on human liver cancer Hep3B cells is 1.48+/-0.18 nM, the activity is obviously superior to that of CA4 monomers, in animal experiments, the tumor inhibition rate reaches 73.2 percent, obvious hematological and hepatorenal toxicity is not caused, the medicine kinetics shows that intravenous injection can be effectively converted into CA4 and plays an anti-tumor role, and the oral administration can release CA4; 。

Inventors

  • LOU YAN
  • QIU YUNQING
  • WANG YUJING
  • Ying Shuaibing

Assignees

  • 浙江大学医学院附属第一医院(浙江省第一医院)

Dates

Publication Date
20260508
Application Date
20260410

Claims (9)

  1. 1. A CA4 dimer prodrug compound or stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof is characterized in that the structural formula of the compound is shown in a general formula I: ; Wherein R is-C (O) -or-C (O) C (O) -; when R is-C (O) -the compound is bis (2-methoxy-5- ((Z) -3,4, 5-trimethoxystyryl) phenyl) carbonate, which is abbreviated as CA4-dimer1, and the structural formula is shown as a general formula II; When R is-C (O) C (O) -the compound is bis (2-methoxy-5- ((Z) -3,4, 5-trimethoxystyryl) phenyl) ester, which is abbreviated as CA4-dimer2, and the structural formula is shown as a general formula III: 。
  2. 2. The method of preparing a CA4 dimer prodrug compound according to claim 1, wherein the compound is CA4 dimer1, comprising the steps of: step 1, reacting (1, 2, 3-trimethoxybenzene-5-yl) methanol with phosphorus tribromide in dichloromethane, and purifying by extraction and column chromatography to obtain 5- (bromomethyl) -1,2, 3-trimethoxybenzene; step 2, reacting the product obtained in the step 1 with triphenylphosphine in tetrahydrofuran, and carrying out solid-liquid separation to obtain triphenyl (3, 4, 5-trimethoxybenzyl) phosphorus; Step 3, condensing the product obtained in the step 2, 3-hydroxy-4-methoxybenzene-1-formaldehyde and potassium carbonate in ethanol, and purifying by column chromatography to obtain (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenol; Step 4, reacting (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenol, 4-nitrophenyl chloroformate and pyridine in methylene dichloride at 70-90 ℃ for 4-10h to obtain an intermediate (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenyl (4-nitrophenyl) carbonate; and 5, carrying out coupling reaction on the product obtained in the step 4 and another part of (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenol under alkaline conditions, and purifying to obtain the target compound CA4-dimer1.
  3. 3. The method of preparing a CA4 dimer prodrug compound according to claim 1, wherein the compound is CA4-dimer2, comprising the steps of: step 1, reacting (1, 2, 3-trimethoxybenzene-5-yl) methanol with phosphorus tribromide in dichloromethane, and purifying by extraction and column chromatography to obtain 5- (bromomethyl) -1,2, 3-trimethoxybenzene; step 2, reacting the product obtained in the step 1 with triphenylphosphine in tetrahydrofuran, and carrying out solid-liquid separation to obtain triphenyl (3, 4, 5-trimethoxybenzyl) phosphorus; Step 3, condensing the product obtained in the step 2, 3-hydroxy-4-methoxybenzene-1-formaldehyde and potassium carbonate in ethanol, and purifying by column chromatography to obtain (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenol; and 4, performing condensation reaction on (Z) -2-methoxy-5- (3, 4, 5-trimethoxystyryl) phenol and oxalyl chloride under alkaline conditions, and purifying to obtain the target compound CA4-dimer2.
  4. 4. A pharmaceutical composition comprising a CA4 dimer prodrug compound of claim 1, and stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.
  5. 5. The pharmaceutical composition of claim 4, further comprising one or more pharmaceutically acceptable carriers or vehicles.
  6. 6. Use of a CA4 dimer prodrug compound of claim 1, its stereoisomers, tautomers, solvates or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of claim 5, in the preparation of an antitumor drug.
  7. 7. The use according to claim 6, wherein the antitumor drug exerts an antitumor effect by releasing CA4 and inhibiting tubulin polymerization and bile acid synthesis key enzyme CYP7A1 expression.
  8. 8. The use according to claim 6, wherein the anti-tumor drug is a drug for the treatment of solid tumors.
  9. 9. The use according to claim 8, wherein the antitumor drug is for preventing or treating liver cancer, stomach cancer, colorectal cancer or non-small cell lung cancer.

Description

CA4 dimer prodrug compound and preparation method and application thereof Technical Field The invention belongs to the field of medicinal chemistry, and particularly relates to a CA4 dimer prodrug compound, and a preparation method and application thereof. Background Hepatocellular carcinoma (Hepatocell μ Lar Carcinoma, HCC) is one of the leading causes of cancer-related death worldwide. HCC incidence is statistically sixth on the global scale, third among cancer-related deaths, and patients with middle and advanced stages lose surgical opportunities due to tumor metastasis or liver failure. Current first-line treatment regimens rely on multi-target tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib) and immune checkpoint inhibitors (e.g., atilizumab), only about 30% of HCC patients benefit from sorafenib treatment, and most patients develop resistance within 6 months of treatment. Although combination therapy (anti-PD-L1 antibody + anti-CTLA-4 antibody) improves the 4-year overall survival of advanced HCC patients to 25.2%, drug toxicity and high cost limit its wide application, and development of a novel anti-HCC drug with high efficacy and low toxicity is urgent. Inhibition of tumor angiogenesis and tubulin aggregation has become one of the key strategies for advanced HCC system treatment. Combretastatin A4 (CA 4) is used as a natural microtubulin inhibitor to be combined with tubulin reversibly, and CA4 can selectively destroy the microtubule skeleton of tumor vascular endothelial cells to induce interruption of tumor blood supply, thereby providing a new direction for liver cancer treatment. In our earlier study, CA4 binds to CYP7A1 and exerts an inhibitory effect, and the expression of CTSB, CSTD proteins is affected by autophagy pathways, thereby achieving an antitumor effect. CA4 has proved to have broad-spectrum anti-tumor effect, and has excellent anti-tumor effect on cells or animal models of tumors such as liver cancer, colorectal cancer, glioma, non-small cell lung cancer and the like. However, the clinical application of CA4 faces two major bottlenecks, namely, firstly, poor pharmacokinetics due to high lipophilicity and low water solubility and less than 2% of oral bioavailability, and secondly, phenolic hydroxyl groups are oxidized in vivo through cytochrome P450 to generate quinone metabolites, which cause dose-limiting hepatotoxicity. Existing prodrug strategies have developed many CA4 prodrugs to enhance water solubility, therapeutic effect and reduce side effects, but have heretofore failed to effectively balance the efficacy and safety of CA 4. A study (PMID: 14977848) discloses a CA4 phosphate prodrug (CA 4P), but its plasma Cmax reaches 95.2 μg/mL after intravenous injection, and phosphate metabolism places a heavy burden on the kidneys. In addition to phosphate prodrugs, the prior art (e.g., PMID: 40323152) discloses CA4 dimer prodrugs based on aliphatic carbon chains or disulfide linkages, but both strategies suffer from significant pharmaceutical drawbacks in that the introduction of aliphatic carbon chains further increases the lipid solubility of the molecule, resulting in poorer water solubility, and additional carbon chains introduce unnecessary metabolic loads, while disulfide linkage strategies are highly susceptible to disulfide exchange reactions during synthesis and storage, resulting in poor product homogeneity, greatly increasing the difficulty of synthesis and purification, and related drawbacks still limiting their use. Therefore, there is a need to open a CA4 dimer prodrug compound that combines high drug release, metabolic safety and ease of synthesis, and a method of synthesizing the same. Disclosure of Invention In order to overcome the defects of the prior art, the invention provides a CA4 dimer prodrug compound, and a preparation method and application thereof. The invention adopts the carbonic ester or oxalic ester of the metabolite nontoxic (CO 2 and formic acid) as the connecting bond for the first time to construct the symmetrical CA4 dimer, thereby ensuring the high-efficiency release of the active medicine and simultaneously having the metabolic safety and the synthesis simplicity. In a first aspect, the present invention provides a CA4 dimer prodrug compound, and stereoisomers, tautomers, solvates or pharmaceutically acceptable salts thereof, wherein the structural formula of the compound is shown in formula I: ; wherein R is-C (O) -or-C (O) C (O) -. As a preferred aspect of the present application, a CA4 dimer prodrug compound, and stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof, is characterized in that: when R is-C (O) -the compound is bis (2-methoxy-5- ((Z) -3,4, 5-trimethoxystyryl) phenyl) carbonate, which is abbreviated as CA4-dimer1, and the structural formula is shown as a general formula II; When R is-C (O) C (O) -the compound is bis (2-methoxy-5- ((Z) -3,4, 5-trimethoxystyryl) phenyl) ester, which is abbrevia