CN-121987814-A - ROS response type prostate cancer targeting prodrug, and preparation method and application thereof

Abstract

The invention discloses a ROS response type prostate cancer targeting prodrug, and a preparation method and application thereof, and belongs to the technical field of biological medicines. The prodrug is formed by covalent linkage of a prostate cancer targeting peptide SSYEELR, a ROS-responsive ketal (TK) linker and an active molecule DEVIMISTAT. The preparation method comprises the steps of coupling DEVIMISTAT with a TK linker to obtain an intermediate Dev-TK, and coupling the intermediate Dev-TK with SSYEELR peptide segment to obtain a target product. The prodrug can specifically release DEVIMISTAT in a tumor high-activity oxygen microenvironment in a cleavage way, and active targeted delivery is realized by means of SSYEELR peptide. The invention provides a novel strategy for treating the prostate cancer, which has the advantages of accurate targeting, controllable release, enhanced curative effect and potential for reducing toxicity.

Inventors

• YIN MIN
• WU ZONGJIAN
• YUAN YUECHUN
• SUN YANG
• ZHOU LIBIN
• TAN XUEYING
• HU JINGBO

Assignees

• 宁波市医疗中心李惠利医院(宁波大学附属李惠利医院)

Dates

Publication Date

20260508

Application Date

20260409

Claims (9)

1. 1. A ROS-responsive prostate cancer targeting prodrug characterized in that it is a compound having the structure of formula (I): 。
2. 2. The ROS-responsive prostate cancer targeting prodrug of claim 1, wherein the ROS-responsive prostate cancer targeting prodrug cleaves a C-S bond under reactive oxygen species, releasing DEVIMISTAT and SSYEELR peptide fragments.
3. 3. The ROS-responsive prostate cancer targeting prodrug of claim 2, wherein the SSYEELR peptide has the formula (II): 。
4. 4. a method for preparing the ROS-responsive prostate cancer targeted prodrug of any one of claims 1-3, said method comprising the steps of: S1, reacting DEVIMISTAT and a TK linker serving as raw materials in an organic solvent in the presence of a condensing agent and alkali to generate an intermediate Dev-TK, wherein the molar ratio of DEVIMISTAT to the TK linker is 1:1.2; And S2, reacting Dev-TK and SSYEELR peptide fragments obtained in the step S1 serving as raw materials in an organic solvent in the presence of a condensing agent and alkali to obtain a target compound Dev-TK-SSY, wherein the molar ratio of the Dev-TK to the SSYEELR peptide fragments is 1:1.5.
5. 5. The process according to claim 4, wherein in the step S1, the organic solvent is anhydrous methylene chloride, the TK linker is 2,2' - (propane-2, 2-diylbis (sulfadiyl)) diethylamine, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the base is N, N-diisopropylethylamine.
6. 6. The preparation method according to claim 5, wherein the specific operation of the step S1 is that DEVIMISTAT is dissolved in anhydrous dichloromethane, TK linker and condensing agent are added in sequence under ice bath cooling, then alkali is added dropwise, after the dropwise addition, the reaction system is moved to room temperature and stirred for 12: 12 h, then the reaction solution is poured into saturated sodium chloride solution, the organic phases are combined after extraction by dichloromethane, the organic phases are dried by anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain an intermediate Dev-TK.
7. 7. The process according to claim 4, wherein in the step S2, the organic solvent is anhydrous N, N-dimethylformamide, the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the base is N, N-diisopropylethylamine.
8. 8. The process according to claim 7, wherein the step S2 is carried out by dissolving Dev-TK in organic solvent, adding peptide SSYEELR and condensing agent, adding alkali, agitating at room temperature for 18: 18 h, removing most solvent, purifying by preparative high performance liquid chromatography, and freeze drying.
9. 9. Use of a ROS-responsive prostate cancer targeted prodrug of any one of claims 1-3 in the preparation of a medicament for the treatment of prostate cancer.

Description

ROS response type prostate cancer targeting prodrug, and preparation method and application thereof Technical Field The invention relates to the technical field of biological medicines, in particular to a ROS response type prostate cancer target prodrug, and a preparation method and application thereof. Background Prostate cancer is one of common malignant tumors of men, and the treatment means comprise surgery, radiotherapy, chemotherapy, hormone treatment, targeted treatment and the like. However, traditional chemotherapeutic drugs often cause remarkable toxic and side effects on normal tissues while killing tumor cells, and are easy to induce multi-drug resistance, so that the clinical application of the traditional chemotherapeutic drugs is limited. Therefore, the development of targeted anti-prostate cancer drugs with high selectivity and low toxic and side effects is an important direction of current research. DEVIMISTAT (also known as CPI-613) is a small molecule inhibitor of a key enzyme of the targeted mitochondrial tricarboxylic acid cycle, induces apoptosis of tumor cells by interfering with energy metabolism of the tumor cells, and shows good anti-tumor activity in various solid tumors and blood system tumors. However, DEVIMISTAT itself lacks tissue selectivity, is easily distributed throughout the body following systemic administration, and results in toxicity to normal cells (especially high-metabolic tissues), limiting its therapeutic window and potential for clinical use. In order to improve tumor targeting of drugs, prodrug strategies are widely adopted. Among them, reactive Oxygen Species (ROS) -responsive prodrugs are receiving great attention due to their characteristic of specifically releasing active ingredients at high ROS levels in tumor microenvironments. Tumor cells often have significantly elevated ROS levels due to metabolic abnormalities, which provides ideal endogenous trigger conditions for the precise release of ROS-responsive drugs. Ketone Thiol (TK) is used as a classical ROS response type connector, C-S bond rupture can occur under the action of ROS such as H 2O2 and the like, and the controllable release of the medicine is realized. Meanwhile, peptide-mediated targeted delivery systems show great potential in tumor targeted therapy due to their high affinity, low immunogenicity and good biocompatibility. SSYEELR is a functional peptide with prostate cancer specific recognition capability, and active targeting delivery of drugs can be realized through specific binding to a prostate cancer cell surface over-expression receptor. However, there is currently no report on the construction of a prodrug system with dual targeting (physical targeting + chemical response) function by covalently binding DEVIMISTAT to prostate cancer targeting peptide SSYEELR via ROS-responsive linkers. The prior art still lacks a high-efficiency low-toxicity targeting prodrug capable of realizing specific delivery of the prostate cancer and controllable release DEVIMISTAT in a tumor microenvironment. Disclosure of Invention To overcome the above drawbacks of the prior art, a first object of the present invention is to provide a ROS-responsive prostate cancer targeting prodrug, which is a compound having the structure of formula (I): 。 Compared with the prior art, the ROS-responsive prostate cancer targeting prodrug SSYEELR-TK-DEVIMISTAT (namely a structural compound in a formula (I)) based on a ketal and thiol linker is provided, and DEVIMISTAT and SSYEELR peptides are connected through chemical coupling to realize specific accumulation in prostate cancer tissues and trigger drug release under a high ROS environment, so that the treatment effect is improved, the systemic toxicity is reduced, and a new drug design and delivery strategy is provided for the accurate treatment of prostate cancer. In one possible embodiment, the ROS-responsive prostate cancer targeting prodrug cleaves the C-S bond under reactive oxygen species, releasing DEVIMISTAT and SSYEELR peptide fragments. Compared with the prior art, the ROS response type connector of ketal (TK) is introduced, so that the prodrug can generate specific C-S bond cleavage in the tumor-specific high-activity oxygen microenvironment, and the accurate and controllable release of the active drug DEVIMISTAT is realized. The design utilizes the difference of endogenous ROS level between tumor tissues and normal tissues, so that the medicine is preferentially activated at a focus part and is kept stable in the normal tissues, thereby obviously reducing the toxic and side effects on the whole body normal tissues while enhancing the efficacy of the tumor part, and improving the safety window and targeting of treatment. In one possible embodiment, the SSYEELR peptide has the structural formula shown in formula (II): 。 The second object of the present invention is to provide a method for preparing the ROS-responsive prostate cancer targeted prodrug, which speci