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CN-121974839-A - Seleno-heptamethine indole cyanine compound and preparation method and application thereof

CN121974839ACN 121974839 ACN121974839 ACN 121974839ACN-121974839-A

Abstract

The invention discloses a seleno heptamethine indocyanine compound, a preparation method and application thereof, wherein the compound has a structure shown in a formula Se-Cys, and the seleno heptamethine indocyanine compound can be specifically accumulated in cell mitochondria and efficiently remove excessive Reactive Oxygen Species (ROS) generated by radiation-induced mitochondria, so that the radiation damage of normal cells is reduced. Meanwhile, the compound has near infrared fluorescence enhancement function of ROS concentration dependence, can synchronously realize real-time monitoring of ROS level, avoids excessive oxidation, and reduces toxicity of anti-radiation medicines.

Inventors

  • LUO SHENGLIN
  • LI RONG
  • WU ZIFEI
  • HUANG XIE
  • GAO MINGQUAN

Assignees

  • 中国人民解放军陆军军医大学

Dates

Publication Date
20260505
Application Date
20260128

Claims (10)

  1. 1. A seleno heptamethine indocyanine compound characterized by having a structure represented by the following formula Se-Cys: In the formula, 。
  2. 2. The selenomethylindole cyanine compound of claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof: 、 、 。
  3. 3. A process for the preparation of seleno-heptamethine indocyanine compounds according to claim 1 or 2, characterized in that it comprises reacting the compound Se-Cy0 with the compound R-H in the presence of Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) to give Se-Cys, In the formula, R is R 1 or R 2 , R 1 or R 2 are as defined in claim 1.
  4. 4. The method of claim 3, wherein the reaction is carried out at 0℃to room temperature under nitrogen.
  5. 5. The method of claim 3, wherein the molar ratio of Se-Cy0 to selenium-containing compound R-H is from (1:1) to (1:4).
  6. 6. A process for producing a seleno-heptamethine indocyanine compound according to claim 1 or 2, The method comprises the following steps: 1) 2, 3-trimethyl 3H indole and 3-iodopropanol react in acetonitrile solvent to generate indole quaternary ammonium salt 1a; 2) Under the protection of nitrogen, carrying out reflux reaction on the 1a obtained in the step 1) and a chlorocyclohexene condensing agent in an organic solvent to obtain a compound Se-Cy0; 3) Dissolving Se-Cy0 obtained in the step 2) and a selenium-containing compound R-H (S-2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- (methylseleno) butyric acid or (R) -2- ((tert-butoxycarbonyl) amino) -3- ((4-methylbenzyl) seleno) propionic acid into methylene dichloride for reaction, adding DCC and DMAP under the protection of nitrogen, continuing the reaction, and separating to obtain a target product Se-Cys after the reaction is finished.
  7. 7. The process of claim 6, wherein in step 1), the molar ratio of 2, 3-trimethyl 3H indole to 3-iodopropanol is 1.5:1; in the step 2), the organic solvent is a mixed solvent of toluene and n-butanol, the volume ratio of toluene to n-butanol is 7:3, and the molar ratio of the indole quaternary ammonium salt 1a to the chlorocyclohexene condensing agent is (2:1) - (3:1); In step 3), the molar ratio of Se-Cy0 to selenium-containing compound R-H is (1:1) - (1:4).
  8. 8. The preparation method of claim 6, wherein in the step 3), column chromatography is adopted for separation, and the eluent is a mixed solvent of dichloromethane and methanol, and the volume ratio is (90:1) - (15:1).
  9. 9. Use of a seleno heptamethine indocyanine compound according to claim 1 or 2 for the preparation of a radioprotective medicament.
  10. 10. Use of a seleno heptamethine indocyanine compound according to claim 1 or 2 for the preparation of a reagent for monitoring ROS concentration at a radiation site.

Description

Seleno-heptamethine indole cyanine compound and preparation method and application thereof Technical Field The invention relates to the field of pharmaceutical chemistry, in particular to a seleno heptamethine indocyanine compound, a preparation method and application thereof. Background Ionizing Radiation (IR) comes from natural and artificial sources, including cosmic rays, environmental radionuclides, nuclear activity, accidents, and medical exposures, and constitutes an increasing threat to human health. Organs sensitive to human radiation, such as bone marrow, intestinal tract, brain, are prone to cause hematopoietic dysfunction, anemia, hematochezia, dizziness, vomiting, and even death due to systemic infection after irradiation. In recent decades, although the development of radioprotectors has progressed more, most remain in preclinical studies, and there are very few radioprotectors that are truly available for clinical approval. According to different radiation-resistant mechanisms, current radioprotectors mainly include radical scavengers, DNA repair enhancers, immunomodulators, and the like. For example, the sulphur-containing compounds amifostine, the natural antioxidants soy isoflavones and resveratrol and the like. However, the clinical efficacy of these drugs is often limited by a narrow therapeutic window and a large number of toxic and side effects. In addition, the mechanism of radiation damage and key targets are not completely clearly explained, and are also the main reasons for the non-ideal effect of many radiation-resistant actions at present. IR-induced damage is closely related to mitochondrial redox imbalance. Radiation produces acute ROS by direct ionization and hydroradiolysis, driving lipid peroxidation, protein oxidation, and severe damage to mitochondrial DNA (mtDNA), which lacks powerful structural protection and has limited repair capacity. This results in mitochondrial dysfunction, including loss of Mitochondrial Membrane Potential (MMP), calcium ion (Ca 2 +) imbalance, and ATP depletion, thereby promoting cell death and organ damage. Therefore, the development of a novel approach that can selectively accumulate in mitochondria, timely scavenge radiation-induced excess mitochondrial ROS, protect the normal structure and function of mitochondria, is considered to be a promising approach for the development of radioprotectors. For example, CY-TMP, which the present inventors have developed, is a mitochondrial targeting radioprotectant that chemically couples the ROS scavenger TEMPO with a mitochondrial targeted heptamethine indocyanine molecule, exhibiting significant radioprotection in vivo, confirming the effectiveness of a mitochondrial targeting radioprotection strategy. However, the compound is only dependent on an exogenous ROS scavenging mechanism, so that the endogenous antioxidant defense system of the organism is difficult to activate, and the protective effect is still limited. Meanwhile, the existing radioprotectors lack in-time evaluation of the treatment effect of radiation-induced damage, so that excessive protection is caused, and toxic and side effects occur. Based on the defects or shortcomings of the technology, the invention develops a novel radioprotectant with mitochondrial targeting, ROS scavenging and ROS level monitoring, and designs and prepares a selenium-containing heptamethine indocyanine small molecule compound for radioprotection by utilizing exogenous and endogenous dual antioxidation effects of selenium. The selenium-containing heptamethine indocyanine small molecule is characterized in that selenium-containing groups are introduced into a mitochondria-targeted heptamethine indocyanine molecular skeleton, so that the obtained compound can be specifically accumulated in cell mitochondria, and excessive Reactive Oxygen Species (ROS) generated by the mitochondria induced by radiation can be efficiently removed, thereby reducing the radiation damage of normal cells. The selenium-containing heptamethine indocyanine small molecule has the function of scavenging exogenous free radicals, and can regulate the expression of endogenous antioxidant selenoprotein, such as Glutathione Peroxidase (GPXs) and selenoprotein S (SELS), through selenium removal, so as to enhance the radioprotection. More surprisingly, the compound has near infrared fluorescence enhancement function of ROS concentration dependence, and provides basis for synchronously realizing real-time monitoring of ROS level, avoiding excessive antioxidation, reducing potential toxicity of anti-radiation drugs and the like. Disclosure of Invention The invention aims to provide a seleno-heptamethine cyanine compound, a preparation method and application thereof, wherein the seleno-heptamethine cyanine small molecular compound can be specifically accumulated in mitochondria, can efficiently remove a large amount of ROS generated by mitochondria of cells induced by radiation, and can reduce oxidat