Preparation method and application of fluorescent response type manganese carbonyl carbon monoxide release agent

Abstract

The application discloses a fluorescent response type manganese carbonyl carbon monoxide releasing agent, a preparation method and application, wherein the compound has the following structural formula: the manganese carbonyl compound provided by the application has good photosensitivity and fluorescent characteristics, CO release can be accurately controlled through green light, the release process can be tracked in real time by using the change of the fluorescent intensity, and the manganese carbonyl compound is expected to be a photo-triggered carbon monoxide releasing agent with application prospect.

Description

Technical Field

[0001] This invention relates to the field of carbon monoxide release agents. More specifically, this invention relates to a fluorescently responsive manganese carbonyl carbon monoxide release agent, its preparation method, and its application. Background Technology

[0002] Although carbon monoxide (CO) is often considered a toxic gas, known as a "silent killer," research shows that the human body produces a small amount of CO endogenously every day (about 10 mL / day), which plays an important physiological role in the body and is considered the second most important gaseous messenger molecule after NO. In recent years, studies have found that CO has various biological effects in organisms, including dilating vasomotor and bronchial smooth muscle, inhibiting platelet aggregation, regulating inflammatory responses, and exerting antioxidant, anti-apoptotic, and anti-proliferative effects. It also plays an important regulatory role in physiological processes such as the nervous, respiratory, and circulatory systems, as well as in pathological processes such as acute lung injury, organ ischemia-reperfusion injury, and organ transplant rejection.

[0003] Currently, there are two main clinical application routes for CO: (1) direct inhalation of a certain concentration of CO gas; and (2) oral administration of prodrugs that can release CO via liver enzyme catalysis (such as CH2Cl2). However, both methods have certain limitations. In the direct inhalation method, the concentration and dosage of CO are difficult to control precisely, and the release process is not easy to track, which may lead to patients or medical personnel accidentally inhaling high concentrations of CO, posing a risk of poisoning. CH2Cl2, as a CO donor, not only has potential carcinogenicity but also needs to be metabolized by the body to enter the bloodstream, which may cause certain damage to the central nervous system and liver. Therefore, in order to achieve the safe and effective application of CO, it is urgent to explore new drug delivery strategies.

[0004] Transition metal carbonyl compounds are a class of organometallic compounds that can undergo carbonyl (CO) leaving reactions under specific conditions (such as light, substitution reactions, and redox reactions). Utilizing this property, transition metal carbonyl compounds capable of releasing CO under specific conditions can be designed and synthesized, namely carbon monoxide-releasing molecules (CORMs). CORMs offer advantages such as strong targeting, controllable release timing, and easily adjustable dosage, providing new possibilities for the clinical application of CO.

[0005] Nearly one hundred carbon monoxide release agents (CORMs) have been reported in the literature, covering most transition metal elements. Despite the wide variety of CORMs, none have yet entered clinical trials. Ideal CORMs should possess the following key characteristics: controllable CO release performance, real-time tracking of the release process, good cellular internalization ability, and ideal pharmacokinetic / pharmacodynamic (ADME) behavior and tissue targeting.

[0006] Therefore, the visible light excitation CO release performance, controllability, and traceability of CORMs directly determine their pharmaceutical prospects, making it one of the key research directions. Literature often uses the introduction of large conjugated ligands to regulate the excitation wavelength or the introduction of fluorescent groups to track the CO release process, but research in this area remains very weak. Currently, CORMs that simultaneously meet the above conditions are still relatively limited, greatly restricting their development as drug molecules. Therefore, there is an urgent need to synthesize more CORMs that can be excited by visible light and possess fluorescence properties. Summary of the Invention

[0008] To address the aforementioned problems, this invention provides a fluorescently responsive manganese carbonyl carbon monoxide release agent with fluorescence properties. This compound can release CO upon irradiation with green light, and its release process can be tracked through fluorescence changes.

[0009] In a first aspect, the present invention provides a fluorescently responsive manganese carbonyl carbon monoxide releaser, the compound having the following structural formula: .

[0010] A second aspect of the present invention provides a method for preparing the aforementioned fluorescently responsive manganese carbonyl carbon monoxide release agent, comprising the following steps: 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylate ethyl ester condenses with quinoline-2-carboxaldehyde to form 7-(diethylamino)-2-oxo-2H-chromene-3-carbazide, which then reacts with... Coordination forms the target product.

[0011] The preparation equation is shown below: A third aspect of the present invention, a preferred embodiment of the present invention, provides a method for preparing the aforementioned fluorescent responsive manganese carbonyl carbon monoxide release agent, comprising the following steps: S1. 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylate ethyl ester was reacted with hydrazine hydrate in a mixed solvent of methanol and anhydrous ethanol under reflux to obtain the precursor 7-(diethylamino)-2-oxo-2H-chromene-3-carbazide. S2. The precursors 7-(diethylamino)-2-oxo-2H-chromene-3-carbonylhydrazine and pentacarbonylmanganese bromide obtained in step S1 were added to a mixed solvent of dichloromethane, methanol, and quinoline-2-carboxaldehyde. The mixture was refluxed under light-protected conditions. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain a reddish-brown solid. The solid was recrystallized from dichloromethane and n-hexane to obtain the target product, manganese carbonyl compound.

[0012] Preferably, in step S1, the volume ratio of methanol to anhydrous ethanol is 1:1, the reflux reaction temperature is 70°C, and the reaction time is 4 hours.

[0013] Preferably, in step S2, the volume ratio of dichloromethane to methanol is 1:1, the reflux reaction temperature is 70°C, and the reaction time is 4 hours.

[0014] On the other hand, a preferred embodiment of the present invention provides an application of the aforementioned fluorescent responsive manganese carbonyl carbon monoxide releaser as a light-controlled carbon monoxide releaser.

[0015] Preferably, the fluorescently responsive manganese carbonyl carbon monoxide releaser can release carbon monoxide under green light irradiation.

[0016] On the other hand, a preferred embodiment of the present invention provides the application of the fluorescence-responsive manganese carbonyl carbon monoxide releaser as described in claim 1 in fluorescence imaging.

[0017] The present invention has at least the following beneficial effects: the manganese carbonyl compound provided by the present invention has both good photosensitivity and fluorescence properties, and can precisely control CO release through green light, and can track the release process in real time by utilizing the change of its fluorescence intensity, and is expected to serve as a promising phototriggered carbon monoxide release agent.

[0018] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0019] Figure 1 The infrared spectrum changes of manganese carbonyl compounds under dichloromethane and green light irradiation. Figure 2 The figure shows the lnA-t curve of manganese carbonyl compounds under dichloromethane and green light irradiation.

[0020] Figure 3 The graph shows the fluorescence spectrum changes of manganese carbonyl compounds under dimethyl sulfoxide and green light illumination.

[0021] Figure 4 The NMR spectrum of 7-(diethylamino)-2-oxo-2H-chromene-3-carbonylhydrazide in CDCl3.

[0022] Figure 5 This is the NMR spectrum of manganese carbonyl compounds in CDCl3. Detailed Implementation

[0023] The present invention will now be described in further detail with reference to the accompanying drawings, so that those skilled in the art can implement it based on the description.

[0024] The following description is intended to disclose the present invention and enable those skilled in the art to implement it. The preferred embodiments described below are merely examples, and other obvious modifications will occur to those skilled in the art. The basic principles of the invention defined in the following description can be applied to other embodiments, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the invention.

[0025] It is understood that the term "a" should be understood as "at least one" or "one or more", that is, in one embodiment, the number of an element can be one, while in another embodiment, the number of the element can be multiple, and the term "a" should not be understood as a limitation on the number.

[0026] Example 1: Preparation of 7-(diethylamino)-2-oxo-2H-chromene-3-carbonylhydrazine Ethyl 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylic acid (1 mmol) was dissolved in a mixed solvent of EtOH (6 mL) and MeOH (2 mL), and hydrazine hydrate (146 μL, 4 mmol) was slowly added dropwise. The mixture was refluxed at 70 °C for 4 h. After the reaction solution was cooled, it was filtered to obtain a yellow solid. The product was purified by recrystallization from dichloromethane / n-hexane to obtain the target compound (224 mg, yield 81%), namely 7-(diethylamino)-2-oxo-2H-chromene-3-carbohydrazine.

[0027] Example 2 Preparation of a fluorescently responsive manganese carbonyl carbon monoxide release agent The 7-(diethylamino)-2-oxo-2H-chromene-3-carbonylhydrazide (0.2 mmol, 55 mg) prepared in Example 1 was dissolved in a mixed solvent of dichloromethane (3 mL) and methanol (3 mL), and then quinoline-2-carboxaldehyde (0.2 mmol, 32 mg) and... (0.2 mmol, 56 mg) The above reaction solution was refluxed for 4 h under light-protected conditions. After cooling, the reaction solution was filtered to obtain a reddish-brown solid. The crude product was purified by recrystallization from a dichloromethane / n-hexane system to obtain the target compound (100 mg, yield 80%), namely the fluorescently responsive manganese carbonyl carbon monoxide release agent.

[0028] The target product is a fluorescently responsive manganese carbonyl carbon monoxide releaser. This compound is readily soluble in dichloromethane and dimethyl sulfoxide, but exhibits poor solubility in other organic solvents. Its infrared spectrum is shown at 2030, 1945, and 1932. There are three typical carbonyl characteristic absorption peaks at this point.

[0029] Example 3 Carbon monoxide release experiment Based on the spectral characteristics of this manganese carbonyl complex, which has a maximum absorption wavelength extension of 451 nm (green light band) in dimethyl sulfoxide, this study selected green light as the excitation source to trigger its photodegradation process.

[0030] In the experiment, the manganese carbonyl complex (10 mg, 0.0158 mmol) was dissolved in dichloromethane (5 mL). The solution was irradiated with a green light source (at a fixed distance of 13 cm) under constant stirring and at room temperature. Samples (0.15 mL each time) were taken periodically, and the reaction progress was monitored in real time using infrared spectroscopy. The spectral monitoring results ( Figure 1 The results showed that the intensity of the characteristic carbonyl (C≡O) stretching vibration absorption peak of the complex molecule gradually decreased with the extension of illumination time. This phenomenon clearly confirms that the complex underwent a photoinduced dissociation reaction under green light, and the carbonyl ligand left the metal center in the form of carbon monoxide (CO) molecules, realizing the controlled release of CO.

[0031] Photolysis kinetic analysis (Figure 2, Table 1) further indicates that the green light-induced CO release process of this complex in dichloromethane follows a pseudo-first-order kinetic model. The calculated kinetic parameters (Table 1) show that this complex possesses extremely high photoreactivity, with a photolysis half-life ( The reaction took only about 17 minutes, and the decomposition reaction was almost complete after about 40 minutes of illumination. This indicates that precise spatiotemporal control of CO release in the system can be achieved by accurately controlling the illumination time.

[0032] Table 1. Kinetic data of CO release from manganese carbonyl compounds under the action of anti-inflammatory drugs and amino acids. compound molecules <![CDATA[k×10 -3 / (min -1 )]]> <![CDATA[t 1 / 2 (min)]]> Manganese carbonyl compounds 39.6 17.5 Furthermore, to achieve visualized monitoring of the CO release process, this study investigated the fluorescence properties of the complex before and after photolysis. The fluorescence spectroscopy results (Figure 3) show that the complex exhibits significant photoluminescence changes in dimethyl sulfoxide. Under 440 nm excitation, the manganese carbonyl compound parent compound exhibits fluorescence of a certain intensity at 488 nm. With prolonged illumination, the fluorescence intensity shows a continuous increasing trend, reaching approximately 10 times the initial intensity upon complete reaction.

[0033] This result reveals that the complex exhibits a "fluorescence off-on" photoresponse characteristic, meaning that the decomposition products show significantly enhanced fluorescence compared to the parent compound. The substantial difference in fluorescence brightness provides a solid theoretical and experimental basis for the real-time visual detection of the carbon monoxide release process.

[0034] In summary, this manganese carbonyl complex possesses both excellent photosensitivity and fluorescence imaging properties, achieving not only efficient photocontrolled CO release but also overcoming the tracking difficulties of CORMs in biological applications through fluorescence enhancement. Therefore, the complex developed in this study represents a class of phototriggered carbon monoxide releasers (PhotoCORMs) with broad application prospects and potential practical value in the biomedical and therapeutic fields.

[0035] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and illustrations shown and described herein.

Claims

1. A fluorescently responsive manganese carbonyl carbon monoxide release agent, characterized in that, It has the following structural formula: 。 2. A method for preparing the fluorescently responsive manganese carbonyl carbon monoxide release agent as described in claim 1, characterized in that, Includes the following steps: 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylate ethyl ester condenses with quinoline-2-carboxaldehyde to form 7-(diethylamino)-2-oxo-2H-chromene-3-carbazide, which then reacts with... Coordination forms the target product.

3. A method for preparing the fluorescently responsive manganese carbonyl carbon monoxide release agent as described in claim 2, characterized in that, Includes the following steps: S1. 7-(diethylamino)-2-oxo-2H-chromene-3-carboxylate ethyl ester was reacted with hydrazine hydrate in a mixed solvent of methanol and anhydrous ethanol under reflux to obtain the precursor 7-(diethylamino)-2-oxo-2H-chromene-3-carbazide. S2. The precursors 7-(diethylamino)-2-oxo-2H-chromene-3-carbonylhydrazine and pentacarbonylmanganese bromide obtained in step S1 were added to a mixed solvent of dichloromethane, methanol, and quinoline-2-carboxaldehyde. The mixture was refluxed under light-protected conditions. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain a reddish-brown solid. The solid was recrystallized from dichloromethane and n-hexane to obtain the target product, manganese carbonyl compound.

4. The fluorescently responsive manganese carbonyl carbon monoxide release agent as described in claim 2, characterized in that, In step S1, the volume ratio of methanol to anhydrous ethanol is 1:1, the reflux reaction temperature is 70°C, and the reaction time is 4 hours.

5. The fluorescently responsive manganese carbonyl carbon monoxide release agent as described in claim 2, characterized in that, In step S2, the volume ratio of dichloromethane to methanol is 1:1, the reflux reaction temperature is 70°C, and the reaction time is 4 hours.

6. The application of the fluorescent responsive manganese carbonyl carbon monoxide release agent as described in claim 1 as a light-controlled carbon monoxide release agent.

7. The application as described in claim 6, characterized in that, The fluorescently responsive manganese carbonyl carbon monoxide releaser can release carbon monoxide under green light irradiation.

8. The application of the fluorescence-responsive manganese carbonyl carbon monoxide release agent as described in claim 1 in fluorescence imaging.

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