Ion-modified protoporphyrin gallium compound and preparation method and application thereof
阅读说明：本技术 离子修饰的原卟啉镓化合物及其制备方法和应用 (Ion-modified protoporphyrin gallium compound and preparation method and application thereof ) 是由 张雷 朱迎男 张�浩 于 2020-06-24 设计创作，主要内容包括：本发明属于有机合成和药物领域,具体涉及一种离子修饰的原卟啉镓化合物及其制备方法和应用。离子修饰的原卟啉镓化合物具有以下结构：其中m为1,2或3；n为1,2或3；R1为乙基或乙烯基；R2为H,COO<Sup>-</Sup>或SO<Sup>3-</Sup>；M-X为Ga-Cl或者Ga-NO3；当原卟啉类化合物络合镓之后,除了具有原卟啉类光敏剂光动力抗菌的性能,同时又赋予化合物阻断铁代谢的抗菌机制,双管齐下,协同抗菌,有利于降低最小抑菌浓度,提高抗菌效率,增强对细菌的靶向性,克服细菌耐药性。(The invention belongs to the field of organic synthesis and medicines, and particularly relates to an ion-modified gallium protoporphyrin compound, and a preparation method and application thereof. The ion-modified gallium protoporphyrin compound has the following structure: wherein m is 1, 2 or 3; n is 1, 2 or 3; r1 is ethyl or vinyl; r2 is H, COO ‑ Or SO 3‑ (ii) a M-X is Ga-Cl or Ga-NO 3; after the protoporphyrin compound is complexed with gallium, the protoporphyrin photosensitizer has photodynamic antibacterial performance, and simultaneously endows the compound with an antibacterial mechanism for blocking iron metabolism, so that the compound can synergistically resist bacteria under double conditions, thereby being beneficial to reducing the minimum antibacterial concentration, improving the antibacterial efficiency, enhancing the targeting property of bacteria and overcoming the drug resistance of the bacteria.)
1. An ion-modified gallium protoporphyrin compound having the following structure:
wherein m is 1, 2 or 3; n is 1, 2 or 3; r1 is ethyl or vinyl; r2 is H, COO-Or SO3-(ii) a M-X is Ga-Cl or Ga-NO 3.
2. A method for preparing an ion-modified gallium protoporphyrin compound according to claim 1, wherein the synthetic route is as follows:
wherein m is 1, 2 or 3; n is 1, 2 or 3; r1Is ethyl or vinyl; r2Is H, COO-Or SO3 -(ii) a M-X is Ga-Cl or Ga-NO3。
3. The method for preparing an ion-modified gallium protoporphyrin compound according to claim 2, comprising the steps of:
1) Compound C1Dissolving with an organic solvent, adding oxalyl chloride at-5 ℃, stirring for 1-6 h, and performing vacuum evaporation to obtain a compound C2；
2) Compound C2Dissolving the mixture by using an organic solvent, and adding a compound C at the temperature of-5 DEG C6Stirring for 6-12 h, vacuum evaporating, adding water into the solid, stirring for 6-12 h, filtering, and drying to obtain a compound C3；
3) Compound C3Dissolving the mixture in an organic solvent, and adding a compound C at the temperature of 25-60 DEG C7Stirring for 6-12 h, filtering, leaching with an organic solvent, and drying to obtain the final productTo compound C4；
4) Compound C4Dissolving the mixture by using N, N-dimethylformamide or dimethyl sulfoxide, and adding a compound C at the temperature of 100-160 DEG C8Stirring for 12-24 h, dialyzing, and freeze-drying to obtain a compound C5。
4. The method of claim 3, wherein the organic solvent is dichloromethane, tetrahydrofuran, acetonitrile or acetone.
5. The method for preparing an ion-modified gallium protoporphyrin compound according to claim 3, wherein the molar ratio of the compound C1 to oxalyl chloride in the step 1) is 1: 1-2; the molar ratio of the compound C2 to the compound C6 in the step 2) is 1: 1-1.5; the molar ratio of the compound C3 to the compound C7 in the step 3) is 1: 1-1.5; the molar ratio of the compound C4 to the compound C8 in the step 4) is 1: 1-1.5.
6. Use of the ionically-modified gallium protoporphyrin compound of claim 1 as an antibacterial agent.
Technical Field
The invention belongs to the field of organic synthesis and medicines, and particularly relates to an ion-modified gallium protoporphyrin compound, and a preparation method and application thereof.
Background
Bacterial infections have become one of the major problems threatening human health. Since the first discovery of penicillin by fleming in 1928, antibiotics made a tremendous contribution in the fight between human beings and pathogenic bacteria, saving the lives of countless people. However, the abuse of antibiotics by people for a long time has led to the emergence of multiple drug-resistant bacteria worldwide, even "superbacteria". Along with the emergence of polymyxin drug-resistant bacteria, the 'last line of defense' constructed by antibiotics is also at risk. China is a large antibiotic consuming country and also one of the most serious countries with bacterial drug resistance. The emergence of multi-drug resistant bacteria and the potential explosive epidemic trend have caused panic in countries around the world, and many countries are working on finding new drugs and new methods to overcome multi-drug resistant bacteria, and photodynamic antibacterial therapy is one of the most promising methods.
Photosensitizers are the key to the success of photodynamic antibacterial therapy. The ideal photosensitizer has the characteristics of high efficiency, low toxicity, wide antimicrobial spectrum, high active oxygen yield, no damage to normal cells and the like. The porphyrin compound and the derivatives thereof are natural photosensitizers, widely exist in organisms, have good spectral characteristics and higher singlet oxygen yield, and have the advantages of good biocompatibility, no eukaryotic cytotoxicity and the like due to the unique structure.
Disclosure of Invention
The invention aims to provide an ion-modified protoporphyrin gallium compound and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
an ion-modified gallium protoporphyrin compound having the following structure:
wherein m is 1, 2 or 3; n is 1, 2 or 3; r1 is ethyl or vinyl; r2 is H, COO-Or SO3-(ii) a M-X is Ga-Cl or Ga-
The invention also comprises a preparation method of the ion-modified protoporphyrin gallium compound, and the synthetic route is as follows:
wherein m is 1, 2 or 3(ii) a n is 1, 2 or 3; r1Is ethyl or vinyl; r2Is H, COO-Or SO3 -(ii) a M-X is Ga-Cl or Ga-NO3。
The method specifically comprises the following steps:
1) Compound C1Dissolving with an organic solvent, adding oxalyl chloride at-5 ℃, stirring for 1-6 h, and performing vacuum evaporation to obtain a compound C2；
2) Compound C2Dissolving the mixture by using an organic solvent, and adding a compound C at the temperature of-5 DEG C6Stirring for 6-12 h, vacuum evaporating, adding water into the solid, stirring for 6-12 h, filtering, and drying to obtain a compound C3；
3) Compound C3Dissolving the mixture in an organic solvent, and adding a compound C at the temperature of 25-60 DEG C7Stirring for 6-12 h, filtering, leaching with an organic solvent, and drying to obtain a compound C4；
4) Compound C4Dissolving the mixture by using N, N-dimethylformamide or dimethyl sulfoxide, and adding a compound C at the temperature of 100-160 DEG C8Stirring for 12-24 h, dialyzing, and freeze-drying to obtain a compound C5；
5. The method of
The molar ratio of the compound C1 to the oxalyl chloride in the step 1) is 1: 1-2; the molar ratio of the compound C2 to the compound C6 in the step 2) is 1: 1-1.5; the molar ratio of the compound C3 to the compound C7 in the step 3) is 1: 1-1.5; the molar ratio of the compound C4 to the compound C8 in the step 4) is 1: 1-1.5.
The invention also includes the use of said ion-modified gallium protoporphyrin compound as an antibacterial agent.
Compared with the prior art, the invention has the beneficial effects that:
after the protoporphyrin compound is complexed with gallium, the protoporphyrin photosensitizer has photodynamic antibacterial performance, and simultaneously endows the compound with an antibacterial mechanism for blocking iron metabolism, so that the compound can synergistically resist bacteria under double conditions, thereby being beneficial to reducing the minimum antibacterial concentration, improving the antibacterial efficiency, enhancing the targeting property of bacteria and overcoming the drug resistance of the bacteria.
The invention takes protoporphyrin or Meso-protoporphyrin which exists in a large amount in an organism as a raw material, selects two carboxyl groups on the protoporphyrin as modification groups, carries out amidation reaction with groups with tertiary amine and primary amine, carries out cation or zwitterion modification, and then carries out complexation with gallium salt to obtain a series of novel protoporphyrin gallium photosensitizers.
The ion-modified protoporphyrin gallium compound prepared by the invention has the advantages of simple synthesis operation, high product purity and better photo-thermal stability; the photosensitizer can be well dissolved in deionized water and physiological saline, the quenching of cluster condensation of the photosensitizer under physiological conditions is avoided, and the generation amount of active oxygen is high; protoporphyrin and gallium are combined, and the mechanism of photodynamic-iron blocking synergistic antibacterial is utilized, so that bacteria can be efficiently killed under the conditions of light and darkness; the cationic modified protoporphyrin gallium further promotes the killing effect of the photosensitizer on bacteria by utilizing the mechanism of electrostatic adsorption of positive charges on quaternary ammonium groups and negative charges on the surfaces of the bacteria.
Drawings
FIG. 1 is a scheme showing the synthesis of CMP-Ga in example 1 of the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of CMP in example 1 of the present invention.
FIG. 3 is a high resolution mass spectrum of CMP in example 1 of the present invention.
FIG. 4 is a UV-VIS analysis chart of the complexing process of CMP-Ga in example 1 of the present invention.
FIG. 5 is a scheme for the synthesis of ZMP-Ga in example 2 of the present invention.
FIG. 6 is a NMR spectrum of ZMP in example 2 of the present invention.
FIG. 7 is a high resolution mass spectrum of ZMP in example 2 of the present invention.
FIG. 8 is a UV-VIS analysis of ZMP-Ga during complexation in example 2 of the present invention.
FIG. 9 shows a scheme for synthesizing SMP-Ga according to example 3 of the present invention.
FIG. 10 is a graph showing the antibacterial effect of CMP-Ga under light in example 4 of the present invention.
FIG. 11 is a graph showing the antibacterial effect of CMP-Ga in example 4 of the present invention under dark conditions.
FIG. 12 is a graph showing the antibacterial effect of ZMP-Ga in light conditions in example 5 of the present invention.
FIG. 13 is a graph showing the antibacterial effect of ZMP-Ga in dark conditions in example 5 of the present invention.
FIG. 14 is a graph showing the antibacterial effect of SMP-Ga in example 6 under light conditions.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention will be further described in detail with reference to the accompanying drawings and preferred embodiments.