CN-118852216-B - Gold (I) complex and preparation method and application thereof

Abstract

The invention discloses a gold (I) complex, a preparation method and application thereof, wherein the gold (I) complex is shown as a compound in a formula I: The compound of formula I in the invention is a highly sterically hindered N-heterocyclic carbene (NHC) gold (I) complex. The invention designs a series of stable active gold (I) complexes containing large-steric-hindrance NHC ligands by using a steric-hindrance regulation strategy, and the large-steric-hindrance gold complexes can resist excessive mercapto compounds in cells, have good stability, can have normal catalytic activity in cells, have good probe imaging and prodrug activating properties, show high-efficiency in-vitro and in-vivo antitumor activity and have good antibacterial activity.

Inventors

• ZOU TAOTAO
• ZHONG ZHI
• XIONG XIAOLIN

Assignees

• 中山大学

Dates

Publication Date

20260505

Application Date

20240703

Claims (5)

1. 1. A compound is characterized in that the structural formula of the compound is shown as follows: 。
2. 2. a pharmaceutical composition comprising a compound of claim 1.
3. 3. A method of treating cancer comprising administering to a subject in need thereof a compound of claim 1, wherein the cancer is at least one of cervical epidermoid carcinoma, lung carcinoma, breast carcinoma, melanoma, and colon carcinoma.
4. 4. The method of claim 3, wherein the treatment comprises at least one of (I) the compound inducing an increase in intracellular ROS levels as a result of a peroxidase-mediated Fenton-like reaction to produce hydroxyl radicals to promote apoptosis of tumor cells, (II) the compound inducing immunogenic death of tumor cells, (III) the compound inducing eversion of calreticulin on the endoplasmic reticulum of tumor cells to the cell surface, releasing high mobility group protein 1, secreting adenosine triphosphate, and (IV) the compound does not inhibit immune function.
5. 5. The method according to claim 3, wherein said effective amount of said compound for said treatment is 0.1 mg/kg to 50mg/kg.

Description

Gold (I) complex and preparation method and application thereof Technical Field The invention relates to the technical field of medicinal chemistry, in particular to a gold (I) complex, a preparation method and application thereof. Background Cisplatin is widely used as a first-line clinical antitumor drug for treating lung cancer, head and neck squamous carcinoma, gastric cancer and reproductive system cancer, however, the drug resistance and toxic and side effects of the platinum drugs limit the further clinical use of the drugs. The search for other metal complexes with different anticancer mechanisms is an important strategy to overcome cisplatin resistance. Unlike platinum complexes acting on the N binding site of DNA bases, gold complexes show high affinity for thiol (SH) and seleno (Se -), especially with thioredoxin reductase (TrxR) overexpressed in tumor cells and containing both Cys and Sec, which inhibits IC 50 to nanomolar to picomolar levels, e.g., auranofin can exert its anticancer activity by inhibiting TrxR in tumor cells. However, since a large number of thiol-containing biomolecules such as serum albumin and Glutathione (GSH) exist in vivo, gold with high reactivity can also competitively bind to the biomolecules, and these off-target effects lead to reduced anticancer activity and potential toxic and side effects, and how to regulate the reactivity of gold complexes to thiol is an important direction for researching gold anticancer complexes at present. The gold complex reported at present mainly has the active site masked and is activated in tumor cells by means of ligand exchange, illumination or bioorthometric mode step by step, so that it is necessary to develop an active gold complex capable of avoiding the attack of biological thiol without losing the catalytic activity and anti-tumor activity. Disclosure of Invention The present invention aims to solve at least one of the above technical problems in the prior art. Therefore, the invention aims to provide a gold (I) complex, and a preparation method and application thereof. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: in a first aspect of the invention, there is provided a compound of formula I: Wherein R 1、R2 is independently selected from optionally substituted or unsubstituted C 1～C12 alkyl, C 3～C12 cycloalkyl, C 2～C12 alkenyl, C 2～C12 alkynyl, C 6～C20 aromatic hydrocarbon ring group or C 3～C60 aromatic heterocyclic group, R 3、R4 is independently selected from deuterium, H, optionally substituted or unsubstituted C 1～C12 alkyl, C 1～C12 alkoxy, C 3～C12 cycloalkyl, C 2～C12 alkenyl, C 2～C12 alkynyl, C 6～C20 aromatic hydrocarbon ring group or C 3～C60 aromatic heterocyclic group, the hetero atom in the aromatic heterocyclic group is N, O, S, and L is an anion. "Cycloalkyl" as used herein refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and polycycloalkyl rings, such as bicyclopropyl, dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like, wherein each of the polycycloalkyl rings may be attached to the same carbon atom, e.g.Or may be bound to adjacent and/or spaced apart different carbon atoms, e.g "Alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbyl group having the specified number of carbon atoms and having at least 1 carbon-carbon double bond (> c=c <). For example, C a～Cb alkenyl refers to an alkenyl-containing unsaturated hydrocarbon group having a to b carbon atoms, and specific examples of alkenyl groups include ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like. "Alkynyl" as used herein refers to a straight or branched monovalent hydrocarbon radical containing at least one carbon-carbon triple bond. The term "alkynyl" is also intended to include those hydrocarbyl groups having one triple bond and one double bond. For example, specific examples of C 2～C6 alkynyl groups include ethynyl, propynyl, and the like. In some embodiments of the invention, the aromatic hydrocarbon ring group is selected from phenyl, naphthyl, anthracenyl, perylenyl, tetracenyl, pyrenyl, benzopyrenyl,A group, a biphenyl group, an acenaphthene group, a fluoranthene group, and a fluorenyl group. In some embodiments of the invention, the aromatic heterocyclic group is selected from thienyl, bithiophene (e.g., bithiophene, three or more thienyl linked to form a polybiphenyl), thienophenyl (e.g., dithienylphenanthrenequinone), thienobenzoquinone (e.g., dithienylquinone), thiopyranyl, dithiopyranyl, thiopyranophenyl, thiopyranobenzoquinone, thiazolyl, benzothiazolyl, benzothiadiazolyl, thianthrenyl, pyridyl, phenylpiperazinyl, benzimido, benzimidylphenyl, benzimidyl anthraquinone, benzimidophenyl quinone, naphthalimido