Mitochondrial targeting Devimistat derivative as well as preparation method and application thereof

By conjugating a mitochondrial-targeting derivative with the TPP group to Devimistat, the problem of insufficient accumulation of Devimistat in mitochondria was solved, achieving highly efficient inhibition of proliferation and induction of apoptosis in tongue squamous cell carcinoma cells, significantly reducing the IC50 value, improving the chemical structural stability, and making it suitable for anti-tumor drugs.

CN122277608APending Publication Date: 2026-06-26YUYAO PEOPLES HOSPITAL
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Patent Information

Application Number
CN202610409848.2
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2026-03-31
Publication Date
2026-06-26

AI Technical Summary

Technical Problem

The existing Devimistat molecule lacks subcellular targeting, resulting in low effective accumulation of the drug in mitochondria, which limits its efficacy and may cause metabolic toxicity at non-target sites. At the same time, current research has failed to design mitochondrial-targeting derivatives with good stability and unexpected killing activity for oral and tongue squamous cell carcinoma cells with high transmembrane potential.

Method used

By coupling the 3-aminopropyl(triphenyl)phosphine bromide (TPP) group with Devimistat, the specific accumulation of the drug in the mitochondrial matrix is ​​achieved by utilizing the affinity of the TPP cation for the mitochondrial transmembrane potential. The stable amide bond direct coupling avoids the complexity of ROS-responsive nanosystems.

Benefits of technology

It significantly increased the effective concentration of the drug in tumor cells, enhanced the inhibitory effect on the proliferation of tongue squamous cell carcinoma cells, efficiently triggered the endogenous apoptosis program, and reduced the IC50 value to 2.9 ± 0.01 μM, which is much lower than the original drug's 23.5 ± 0.02 μM, and also showed good chemical stability.

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Abstract

The invention relates to the field of medical chemistry, in particular to a Devimistat derivative with a mitochondrial targeting function, a preparation method of the Devimistat derivative and application of the Devimistat derivative in antitumor drugs. 3-aminopropyl (triphenyl) phosphonium bromide (TPP) groups with mitochondrial tropism and antitumor active molecules Devimistat are subjected to covalent coupling to obtain the Devimistat derivative with the mitochondrial targeting function. The affinity of TPP positive ions to mitochondrial transmembrane potential is utilized to drive the drug to be specifically accumulated in a mitochondrial matrix. According to the derivative, the effective concentration of the medicine in tumor cells is remarkably improved on the basis of keeping the interference of the raw medicine on tricarboxylic acid circulation and inhibiting the activity of PDH and KGDH compounds, so that the problem that the drug effect of Devimistat is limited due to lack of targeting is solved.
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