Anti-tumor application of spiro-three-membered ring and spiro-five-membered ring type peptide deformylase inhibitor

Abstract

The invention discloses a novel peptide deformylase inhibitor containing spiro-three-membered ring and spiro-five-membered ring types. The novel peptide deformylase inhibitor containing the spiro-three-membered ring and spiro-five-membered ring types has antibacterial activity and anti-tumor activity. The peptide deformylase inhibitor containing the spiro-three-membered ring and spiro-five-membered ring types can serve as a novel antibacterial agent, by inhibiting the activity of peptide deformylase needed in synthesis of bacterium proteins, the novel peptide deformylase inhibitor is effective on multiple antibiotic resistant Gram-positive bacterium strains, the synthesis process of proteins of human bodies is not affected, and accordingly bacteria are killed selectively. The peptide deformylase inhibitor containing the spiro-three-membered ring and spiro-five-membered ring types can further serve as a novel anti-cancer drug; by inhibiting peptide deformylase in mitochondria of cancer cells, energy balance of the cells can be affected, accordingly mitochondrial membranes are depolarized, ATP is used up, and cell apoptosis is promoted; and the novel peptide deformylase inhibitor has good inhibiting activity to multiple cancer cell bacterial strains such as colorectal cancer cell bacterial strains, lung cancer cell bacterial strains, gastric cancer cell bacterial strains and liver cancer cell bacterial strains at the low concentration.

Description

technical field [0001] The invention belongs to the technical research field of antibacterial and anticancer drugs, and relates to a class of peptide deformylase inhibitors, in particular to novel spiro three-membered ring and spiro five-membered ring-like peptide deformylase inhibitors. Background technique [0002] Antibiotics refer to a series of chemical substances that can inhibit and kill pathogens at a certain concentration, including metabolites produced by microorganisms, animals and plants, as well as chemically synthesized or semi-synthesized compounds. Antibiotics not only refer to antibacterial substances, but also antitumor, antiviral, antiparasitic and other substances also belong to the category of antibiotics. Antibiotics are an important pillar enabling us to live longer, healthier lives and benefit from modern medicine. [0003] With the emergence and widespread use of antibiotics, the problem of antibiotic resistance has become increasingly prominent, an...

AI Technical Summary

Problems solved by technology

[0009] Although many PDF inhibitors have been developed for preclinical research, and even some compounds have entered the clinic (such as formula (b) ~ (d)), but due to the nature of the compound itself, the activity is not good, or it shows Clinical toxicity, ultimately failed to market

For example: actinomycin Actinonin is the first PDF inhibitor discovered, which shows good activity against Gram-positive bacteria and negative bacteria, but due to the instability of metabolism in the body, it eventually has no activity in vivo

LBM415, which has entered the Phase I clinical trial of antibacterial activity, has broad-spectrum activity, but it was found that high doses can cause methemoglobinemia (Clin.Pharmacol.Ther.2011, 90, 256); GSK1322322, also terminated by the FDA antibacterial activity Phase I clinical study of the same reason, the occurrence of metabolically active compounds, causing toxicity to the body (see the project number NCT01818011 in ClinicalTrials.gov for reasons for termination of clinical trials)

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