Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Aminopeptidase N (APN) is a zinc metallopeptidase implicated in cancer cell survival.
• APN inhibition triggers an amino acid deprivation response (AADR) in cancer cells, leading to apoptosis.
• APN inhibitors may overcome resistance to cancer therapies like TRAIL-based treatments.

Purpose of the Study:

• To synthesize and evaluate novel semicarbazone and thiosemicarbazone derivatives as APN inhibitors.
• To assess the anti-proliferative activity of these compounds against APN-expressing cancer cells.

Main Methods:

• Synthesis of substituted acetamidophenones, semicarbazones, and thiosemicarbazones.
• Determination of APN inhibitory activity.
• Evaluation of selective anti-proliferative effects on cancer cell lines.

Main Results:

• Several synthesized semicarbazone and thiosemicarbazone compounds exhibited significant APN inhibitory activity.
• These compounds demonstrated selective anti-proliferative effects against cancer cells expressing APN.
• This study reports the first Schiff base compounds of these types to inhibit M1 family aminopeptidases and metalloenzymes.

Conclusions:

• Novel semicarbazones and thiosemicarbazones are effective inhibitors of Aminopeptidase N.
• These compounds represent a new class of potential therapeutic agents for overcoming cancer treatment resistance.
• The findings open new avenues for developing targeted cancer therapies.