PRODRUGS FOR NITROREDUCTASE BASED CANCER THERAPY- 2: Novel amide/Ntr combinations targeting PC3 cancer cells

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Gene-directed enzyme prodrug therapy (GDEPT) utilizes nitroreductases (NTRs) to activate prodrugs selectively in cancer cells, minimizing toxicity to healthy tissues.
• There is a need for novel prodrug/NTR combinations to overcome limitations of current therapies and expand treatment options.

Purpose of the Study:

• To design and synthesize novel nitro-containing aromatic amides as potential prodrug candidates.
• To evaluate the efficacy and safety of these novel compounds in NTR-based cancer therapy.

Main Methods:

• In silico ADMET and molecular docking studies were performed on designed compounds (A1-A23).
• Reduction potentials of prodrug candidates were assessed using Ssap-NtrB and HPLC.
• Cytotoxic properties and prodrug efficacy were investigated in Hep3B and PC3 cancer cell lines.

Main Results:

• Compounds A5, A6, and A20 demonstrated promising prodrug characteristics.
• In silico and in vitro studies supported the potential of these novel amides in NTR-based cancer therapy.
• The A5, A6, and A20/Ssap-NtrB combinations showed comparable or improved efficacy over the benchmark CB1954/NfsB.

Conclusions:

• Nitroaromatic amides A5, A6, and A20 are identified as potential prodrugs for NTR-based cancer therapy.
• The Ssap-NtrB enzyme effectively reduces these novel prodrugs, leading to cytotoxic effects in cancer cells.
• These findings suggest promising new prodrug/enzyme combinations for targeted cancer treatment.