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In this study, a series of trinitroaniline derivatives (TNA1‐8) were synthesized and investigated as potential antitumor agents for enzyme‐prodrug therapy. Enzymatic efficiency of Ssap‐NtrB on prodrug candidates was determined with HPLC analysis and kinetic studies. The anti‐proliferative properties of compounds were determined against four cancer cell lines (Hep3B, PC3, HT‐29, and Saos‐2) and a healthy cell line (HUVEC) via MTT assay. Intracellular and extracellular prodrug‐enzyme treatments were carried out on Hep3B cells. Herewith, the expression of the Ssap‐NtrB gene was confirmed with this study. IC50 values of piperidine and 1,3‐cyclohexyl derivatives (TNA4 and TNA7) were identified as 1.724 nM and 1.640 nM at extracellular conditions. In intracellular conditions, it was determined as 0.293 μM and 0.393 μM, respectively. In summary, 2,4,6‐trinitroaniline derivatives, especially compounds TNA4 and TNA7 might be used as prodrug candidates along with Ssap‐NtrB for hepatocellular carcinoma therapy and the development of new prodrugs at cancer treatments.

Suicide gene therapy has recently emerged as a method used in cancer treatments. These therapies utilized enzymes that are expressed in the cell. In this study, Staphylococcus saprophyticus supsp. saprophyticus Nitroreductase gene (Ssap-NtrB) was subcloned into the eukaryotic expression vector namely pcDNA3.1 / V5 / His B. For this purpose, Nitroreductase gene region was firstly amplified from the pET14B vector using PCR strategy and cloned into the pGEM-T-Easy vector. After this step, the Ssap-NtrB gene was restricted with KpnI/ApaI and was ligated into pcDNA3.1 / V5 / His B vector. Recombinant colonies were verified using KpnI/ApaI restriction enzymes. As a result, the Ssap-NtrB gene was cloned into pcDNA3.1/V5/His B vector and was readyfor use in suicide gene therapy in eukaryotic human cancer cells.

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