Prodrugs for nitroreductase based cancer therapy

11. Drug Chemistry Congress, Antalya, Türkiye, 9 - 12 Mart 2023, ss.7

Mehmet Ay

Çanakkale Onsekiz Mart University, Faculty of Sciences, Department of Chemistry,

Natural Products and Drug Research Laboratory 17020 Terzioğlu Campus, Çanakkale TÜRKİYE

mehmetay06@comu.edu.tr

Chemotherapeutic drugs in clinical use cause very harmful side effects. To overcome this problem,

nowadays some cancer therapy approaches were evaluated namely GDEPT (Gene-Directed Enzyme

Prodrug Therapy) and ADEPT (Antibody-Directed Enzyme Prodrug Therapy). Prodrugs for targeted

tumor therapies have been extensively studied in recent years due to not only maximising therapeutic

effects on tumor cells but also reducing or eliminating serious side effects on healthy cells. This strategy

uses prodrugs which are safe for normal cells and form toxic metabolites (drugs) after selective

reduction by enzymes in tumor tissues. Nitroreductase enzymes catalyze the conversion of the nitro

group of prodrug compounds via hydroxylamine to amine group and the active drug inhibits tumor

formation by binding to DNA. E. coli NTR/CB1954 (5-aziridinyl-2,4- dinitrobenzamide) is the best known

combination that have studied phase I/II trial for different cancer types. So more effective

NTR/prodrug combination should be investigated for cancer therapies. Along this line, we explored

and characterized a novel nitroreductase (Ssap-NtrB-cloned from S. saprophyticus) with enhanced

activity-selectivity and implemented various applications. Several series of nitro group containing

compounds were designed, synthesized and the interaction of prodrugs with Ssap-NtrB were

investigated by spectroscopic techniques and HPLC analysis. Resulting metabolites were analyzed by

LC-MS/MS. Michaelis-Menten kinetic parameters were calculated for reduction reactions of prodrugs

and compared common known prodrugs like as CB1954 and SN23862. The prodrugs were evaluated

by MTT and SRB assay in different cancer cell lines, Hep3B, HT-29, PC-3 and Saos-2 in addition to non-

cancer cell, HUVEC. Proposed enzyme/prodrug combinations may be used in NTR based cancer

therapy [1-6].

Acknowledgement: The Scientific and Technological Research Council of Turkey-TUBITAK was

acknowledged for financial support (Grant No. 110T754 and 113Z706).

References

1) Çelik, A.*; Yetiş, G., Bioorganic & Medicinal Chemistry, 2012, 20(11), 3540-3550.

2) Güngör, T.; Yetiş, G.; Önder, F. C.; Tokay, E.; Tok, T. T.; Çelik, A.; Ay, M.* and Köçkar, F.,

Medicinal Chemistry, 2018, 14, 495-507.

3) Güngör, T.; Önder, F. C.; Tokay, E.; Gülhan, Ü. G.; Hacıoğlu, N.; Tok, T. T.; Çelik, A.; Koçkar, F.;

Ay, M.*, European Journal of Medicinal Chemistry, 2019, 171, 383-400.

4) Tokay, E.; Güngör, T.; Hacıoğlu, N.; Önder, F. C.; Gülhan, Ü. G.; Tok, T. T.; Çelik, A.; Ay, M.*;

Koçkar, F.; European Journal of Medicinal Chemistry, 2020, 187, 111937.

5) Güngör, T.; Tokay, E.; Gülhan, Ü. G.; Hacıoğlu, N.; Çelik, A.; Koçkar, F.*; Ay, M.*, Bioorganic

Chemistry, 2020, 105, 104450.

6) Hacıoğlu, N.; Güngör, T.; Tokay, E.; Gülhan, Ü. G.; Çelik, A.; Ay, M.*; Koçkar, F.*, Chemistry

Select, 2021, 6, 6315 –6323.