Synthesis and anticancer activity of selenium-substituted dinucleoside tetraphosphate analogues

Colorectal cancers (CRCs) which have elevated expression of the nucleotide pool cleanser <br/>dUTPase have been found to have increased resistance to thymidylate synthase (TS) inhibitors such as 5-fluorouracil (5-FU) and this enzyme is therefore an attractive target for potentiating anticancer activity of chemotherapy.[1] dUTPase catalyses the hydrolytic cleavage of the anhydride bond between the - and -phosphoryl moieties and following the demonstration of rAp4dU as a substrate of dUTPase,[2] we prepared a novel, selenium-substituted symmetric <br/>5,5-dinucleoside tetraphosphate P4-SedU2 (1 Figure 1 A) using mechanochemistry. <br/> <br/>Figure 1. A Structure of selenium-substituted dinucleoside tetraphosphate substrate of <br/>dUTPase. B Tumour volume plot of mice treated with: untreated (); 1 - 1.5 mg/kg (<br/> RALA/1 - 1.5 mg/kg (). <br/><br/> ); 2:1 <br/>Remarkably treatment of HCT116 CRC xenografted BALB/c SCID mice with 1 formulated <br/>with the amphipathic peptide RALA (H-WEARLARALARALARHLARALARALRACEA-OH) Male <br/>mice showed significant activity in controlling cancer growth. [3] <br/>References: [1] Vértessy, B. G.; Tóth, J., Acc. Chem. Res 2009, 42, 97-106. [2] Ji, D. B., Beharry, A. A., Ford, J. M., Kool, E. T., J. Am. Chem. Soc. 2016, 138, 9005-9008. [3] Wilson, J. J., Bennie, L., Eguaogie, O., Elkashif, A., Conlon, P. F., Jena, L., McErlean, E., Buckley, <br/>N.; Englert, K.; Dunne, N. J.; Tucker, J. H. R.; Vyle, J. S.; McCarthy, H. O., JCR 2024, 369, <br/>63-74