Abstract
Colorectal cancers (CRCs) which have elevated expression of the nucleotide pool cleanser
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
5,5-dinucleoside tetraphosphate P4-SedU2 (1 Figure 1 A) using mechanochemistry.
Figure 1. A Structure of selenium-substituted dinucleoside tetraphosphate substrate of
dUTPase. B Tumour volume plot of mice treated with: untreated (); 1 - 1.5 mg/kg (
RALA/1 - 1.5 mg/kg ().
); 2:1
Remarkably treatment of HCT116 CRC xenografted BALB/c SCID mice with 1 formulated
with the amphipathic peptide RALA (H-WEARLARALARALARHLARALARALRACEA-OH) Male
mice showed significant activity in controlling cancer growth. [3]
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,
N.; Englert, K.; Dunne, N. J.; Tucker, J. H. R.; Vyle, J. S.; McCarthy, H. O., JCR 2024, 369,
63-74
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
5,5-dinucleoside tetraphosphate P4-SedU2 (1 Figure 1 A) using mechanochemistry.
Figure 1. A Structure of selenium-substituted dinucleoside tetraphosphate substrate of
dUTPase. B Tumour volume plot of mice treated with: untreated (); 1 - 1.5 mg/kg (
RALA/1 - 1.5 mg/kg ().
); 2:1
Remarkably treatment of HCT116 CRC xenografted BALB/c SCID mice with 1 formulated
with the amphipathic peptide RALA (H-WEARLARALARALARHLARALARALRACEA-OH) Male
mice showed significant activity in controlling cancer growth. [3]
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,
N.; Englert, K.; Dunne, N. J.; Tucker, J. H. R.; Vyle, J. S.; McCarthy, H. O., JCR 2024, 369,
63-74
| Original language | English |
|---|---|
| Pages | 18 |
| Number of pages | 1 |
| Publication status | Published - Sept 2024 |
| Event | XXV International Round Table on Nucleosides, Nucleotides and Nucleic Acids - Katsushika Campus, Tokyo University of Science, Tokyo, Japan Duration: 03 Sept 2024 → 06 Sept 2024 https://www.irt2024.jp/ |
Conference
| Conference | XXV International Round Table on Nucleosides, Nucleotides and Nucleic Acids |
|---|---|
| Abbreviated title | IRT 2024 Tokyo |
| Country/Territory | Japan |
| City | Tokyo |
| Period | 03/09/2024 → 06/09/2024 |
| Internet address |
