Theoretical analyses and experimental validation of the effects caused by the fluorinated substituent modification of DNA

Abstract

Halogen-modified nucleic acid molecules, such as trifluorothymidine (FTD) and 5-fluorouracil, are widely used in medical science and clinical site. These compounds have a very similar nucleobase structure. It is reported that both of these compounds could be incorporated into DNA. The incorporation of FTD produces highly anti-tumor effect. However, it is not known whether to occur a significant effect by the incorporation of 5-fluorouracil. Nobody knows why such a difference will occur. To understand the reason why there is large differences between trifluorothymidine and 5-fluorouracil, we have performed the molecular dynamics simulations and molecular orbital calculations. Although the active interaction energy between Halogen-modified nucleic acids or and complementary adenine was increased, in only FTD incorporated DNA, more strongly dispersion force interactions with an adjacent base were detected in many thermodynamic DNA conformations. As the results, the conformational changes occur even if it is in internal body temperature. Then the break of hydrogen bonding between FTD and complementary adenine base occur more frequently. The double helix structural destabilization of DNA with FTD is resulted from autoagglutination caused by the bonding via halogen orbitals such as halogen bonding and the general van der Waals interactions such as CH-π, lone pair (LP)-π, and π-π interactions. Therefore, it is strongly speculated that such structural changes caused by trifluoromethyl group is important for the anti-tumor effect of FTD alone.Some types of nucleic acid modifications such as methylation and acetylation are known to directly affect the functions of DNA and RNA. These modifications play a critical role in DNA manipulation and can considerably affect DNA transcription and replication 1-4 . In addition, artificially modified nucleic acid molecules with halogen atoms, such as 5-fluorouracil (5FU) and trifluorothymidine (FTD), have been used in medical science and for clinical therapies 5-9 . The 5FU acts as an antitumor drug by inhibiting the formation of ribosomal RNA by its incorporation into RNA replacing uracil, or inhibiting DNA synthesis by preventing thymidylic acid synthesis 10-12 . Recent studies have shown that 5FU also gets incorporated into DNA, however, the association between this incorporation and the antitumor effects remains unknown. Conversely, FTD, which is incorporated with DNA, possesses a highly effective antitumor potency 13-15 although its structure is similar to that of thymidine. The combination of FTD and tipiracil hydrochloride (FTD/TPI) has been approved by some organizations, such as the FDA (Food and Drug Administration of the United States), as a treatment for colorectal cancer 16 . The reason why FTD has antitumor effect is not known yet, although many studies about it have been reported [17][18][19][20][21][22] . It is said today that the reason is not to form a covalent bond with thymidylate synthase 17 but to lead to DNA dysfunction by the incorporation of FTD into DNA from s...

Theoretical Prediction System of Stabilization Complex Conformation of DNA Binding Protein and the Binding Affinity for Each DNA Sequence

“…3B. Based on our previous theoretical predictions 16 , we validated the sequences with FTD substitutions at thymidine positions adjacent to electron-rich bases (Fig. 3C).…”

“…From our previous study, as shown in Fig. 2B, it is presumed that thymidine adjacent to adenine and guanine having a part of electron rich structure is likely to replace FTD in DNA replication 16 . This is because the uorine atoms at the tri uoromethyl group cause an attractive interaction with an electron-rich molecular orbital via a halogen bonding.…”

Influence of C5‐Substituents on Repair of O4‐Methyl Adducts of Pyrimidines by O6‐Alkylguanine DNA Alkyltransferases

“…Methylation at the O 4 ‐position for the CF 3 dU ‐ O 4 Me containing duplex reduced stability by approximately 10 °C, with a value slightly less than that observed for the C5‐halogenated series. It has been reported that the presence of C5‐trifluoromethyl‐2′‐deoxyuridine in DNA might affect its hydrogen‐bond properties thus influencing CF 3 dU :dA base pairing complementarity due to dispersion forces as well as altering interactions with neighboring bases [36] . Overall, for this series of halogens and trifluoromethyl group at the C5 position for the O 4 ‐methyl analogs, a minimal effect on the reduction of DNA duplex stability compared to T was observed [28] …”