DOSY NMR and MALDI‐TOF evidence of covalent binding the DNA duplex by trimethylammonium salts of topotecan upon near UV irradiation

Abstract

Using DOSY NMR and MALDI-TOF MS techniques, we present evidence that quaternary trimethylammonium salts of topotecan, [TPT-NMe3 ](+) X(-) (X = CF3SO3, HCOO), bind covalently the natural DNA oligomer upon near UV irradiation in water under physiological conditions. It is shown that formate salt is very reactive at pH 7 and requires short irradiation time. This weak irradiation at 365 nm paves the way for a new application of TPT derivatives in clinical use, which can dramatically increase the therapeutic effects of a medicine.

Spontaneous 2′-deoxyguanosine alkylation by a new generation of topoisomerase I inhibitors of the camptothecin family

“…be useful and have reported that the trimethylammonium salts of TPT alkylate DNA oligomers under near-UV irradiation. 16 Further attempts in this direction led us to the discovery of compounds that spontaneously bind to DNA oligomers and can therefore be used in vivo as Top I inhibitors in tumour chemotherapy. Scheme 2 shows the suggested course of a reaction in aqueous solution under near-biological conditions.…”

Preliminary study of mechanism of action of SN38 derivatives. Physicochemical data, evidence of interaction and alkylation of DNA octamer d(GCGATCGC)2

“…Camptothecins selectively bind to the binary covalent complex DNA‐Top I, however this is a weak interaction. Previous study has shown that trimethylamonium salts of TPT can undergo photochemical transformation to intermediate product such as quinone methide (QM), which can alkylate DNA oligomers . Here, we present synthesis, physicochemical studies of 9‐aminomethyl substituted SN38 derivatives, evidence of their interactions, and spontaneous alkylation of the natural DNA octamer.…”

The Mode of SN38 Derivatives Interacting with Nicked DNA Mimics Biological Targeting of Topo I Poisons

“… The part of the MALDI–MS spectrum of negative ions showing the mother peak for the neat parent nicked decamer, at m / z = 6885.8 ([M − H] − ), and a peak of the biohybrid of 2 with decamer 1 at m / z = 7290.9. The difference in masses M = 405 is due to transient intermediate o -methylene quinone formed from parent compound 2 or 3 [ 14 ]. …”

“…During the course of earlier research on camptothecin derivatives, we presented evidence for the formation of a molecular complex with the camptothecin core of topotecan (Hycamtin™), which occurred via selective interaction with the ultimate GC base pair in a natural DNA oligomer [ 12 ] and inside the nick of the model nicked DNA decamer [ 5 , 13 ]. Further studies [ 14 ] led us to disclose new SN38 derivatives that spontaneously alkylate DNA oligomers [ 15 , 16 , 17 ]. Covalent binding was confirmed in model 2′-deoxyguanosine (dG) [ 18 ], 2′-deoxycitidine (dC) [ 19 ], and 2′-deoxyadenosine (dA) [ 20 ] nucleosides.…”