Stereoelectronic Effect on One-Electron Reductive Release of 5-Fluorouracil from 5-Fluoro-1-(2‘-oxocycloalkyl)uracils as a New Class of Radiation-Activated Antitumor Prodrugs

Abstract

A series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (eaq-) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-oxo substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-oxo compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(1) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the pi* orbital of C(5)-C(6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the pi* orbital of 2'-oxo substituent and the sigma* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2')=O pi* and C(1')-N(1) sigma* MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (pi* + sigma*) MO mixing.

Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics

“…14,15 Recently, we reported that 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine (5-FdUrd) derivatives possessing 2-oxoalkyl groups are radiation-activated prodrugs releasing representative antitumor agents 5-FU and 5-FdUrd, respectively, to cause effective cytotoxicity against hypoxic tumor cells. [16][17][18][19][20] Mechanistic studies showed that these prodrugs undergo reduction by capturing reducing hydrated electrons ðe À aq Þ generated by radiolysis of water. 21 This family of prodrugs are radiation-activated only in the hypoxic tumor cells, but not in the aerobic normal cells with sufficient oxygen concentration for trapping e À aq .…”

“…29 It is therefore evident that IQ-FdUrd is activated to release 5-FdUrd via reduction by e À aq occurring exclusively under hypoxic conditions, similar to the 5-FdUrd prodrugs possessing 2-oxoalkyl groups. [16][17][18][19][20] We also conducted laser flash photolysis studies on the reductive activation of IQ-FdUrd employing dimethylaniline (DMA) as an electron donor to get further mechanistic insight into the reductive release of 5-FdUrd. 30 Figure 3a shows the transient absorption spectra created in the 266 nm laser flash photolysis of IQ-FdUrd and DMA in phosphate buffer (pH 7.4).…”

Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

“…Recently, the concept of mutual prodrugs in which two different antineoplastic agents are coupled directly or by means of a spacer has become well accepted [8][9][10][11][12][13][14][15][16][17]. This technique can be used to overcome many problems including poor solubility or absorption, patient acceptability, drug instability and toxicity, and especially drug resistance [11].…”

“…Stock solution (10 µM) of samples was prepared in dimethylsulfoxide (DMSO) and diluted with various concentrations with serum-free culture medium. The in vitro antitumor activity of compounds 1-6 and 5-Fu were determined by MTT assay method [10]. Briefly, exponentially growing B16 or CHO cells were seeded in 96-well plates (5000 to each well) and allowed to attach overnight.…”

Synthesis and Biological Evaluation of New 4β-5-Fu-substituted 4'-Demethylepipodophyllotoxin Derivatives

“…To tackle these problems, numerous modifications of the 5-FU structure have also been performed. The N-1 or/and N-3 substituted derivatives, in particular, have exhibited improved pharmacological and pharmacokinetic properties, including increased bioactivity, selectivity, metabolic stability, absorption and lower toxicity [17][18][19][20][21][22].…”