Synthesis and biological evaluation of prodrugs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate.

We report in this Letter the synthesis of prodrugs of 2-fluoro-2-deoxyarabinose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate. We demonstrate the difficulty of realising a phosphorylation step on the anomeric position of 2-deoxyribose, and we discover that introduction of fluorine atoms on the 2 position of 2-deoxyribose enables the phosphorylation step: in fact, the stability of the prodrugs increases with the degree of 2-fluorination. Stability studies of produgs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate in acidic and neutral conditions were conducted to confirm our observation. Biological evaluation of prodrugs of 2,2-difluoro-2-deoxyribose-1-phosphate for antiviral and cytotoxic activity is reported.

Design, synthesis and biological evaluation of 2'-deoxy-2',2'-difluoro-5-halouridine phosphoramidate ProTides.

We report the synthesis of a series of novel 2'-deoxy-2',2'-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2'-deoxy-2',2'-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.

2'-Fluorosugar analogues of the highly potent anti-varicella-zoster virus bicyclic nucleoside analogue (BCNA) Cf 1743.

We report the preparation of 2'-alpha-F, 2'-beta-F and 2',2'-difluoro analogues of the leading anti-varicella zoster virus (VZV) pentylphenyl BCNA Cf 1743. VZV thymidine kinase showed the highest phosphorylating capacity for the beta-fluoro derivative, that retained equal antiviral potency as the parent compound. In contrast, the alpha-fluoro- and 2',2'-difluoro BCNA derivatives were markedly less (approximately 100-fold) antivirally active.

Synthesis of diiodo butadiynyl-bridged bisphthalocyaninatozinc(II) complexes.

Two functionalized phthalocyanine-based chromophore systems having two iodophthalocyaninatozinc(II) rings bound together through a butadiynyl linkage 1a,b have been synthesized by oxidative Eglinton coupling of the corresponding monomer, and fully characterized. The electronic characteristics of these extensively linearly pi-conjugated compounds were modulated by the introduction of different peripheral substituents into the phthalocyanine moieties and investigated by UV-visible spectroscopy. The reactivity of the two iodo substituents was explored to prepare a novel bisphthalocyanine containing two ethynylphenyl moieties, thus pointing out the possibility of incorporating other electro and/or photoactive moieties in the BisPc system, taking advantage of the iodo-functionalization.

Inhibition of pyrimidine and purine nucleoside phosphorylases by a 3,5-dichlorobenzoyl-substituted 2-deoxy-D-ribose-1-phosphate derivative.

The 3,5-dichlorobenzoyl-substituted 2-deoxy-D-ribose-1-phosphate derivative, designated Cf2891, was found to inhibit a variety of pyrimidine and purine nucleoside phosphorylases (NPs) with preference for uridine- and inosine-hydrolyzing enzymes [uridine phosphorylase (UP; EC 2.4.2.3), pyrimidine nucleoside phosphorylase (PyNP; EC 2.4.2.2) and purine nucleoside phosphorylase (PNP; EC 2.4.2.1)]. Kinetic analyses revealed that Cf2891 competes with inorganic phosphate (P(i)) for binding to the NPs and, depending on the nature of the enzyme, acts as a competitive or non-competitive inhibitor with regard to the nucleoside binding site. Also, the compound prevents breakdown of pyrimidine analogues used in the treatment of viral infections and cancer. Since NPs are abundantly present in tumor tissue and may be overexpressed due to secondary bacterial infections in immunocompromised patients suffering viral infections, Cf2891 may serve as a lead molecule for the development of inhibitors to be used in nucleoside-based combination therapy.

Evaluation of novel phosphoramidate ProTides of the 2'-fluoro derivatives of a potent anti-varicella zoster virus bicyclic nucleoside analogue.

BACKGROUND: Recently, the synthesis and antiviral activity of a series of 2'-fluoro derivatives of the most potent anti-varicella zoster virus (VZV) agent reported to date, the bicyclic nucleoside analogue Cf1743, have been reported. METHODS: Here, we present molecular modelling studies for the interaction of these compounds with VZV-encoded thymidine kinase (TK) and we report the synthesis of a series of phosphoramidate ProTides of these compounds designed to bypass the nucleoside kinase dependence of the parent nucleoside analogues. RESULTS: The phosphoramidate prodrugs were equally effective as their parent compounds against VZV in cell culture, but lost antiviral potency against TK-deficient VZV strains. CONCLUSIONS: ProTide-based kinase bypass is not successful in this case.

Synthesis and nonlinear optical properties of tetrahedral octupolar phthalocyanine-based systems.

Two series of tetrahedral phthalocyanine-based systems presenting a central carbon or silicon atom have been synthesized and fully characterized. Ethynyl spacers connect the peripheral Pc units to the central core. Some of the structures contain four identical Pc moieties, whereas other ones bear either an electron-withdrawing or an electron releasing group in the fourth subunit. The synthetic strategy consisted in metal mediated coupling reactions between tri-tert-butylethynylphthalocyanine and the corresponding methane or silane derivatives. A second-order nonlinear optical (NLO) study, through hyper-Rayleigh scattering measurements, reveals that, by combining centrosymmetrical moieties that are not second-order NLO active by themselves, in an octupolar fashion, a large second-order NLO response is achieved, in contrast to classical octupolar combinations of donor-acceptor NLO active dipolar moieties. In particular, the C-centered tetramer exhibits a large beta(HRS) value, which is among the highest reported so far for octupolar Pc-based molecules. Interestingly, carbon-centered molecules show a better NLO response with respect to the silicon-centered ones, probably due to a different effective symmetry, largely T(d) for the C-centered compounds and D(2d) for the Si-centered systems. While other design strategies for second-order NLO effects have always fundamentally kept on relying on the old dipolar paradigm (even though the resulting molecular structure was octupolar--the most striking exponent of this is the octupolar 1,3,5-triamino-2,4,6-trinitrobenzene molecule, a simple octupolar expansion of the dipolar p-nitroaniline), we here present for the first time that the octupolar symmetry by itself, realized by four nondipolar moieties in a tetrahedral arrangement, results also in a large second-order nonlinear response.

A bis(C60)-bis(phthalocyanine) nanoconjugate: synthesis and photoinduced charge transfer.

A novel dimeric phthalocyanine-C60 nanoconjugate, consisting of a bisphthalocyanine core to which two fullerenes are attached, has been prepared. The synthetic strategy implemented the preparation of a diformyl butadiynyl-bridged bisphthalocynaninato-zinc(II) complex by means of palladium-catalyzed cross-coupling reactions and subsequent dipolar cycloaddition reactions. Photophysical experiments confirm that an intramolecular electron transfer, namely, from the photoexcited ZnPc moiety to the electron-accepting C60 unit, governs the overall photoreactivity of the nanoconjugate. Through-space charge-transfer interactions facilitated by the close proximity of the ZnPc and the C60 moieties play a decisive role in determining the lifetimes of the charge-separated state which range from 10(-10) to 10(-9) seconds.

Synthesis and photoinduced electron-transfer properties of phthalocyanine-[60]fullerene conjugates.

A series of three novel ZnPc-C60 conjugates (Pc=phthalocyanine) 1 a-c bearing different spacers (single, double, and triple bond) between the two electroactive moieties was synthesized and compared to that of ZnPc-C60 conjugate 2, in which the two electroactive moieties are linked directly. The synthetic strategy- towards the preparation of 1 a-c- involved palladium-catalyzed cross-coupling reactions over a monoiodophthalocyanine precursor 4 to introduce the corresponding spacer, and subsequent dipolar cycloaddition reaction to C60. Detailed photophysical investigations of 1 a-c and 2 prompted an intramolecular electron transfer that evolves from the photoexcited ZnPc to the electron-accepting C60. In particular, with the help of femtosecond laser photolysis charge separation was indeed confirmed as the major deactivation channel. Complementary time-dependent density functional calculations supported the spectral assignment, namely, the spectral identity of the ZnPc(*+) radical cation and the C60 (*-) radical anion as seen in the differential absorption spectra. The lifetimes of the correspondingly formed radical ion-pair states depend markedly on the solvent polarity: they increase as polarity decreases. Similarly, although to a lesser extent, the nature of the linker impacts the lifetime of the radical ion-pair states. In general, the lifetimes of these states tend to be shortest in the system that lacks any spacer at all (2), whereas the longest lifetimes were found in the system that carries the triple-bond spacer (1 a).