Radiation- and photo-induced activation of 5-fluorouracil prodrugs as a strategy for the selective treatment of solid tumors

5-Fluorouracil (5-FU) is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5-FU has gastrointestinal and hematological toxicity. Many groups are searching for prodrugs with functions that are tumor selective in their delivery and can be activated to improve the clinical utility of 5-FU as an important cancer chemotherapeutic agent. UV and ionizing radiation can cause chemical reactions in a localized area of the body, and these have been applied in the development of site-specific drug activation and sensitization. In this review, we describe recent progress in the development of novel 5-FU prodrugs that are activated site specifically by UV light and ionizing radiation in the tumor microenvironment. We also discuss the chemical mechanisms underlying this activation.     

Hydrogen peroxide inducible DNA cross-linking agents: targeted anticancer prodrugs

The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylations. These compounds showed 60-90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H(2)O(2)-activated anticancer prodrugs.     

The fragmentation of ionized alkyl phenyl ethers

The energetics of olefin loss from ionized alkyl phenyl ethers have been determined by ionization and appearance energy measurements. It is concluded that the reaction is governed by one or more of three features: (i) the strength of the bond between the phenoxy radical and the alkyl ion; (ii) the ease of isomerization of the alkyl ions, chiefly by H-shifts therein, and (iii) the strength of the C? H bond (primary, secondary and tertiary) involved in the H transfer to oxygen which precedes the olefin loss. The possible participation in the reaction of distonic ions and proton bound radical-molecule pairs is also discussed.     

Dibenzotetraaza crown ethers: a new family of crown ethers based on o-phenylenediamine

Dibenzotetraaza (DBTA) crown ethers possess two o-phenylenediamine moieties. They are homologues of dibenzo crown ether phase-transfer catalysts and were prepared from the condensation of benzimidazoles with oligo(ethyleneglycol) dichlorides and oligo(ethyleneglycol) ditosylates. Compounds with ring sizes ranging from 18-crown-6 to 42-crown-14 were prepared. In addition, various altered benzimidizoles were used to produce DBTA crown ethers with modified substituents and ether bridges, as well as benzimidazolidine crown ethers. The synthetic approach presented here proved to be a convenient route to a new family of crown ethers with overall yields of up to 48% based on the benzimidazole. Yields for the ring-closing step were generally high, ranging from 51% to 94%, without the need for high-dilution conditions. Reaction of the DBTA crown ethers with alkyl and benzyl halides was found to be a facile way to obtain the corresponding tetra(N-organyl) compounds. Picrate extraction studies were carried out to determine phase-transfer catalytic capabilities. Extraction efficiencies for alkali-metal ions were lower than those for dibenzo-18-crown-6. Efficiencies were higher for other metal ions, with some selectivity for Pb(2+). Tetra(N-methyl) DBTA-18-crown-6 generally exhibited higher extraction efficiencies than its N-H analogue, but the selectivity was lower.     

Development of a fast and efficient ultrasonic-based strategy for DNA fragmentation

Several ultrasound-based platforms for DNA sample preparation were evaluated in terms of effective fragmentation of DNA (plasmid and genomic DNA)—ultrasonic probe, sonoreactor, ultrasonic bath and the newest Vialtweeter device. The sonoreactor showed the best efficiency of DNA fragmentation while simultaneously assuring no cross-contamination of samples, and was considered the best ultrasonic tool to achieve effective fragmentation of DNA at high-throughput and avoid sample overheating. Several operation variables were studied—ultrasonication time and amplitude, DNA concentration, sample volume and sample pre-treatment—that allowed optimisation of a sonoreactor-based strategy for effective DNA fragmentation. Optimal operating conditions to achieve DNA fragmentation were set to 100% ultrasonic amplitude, 100 μL sample volume, 8 min ultrasonic treatment (2 min/sample) for a DNA concentration of 100 μg mL⁻¹. The proposed ultrasonication strategy can be easily implemented in any laboratory setup, providing fast, simple and reliable means for effective DNA sample preparation when fragmentation is critical for downstream molecular detection and diagnostics protocols.     

Fluorous phase-transfer activation of catalysts: application of a new rate-enhancement strategy to alkene metathesis

Reactions of the bis(pyridine) complex (H2IMes)(Py)2(Cl)2Ru(=CHPh) and fluorous phosphines P(CH2CH2R(fn))3 (n = a, 6; b, 8; c, 10; R(fn) = (CF2)(n-1)CF3) give (H2IMes)(P(CH2CH2R(fn))3)(Cl)2Ru(=CHPh) (2a-c, 64-73%), which are analogs of Grubbs' second generation catalyst and effective alkene metathesis catalysts under organic monophasic and fluorous/organic biphasic conditions. The latter give rate accelerations, which are believed to arise from phase transfer of the dissociated fluorous phosphine.     

Oxidative fragmentation of bicyclic hydroxy silanes and stannanes: a strategy for the stereoselective synthesis of kainoids

The addition of tin or silicon nucleophiles to bicyclic enones generated by dearomatising cyclisation gives stannanes and silanes stereoselectively. These compounds may be fragmented under oxidative conditions to generate substituted pyrrolidines bearing C2 and C3 substituents closely related to those found in the kainoid series of cyclic amino acids.     

A biaryl cross-coupling strategy for functionalisation of benzocrown ethers

Preparation of (di)benzocrown-substituted aryl-zinc or -boron reagents and their palladium-catalysed cross-coupling with functionalised aryl halides is described for convenient synthesis of novel crown ether systems.     

Iminoboronates: a new strategy for reversible protein modification

Protein modification has entered the limelight of chemical and biological sciences, since, by appending small molecules into proteins surfaces, fundamental biological and biophysical processes may be studied and even modulated in a physiological context. Herein we present a new strategy to modify the lysine's ε-amino group and the protein's N-terminal, based on the formation of stable iminoboronates in aqueous media. This functionality enables the stable and complete modification of these amine groups, which can be reversible upon the addition of fructose, dopamine, or glutathione. A detailed DFT study is also presented to rationalize the observed stability toward hydrolysis of the iminoboronate constructs.     

Laser fragmentation in liquid medium: a new way for the synthesis of PbTe nanoparticles

Synthesis of PbTe nanoparticles has been performed by pulsed laser fragmentation of PbTe micron-sized powders in distilled water with a Nd:YAG laser. The influence of various experimental parameters (wavelength, treatment duration, and output energy) on the yield of fragmentation, the size and the crystallographic structure of the nanoparticles produced has been investigated. Characterization of the nanopowders was performed by X-ray diffraction analyses and transmission electron microscopy observations. Thanks to a careful control of the synthesis parameters, PbTe nanoparticles with an average diameter close to 6 nm and exhibiting a sharp distribution in size have been produced.     

Tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cages: a case of fragmentation versus cyclization

A new strategy for the synthesis of oxa- and aza-cage compounds based on tandem radical cyclizations is described. The iodides 1 lead to oxa-cages 3 after two tandem radical cyclizations. The ester 10aa on reaction with n-Bu₃SnH and AIBN gives rise to the oxa-cage 12aa after two tandem 5-exo-trig cyclizations. On the other hand, reaction of the ketones 17aa and 21 under similar conditions furnished the oxa-cages 20aa and 23, respectively, via a double 5-exo-trig tandem radical cyclization followed by fragmentation.     

Discovering antimalarials: a new strategy

Recent discoveries have uncovered some key processes that occur in the food vacuole of the malarial parasite. Consequently, new families of potential antimalarials that inhibit HRP-2, a hitherto unexplored drug target, were identified using a novel screening method.     

A new method for the preparation of diphenylmethyl ethers

Various diphenylmethyl ethers are prepared under mild conditions by using tri-diphenylmethyl phosphate as alkylating agent. O-Diphenylmethyl-L(?)-Lactic Acid is prepared by this method.     

Total synthesis of (-)-brevenal: a streamlined strategy for practical synthesis of polycyclic ethers

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)(2)-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by Suzuki-Miyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through Suzuki-Miyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.     

Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate

Sodium thiosulfate has been utilized as a rescuing agent for relief of the toxic effects of cisplatin and carboplatin. In this work, we characterized the kinetics of reactions of the trans-dichloro-platinum(IV) complexes cis-[Pt(NH₃)₂Cl₄], ormaplatin [Pt(dach)Cl₄] and trans-[PtCl₂(CN)₄]^2? (anticancer prodrugs and a model compound) with thiosulfate at biologically important pH. An overall second-order rate law was established for the reduction of trans-[PtCl₂(CN)₄]^2? by thiosulfate, and varying the pH from 4.45 to 7.90 had virtually no influence on the reaction rate. In the reactions of thiosulfate with cis-[Pt(NH₃)₂Cl₄] and with [Pt(dach)Cl₄], the kinetic traces displayed a fast reduction step followed by a slow substitution involving the intermediate Pt(II) complexes. The reduction step also followed second-order kinetics. Reductions of cis-[Pt(NH₃)₂Cl₄] and [Pt(dach)Cl₄] by thiosulfate proceeded with similar rates, presumably due to their similar configurations, whereas the reduction of trans-[PtCl₂(CN)₄]^2? was about 1,000 times faster. A common reduction mechanism is suggested, and the transition state for the rate-determining step has been delineated. The activation parameters are consistent with transfer of Cl⁺ from the platinum(IV) center to the attacking thiosulfate in the rate-determining step.     

The fragmentation of isotetronic acid O-methyl ethers under electron impact

The mass spectra of a series of methyl ethers of isotetronic acids have been examined and the modes of fragmentation rationalized on the basis of two general schemes.     

Aldolase antibody activation of prodrugs of potent aldehyde-containing cytotoxics for selective chemotherapy

Prodrugs of potent aldehyde analogues of the anticancer drug doxorubicin (Dox) were synthesized. These prodrugs were efficiently activated by antibody 93F3 and no drug formation was observed in the absence of 93F3 in either phosphate buffered saline or cell culture media. In the presence of antibody 93F3, these prodrugs were activated and decreased the proliferation of human cancer cells in in vitro proliferation assays.     

Photocaged permeability: a new strategy for controlled drug release

Light is used to release a drug from a cell impermeable small molecule, uncloaking its cytotoxic effect on cancer cells.     

Intramolecular dimers: a new design strategy for fluorescence-quenched probes

Fluorogenic probes dual-labeled with reporter and quencher dyes use a change in fluorescence to monitor biochemical events (e.g., substrate binding or enzyme digestion). Such events change the reporter-quencher distance, which affects fluorescence. Recently, it is has been shown that static quenching through intramolecular dimers is an important mechanism that can sometimes be more efficient than F?rster resonance energy transfer (FRET).