Novel boronated derivatives of 5,10,15,20-tetraphenylporphyrin: synthesis and toxicity for drug-resistant tumor cells

We have developed the synthesis of boronated porphyrins for potential application in cancer treatment, based on the functional derivatives of 5,10,15,20-tetraphenylporphyrin. Boronated amide derivatives starting from 5,10,15,20-tetra(p-aminophenyl)porphyrin and 9-o- and 9-m-carborane carboxylic acid chlorides were prepared. Also, the reaction of 2-formyl-5,10,15,20-tetraphenylporphyrin with closo-C-lithium-o- and m-carboranes, as well as with closo-C-lithium monocarbon carborane, yielded neutral and anionic boronated hydroxy derivatives of 5,10,15,20-tetraphenylporphyrin, respectively. Water-soluble forms of neutral compounds were prepared by deboronation of closo-polyhedra with Bu4NF into nido-7,8- and nido-7,9-dicarbaundecaborate anions. Monocarbon carborane conjugated with copper (II) complex of 5,10,15,20-tetraphenylporphyrin was active for a variety of tumor cell lines (IC50 approximately 5 microM after 48-72 h of exposure) but was inert for non-malignant fibroblasts at up to 100 microM. At low micromolar concentrations, this compound caused the death of cells that express P-glycoprotein and other mechanisms of resistance to conventional anticancer drugs.     

Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione

Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K_ass∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na⁺ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K⁺ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.     

Role of the medium acidity in the complex formation of pyropheophorbide <Emphasis Type=Italic>a</Emphasis> with albumin and lipoproteins

The spectral characteristics of the photosensitizer pyropheophorbide a (PPP) complexes with its carriers, that is, serum albumin and low density lipoproteins, were investigated in aqueous solutions at pH 7.4 and 5.0. The acidic pH did not affect the quantitative parameters of PPP binding to lipoproteins, whereas the affinity to albumin decreased. Differential role of acidification in the binding of PPP to biomacromolecules should be considered in the design of PPP-based drugs, given that pH is frequently lowered in the sites of the disease.     

The Effect of Gold Nanoparticle Surface Modification with Polyethylene Glycol on the Absorbed Dose Distribution upon Irradiation with 137Cs and 60Co Photons

Biophysics - Abstract—Modification of the surface of gold nanoparticles with polyethylene glycol (PEG) is widely used to investigate radiosensitization in vivo. This modification may lead to...     

Synthesis and cytotoxicity of novel phosphorusless analogues of edelfosine

Modified series of phosphorusless edelfosine analogues bearing the polar heads of aliphatic bases, N,N-dimethylethanolamine and N,N,N1,N¹-tetramethylethylenediamine, were synthesized, with the length of the spacer varying from three to four methylene units. The cytotoxic characteristics of the compounds synthesized were studied.     

Synthesis and biological activity of homologous piperidine-containing alkyl glycerolipids

The paper provides the synthesis of new phosphorless glycerolipids with an ether bond that contain heterocyclic bases in the polar domain. The physico-chemical characteristics and biological activity of the prepared compounds were studied.     

Mitochondrial mechanisms of apoptosis in response to DNA damage

Genome integrity is essential for cell viability, while damage to the DNA structure is a key factor inducing cell death. Among all cell death programs, those involving mitochondrial proteins are of particular importance. Activation of various protective epigenetic mechanisms in response to DNA damage prevents cell death. The outcome of genotoxic stress—cell death versus survival—depends on the balance of proapoptotic and antiapoptotic signaling. This concept provides a rational basis for improving the efficacy of anticancer therapy by combining DNA-damaging exposures with inhibition of antiapoptotic mechanisms.