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31.
S. M. Elizarov M. G. Alekseeva F. N. Novikov G. G. Chilov D. A. Maslov A. A. Shtil V. N. Danilenko 《Biochemistry. Biokhimii?a》2012,77(11):1258-1265
We demonstrate for the first time the role of phosphorylation in the regulation of activities of enzymes responsible for inactivation of aminoglycoside antibiotics. The aminoglycoside phosphotransferase VIII (APHVIII) from the actinobacterial strain Streptomyces rimosus ATCC 10970 is an enzyme regulated by protein kinases. Two serine residues in APHVIII are shown to be phosphorylated by protein kinases from extracts of the kanamycin-resistant strain S. rimosus 683 (a derivative of strain ATCC 10970). Using site-directed mutagenesis and molecular modeling, we have identified the Ser146 residue in the activation loop of the enzyme as the key site for Ca2+-dependent phosphorylation of APHVIII. Comparison of the kanamycin kinase activities of the unphosphorylated and phosphorylated forms of the initial and mutant APHVIII shows that the Ser146 modification leads to a 6–7-fold increase in the kanamycin kinase activity of APHVIII. Thus, Ser146 in the activation loop of APHVIII is crucial for the enzyme activity. The resistance of bacterial cells to kanamycin increases proportionally. From the practical viewpoint, our results increase prospects for creation of highly effective test systems for selecting inhibitors of human and bacterial serine/threonine protein kinases based on APHVIII constructs and corresponding human and bacterial serine/threonine protein kinases. 相似文献
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Valentina A. Ol’shevskaya Roza G. Nikitina Arina N. Savchenko Marina V. Malshakova Alexander M. Vinogradov Galina V. Golovina Dmitry V. Belykh Alexander V. Kutchin Mikhail A. Kaplan Valery N. Kalinin Vladimir A. Kuzmin Alexander A. Shtil 《Bioorganic & medicinal chemistry》2009,17(3):1297-1306
Chlorins, a class of plant porphyrins, are perspective as photosensitizing agents due to light absorption in the long wavelength spectral region and deeper photodamage of tissues. Aiming at optimization of antitumour properties of chlorins, we synthesized a series of boronated derivatives of chlorin e6 and their complexes containing Zn(II), Pd(II) or Sn(IV). The compounds were synthesized by alkylation of amino or hydroxy derivatives of chlorin e6 with 1-trifluoromethanesulfonylmethyl-o-carborane. Chlorin e6 13(1)-N-{2-[N-(o-carboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 5) formed complexes with serum albumin, a major porphyrin carrier. The binding constant of these complexes was ~4 times bigger than the respective value for the complexes of albumin with boron-free aminochlorin e6. Compound 5 potently sensitized rat fibroblasts to illumination with monochromatic red light: >98% of cells were necrotic by 24 h post-illumination with 1 μM of 5. This compound demonstrated high efficacy in photodynamic therapy of rat M-1 sarcoma. After PDT with 25 mg/kg of 5 the residual tumours were significantly smaller than in animals subjected to PDT with equal concentration of boron-free aminochlorin e6. No signs of general toxicity were detectable after PDT with 5. Thus, boronation can enhance the potency of chlorins in PDT, in particular, due to an increased binding to albumin. Our data expand the therapeutic applicability of boronated chlorins beyond boron neutron capture therapy; these agents emerge as dual efficacy photoradiosensitizers. 相似文献
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Belousov A. V. Morozov V. N. Krusanov G. A. Kolyvanova M. A. Shtil A. A. 《Biophysics》2019,64(1):23-30
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... 相似文献
35.
Lyudmila N. Lysenkova Konstantin F. Turchin Alexander M. Korolev Lyubov G. Dezhenkova Olga B. Bekker Alexander A. Shtil Valery N. Danilenko Maria N. Preobrazhenskaya 《Bioorganic & medicinal chemistry》2013,21(11):2918-2924
A novel way of chemical modification of the macrolide antibiotic oligomycin A (1) at the side chain was developed. Mesylation of 1 with methane sulfonyl chloride in the presence of 4-dimethylaminopyridine produced 33-O-mesyl oligomycin in 56% yield. Reactions of this intermediate with sodium azide produced the key derivative 33-azido-33-deoxy-oligomycin A in 60% yield. 1,3-Dipolar cycloaddition reaction with propiolic acid, methyl ester of propiolic acid, and phenyl acetylene resulted in 33-deoxy-33-(1,2,3-triazol-1-yl)oligomycin A derivatives substituted at N4 of the triazole cycle. The mesylated oligomycin A and 33-deoxy-33-azidooligomycin A did not inhibit F0F1 ATFase ATPase; however, 33-azido-33-deoxy-oligomycin A and the derivatives containing 4-phenyltriazole, 4-methoxycarbonyl-triazole and 3-dimethylaminoethyl amide of carboxyltriazole substituents demonstrated a high cytotoxicity against K562 leukemia and HCT116 human colon carcinoma cell lines whereas non-malignant skin fibroblasts were less sensitive to these compounds. Novel series of oligomycin A derivatives allow for the search of intracellular molecules beyond F0F1 ATP synthase relevant to the cytotoxic properties of this perspective chemical class. 相似文献
36.
Kaluzhny D Ilyinsky N Shchekotikhin A Sinkevich Y Tsvetkov PO Tsvetkov V Veselovsky A Livshits M Borisova O Shtil A Shchyolkina A 《PloS one》2011,6(11):e27151
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 (Kass∼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. 相似文献
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Shchekotikhin AE Dezhenkova LG Susova OY Glazunova VA Luzikov YN Sinkevich YB Buyanov VN Shtil AA Preobrazhenskaya MN 《Bioorganic & medicinal chemistry》2007,15(7):2651-2659
The efficacy of anthracycline based anticancer drugs is limited by pleiotropic drug resistance of tumor cells. Aiming at the design of anthracyclinone congeners capable of circumventing drug resistance, we synthesized naphthoindole containing derivatives of tryptophan and tryptamine. In doing so we adapted the traditional, gramine based approach for tryptophan and tryptamine synthesis. The most potent new compound, 3-(2-aminoethyl)-4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione (16), was equally cytotoxic (IC(50) within low micromolar concentrations) for human K562 leukemia and HCT116 colon carcinoma cell lines and their isogenic sublines with genetically defined determinants of altered drug response, that is, the expression of the multidrug transporter P-glycoprotein and loss of pro-apoptotic p53. Each of these mechanisms conferred resistance to the reference drug adriamycin. In contrast, naphthotryptamine 16, although less potent than adriamycin, was equally toxic for wild type cell lines and drug resistant counterparts. Moreover, at 3-5 microM 16 inhibited topoisomerase I in vitro. Thus, our novel naphthoindole based derivative of tryptamine gained new activities important for anticancer therapy, namely, suppression of topoisomerase I and the ability to overcome resistance mediated by P-glycoprotein expression and p53 dysfunction. 相似文献
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Ol'shevskaya VA Zaitsev AV Luzgina VN Kondratieva TT Ivanov OG Kononova EG Petrovskii PV Mironov AF Kalinin VN Hofmann J Shtil AA 《Bioorganic & medicinal chemistry》2006,14(1):109-120
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. 相似文献
40.
Yu. V. Dutikova O. F. Borisova A. K. Shchyolkina J. Lin S. Huang A. A. Shtil D. N. Kaluzhny 《Molecular Biology》2010,44(5):823-831
5,10,15,20-Tetra-(N-methyl-3-pyridyl)porphyrin (TMPyP3) is a DNA-binding derivative of porphyrins. A comparative study of
the binding of this ligand to biologically significant DNA structures was performed. For this purpose, the interactions of
TMPyP3 with the antiparallel telomeric G-quadruplex d(TTAGGG)4, oligonucleotide dTTAGGGTTAGAG(TTAGGG)2 (not forming a quadruplex structure), double-stranded d(AC)8 · d(GT)8, and single-stranded d(AC)8 and d(GT)8 DNA molecules have been studied. Analysis of absorption isotherms has demonstrated that the binding constants and the number
of binding sites for the complexes TMPyP3: DNA increase in the following order: d(AC)8 < d(GT)8 < d(AC)8 · d(GT)8 = d(TTAGGG)4 < dTTAGGGTTAGAG(TTAGGG)2. It has been for the first time demonstrated that the constant for TMPyP3 binding to unfolded dTTAGGGTTAGAG(TTAGGG)2 strand (1.3 × 107 M−1) is approximately threefold higher than for the G-quadruplex d(TTAGGG)4 (4.7 × 106 M−1). Binding of two TMPyP3 molecules to d(TTAGGG)4 decreases the thermostability of G-quadruplex (ΔTm = −8°C). Circular dichroism spectra of the TMPyP3 complexes with d(TTAGGG)4 suggest that the ligand partially unfolds the G-quadruplex structure. Structural destabilization of the telomeric G-quadruplex
by TMPyP3 can explain the relatively low activity of this ligand as a telomerase inhibitor and a low cytotoxicity for cultured
tumor cells. 相似文献