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The acquisition of multidrug resistance (MDR) to chemotherapy is a major obstacle to successful cancer treatment. Aiming to improve the potency of anthraquinone-derived antitumor compounds against MDR cancer cells, we employed a rational design approach to develop new heteroarene-fused anthraquinones. Shifting the carboxamide group in the naphtho[2,3- f ]indole scaffold from the 3-position to 2 increased the lipophilicity and P-glycoprotein (P-gp) binding of the derivatives, potentially enhancing their ability to circumvent P-gp-mediated MDR. To validate the computations, we developed a scheme for heterocyclization into esters of naphtho[2,3- f ]indole-2-carboxylic acid, based on the 5- endo -dig cyclization of 2-alkynyl-3-amino-1,4-dimethoxyanthraquinone under mild basic conditions using tetra- n -butylammonium fluoride (TBAF). The synthesized naphthoindole-2-carboxamides, particularly compound 1a bearing (S)-3-aminopyrrolidine in the carboxamide fragment, demonstrated the highest antiproliferative activity. Most importantly, 1a suppressed the growth of the P-gp-positive K562/4 leukemia tumor cell line (resistance index = 2.4), while its 3-isomer LCTA-2640 and Dox did not (RI = 125 and 140, respectively). Studies of intracellular uptake and distribution showed that 1a , unlike its 3-substituted isomer, effectively accumulated in resistant tumor cells, confirming the correlation between in silico and experimental data. The lead compound 1a interacts with DNA duplex and inhibits topoisomerase 1 but does not induce oxidative stress. Treatment with 1a increases the population of apoptotic cells in both K562 and K562/4 sublines, regardless of the cell cycle phase. Taken together, this work provides an interesting example of how a little modification in chemical structure can lead to striking differences in antitumor properties. In conclusion, we have identified a potent class of compounds that offer distinct advantages in combating resistant tumor cells. [Display omitted] • A scheme for synthesis of naphtho[2,3- f ]indole-2-carboxylic acid has been developed. • Naphthoindole-2-carboxamides have increased lipophilicity, cellular accumulation and P-gp binding. • Compound 1a interacts with DNA duplex and inhibit topoisomerase 1 (Top1) inducing apoptosis of tumor cells. • Position of pharmacophore is critical for circumvention of P-gp resistance of tumor cells. [ABSTRACT FROM AUTHOR]

Quantum chemical techniques reasonable in practical simulation of carbon-centered radical reactions were evaluated scaling up from addition and cyclization of small radicals to growing chains in homo- , cross- and cyclo- polymerization. The methods preselected via “cost – deviation from experiment” criteria were explored relative to growing molecular systems of radical cyclocopolymerization between divinyl ether and maleic anhydride: alternating cross-propagation with cyclization and side homopolymerization reactions. The following methods were found to be optimal for estimation of activation barriers and thermodynamics parameters: DFT M06-2X with 6-311+G(d) and 6-311+G (2df,p) basis sets or ONIOM M06-2X/6-311+G(d):B3LYP/6-31G(d) – for more complex systems. Spin-restricted open shell calculations by ROMP2/6-311+G (3df, 2p) have shown unfeasible increase in computational costs retaining similar accuracy. The optimal techniques facilitated new mechanistic insights into regulating the polymerization including kinetic-thermodynamic control factors for regulation of furan-/pyran-related isomerism within the chain that is essential for tailoring functionality of the derivatives. The approach builds methodology basis for research of similar macromolecular systems including alike polymeric platforms for preparations of broad biomedical applications. [ABSTRACT FROM AUTHOR]

Abstract: A series of DNA aptamers bearing triazole internucleotide linkages that bind to thrombin was synthesized. The novel aptamers are structurally analogous to the well-known thrombin-inhibiting G-quadruplexes TBA15 and TBA31. The secondary structure stability, binding affinity for thrombin and anticoagulant effects of the triazole-modified aptamers were measured. A modification in the central loop of the aptamer quadruplex resulted in increased nuclease resistance and an inhibition efficiency similar to that of TBA15. The likely aptamer-thrombin binding mode was determined by molecular dynamics simulations. Due to their relatively high activity and the increased resistance to nuclease digestion imparted by the triazole internucleotide linkages, the novel aptamers are a promising alternative to known DNA-based anticoagulant agents. [Copyright &y& Elsevier]

The 8.3 at.% Yb-doped yttrium-scandium-aluminum garnet (YSAG) ceramics were fabricated by a modified reverse co-precipitation method followed by uniaxial and cold isostatic pressing, annealing in air and high-temperature sintering in vacuum. Spectroscopic and lasing properties were investigated in dependence on Y/Sc/Al ratio in ceramic composition. Optical transmission of Yb:YSAG ceramics in visible and near-infrared spectral range exceeds 80 % that indicates a high quality of the Yb:YSAG samples. Among all the ceramics, the Y 2.35 Yb 0.25 Sc 1.00 Al 4.40 O 12 composition demonstrates the best lasing performance and the highest slope efficiency up to 75 %. [ABSTRACT FROM AUTHOR]

The artificial nucleobase 7,8-dihydro-8-oxo-1, N 6-ethenoadenine (X) was investigated with respect to its ability to engage in Ag(I)-mediated base pairing in DNA. Spectroscopic data indicate the formation of dinuclear X –Ag(I) 2 – X homo base pairs and mononuclear X –Ag(I)– C base pairs (C , cytosine). Density functional theory calculations and molecular dynamics simulations indicate that the nucleobase changes from its lactam tautomeric form prior to the formation of the Ag(I)-mediated base pair to the lactim form after the incorporation of the Ag(I) ions. Fluorescence spectroscopy indicates that the two Ag(I) ions of the homo base pair are incorporated sequentially. Isothermal titration calorimetry confirms that the affinity of one of the Ag(I) ions is about tenfold higher than that of the other Ag(I) ion. The computational analysis by means of density functional theory confirms a much larger reaction energy for the incorporation of the first Ag(I) ion. The thermal stabilization upon the formation of the dinuclear Ag(I)-mediated homo base pair exceeds the one previously observed for the closely related nucleobase 1, N 6-ethenoadenine by far, despite very similar structures. This additional stabilization may stem from the presence of water molecules engaged in hydrogen bonding with the additional oxygen atom of the artificial nucleobase X. The highly stabilizing Ag(I)-mediated base pair is a valuable addition to established dinuclear metal-mediated base pairs. [Display omitted] • 7,8-Dihydro-8-oxo-1, N 6-ethenoadenine as a nucleobase for metal-mediated base pairs. • Formation of stable mono- and dinuclear Ag(I)-mediated base pairs. • Metal-mediated base pairs may contain synergistic hydrogen bonds. [ABSTRACT FROM AUTHOR]

Bisstyrylpyridine dyes 1 and 2 , in which two styrylpyridine moieties are connected to each other through the oxo- or azacrown ether unit, and their monomer analogues 3 and 4 have been synthesized and spectroscopically characterized. The prepared bisstyryl dyes 1 and 2 are the rare example of bisstyryls constructed in tail-to-tail mode. The binding of dyes 1 – 4 with salmon DNA has been evaluated using the UV–vis, CD, fluorescence, high-sensitivity differential scanning calorimetry, viscometric data and molecular modeling. The dyes were found to have negligible fluorescence in a buffer solution, but exhibited a significant emission increase upon binding to DNA. The results obtained are consistent with a groove binding mode between mono- and bisstyryls and DNA. [ABSTRACT FROM AUTHOR]

Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a ‘scaffold hopping’ approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3- f ]indole-5,10-dione 2 with an alternative anthra[2,3- b ]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3- b ]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3- f ]indole-5,10-dione 2 . At low micromolar concentrations the selected derivative of ( R )-3-aminopyrrolidine 3c and its stereoisomer ( S )-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro , indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the ‘scaffold hopping’ demonstrated its productivity for obtaining new perspective antitumor drug candidates. [ABSTRACT FROM AUTHOR]

A new theranostic agent of bacteriochlorin family has been synthesized by the reaction between 13 1 -(2-aminoethylcarbamoyl)bacteriochlorin e and N,N’ -di(carboxypentyl)dicarboindocyanine dye. The structure of the synthesized conjugate was confirmed by nuclear-magnetic resonance spectroscopy. In the conjugate, the efficient energy transfer from the dye to bacteriochlorin was observed. The yield of this process, which was shown to be ∼94%, allowed the dye still retain its ability to fluoresce. Accordingly, the fluorescence spectrum contained two major bands corresponding to fluorescence of bacteriochlorin (756 nm) and conjugated dye (672 nm). It was observed that the conjugate efficiently photosensitizes formation of singlet oxygen and photodynamic oxygenation of an organic compound. The data suggest that the obtained synthetic conjugate is promising for application in both fluorescence diagnostics and photodynamic treatment of tumors. [ABSTRACT FROM AUTHOR]

Abstract Derivatives of the anthraquinone (anthracene-9,10-dione) such as doxorubicin, mitoxantrone and others have proved great clinical efficacy for decades. Currently the search in this exceptionally productive chemical class is aimed at optimization of antitumor properties including circumvention of drug resistance. Previously we have reported that heteroarene-fused anthraquinones fused to a 5-membered heterocyclic ring are advantageous in killing drug resistant tumor cells. Herein we present the synthesis and antitumor properties of a series of new anthra[2,3- b ]furan-2-carboxamides. Vast majority of new derivatives were similarly cytotoxic to wild type tumor cell lines and their isogenic sublines with P-glycoprotein overexpression and/or p53 inactivation. Comparison of structurally close derivatives varying in their position relative to the furan moiety, that is, furan-3-carboxamide 1 vs furan-2-carboxamides 5 and 6 , revealed fundamental differences in the cytotoxicity profiles, formation of drug-DNA complexes, efficacy of topoisomerase 1 inhibition and mechanisms of tumor cell death. Together with previous SAR data on the role of individual substituents, these results provide evidence that regioisomerization of anthra[2,3- b ]furancarboxamides generates the practically perspective derivatives whose properties may vary significantly. Graphical abstract Image 1 Highlights • A series of new anthra[2,3- b ]furan-2-carboxamides was synthesized and evaluated. • Individual compounds were potent against wild type and drug resistant tumor cells. • Anthra[2,3- b ]furan-2-carboxamides inhibit topoisomerase 1-mediated DNA unwinding and induce apoptosis. • Position of the carboxamide moiety is important for antitumor properties. [ABSTRACT FROM AUTHOR]

Abstract Here, a combined molecular modelling methodology was used to identify the binding mode of 4,11-bis((2-guanidinoethyl)amino)anthra[2,3- b ]thiophene-5,10-dione (1), a previously reported G4 ligand. After calculating the optimal interaction parameters 1 with the target, two series of tri-armed ligands based on furan- or thiophene-fused anthraquinone scaffolds were designed and synthesized. The new compounds bearing an additional side chain at the 2-position of the heterocycle and the 4,11-side chains with different spacer lengths and structures of terminal groups demonstrated much stronger affinity for telomeric G4 (4–15 times) versus the parental ligand. Moreover, the specificity to the quadruplex over duplex DNA was significantly improved (up to 75 times) when the 3-guanidinopropyl side chain was introduced at the 2-position of the heterocycle ring. All tri-armed ligands demonstrated modest antiproliferative potency, which is likely due to low intracellular penetration. Nevertheless, this work shows how computer-aided rational design of new potent compounds can be used for targeted anticancer therapy. Graphical abstract Image 1 Highlights • Molecular modelling was applied for rational design of new G-quadruplex ligands. • Two series of G4 ligands were designed and synthesized. • Additional side "arm" provides stronger stabilization of telomeric quadruplex. • Modifications significantly improves specificity to the G4 over duplex DNA. • Compounds inhibit growth of cancer cells at micromolar concentrations. [ABSTRACT FROM AUTHOR]

Abstract: Bi+-doped single crystals of triple chloride CsCdCl3 were prepared by the Bridgman method. Bismuth monocation is responsible for characteristic two-peaked absorption feature in visible and long lived NIR luminescence in this crystal. The splitting of the Bi+ lowest electronic states by crystal field is considered. The absorption spectrum is assigned to optical transitions of A→E type in two nonequivalent Bi+ positions of D3h and C3v symmetry. The possibility of Jahn–Teller effect in Bi+ excited states of E type is discussed in relation with absorption and luminescence excitation spectra properties. [Copyright &y& Elsevier]

Abstract: Monocation Bi+ isomorphically substitutes potassium in KAlCl4 and KMgCl3 chlorides. Having the unique 6p2 open-shell electronic configuration, Bi+ possesses a number of low-lying excited states, and displays broadband long-lived NIR photoluminescence in ternary chloride crystals. [Copyright &y& Elsevier]

GelRed (GR) is a widely used nucleic acid-binding dye. It interacts with double-stranded DNA (dsDNA) via intercalation between the base-pairs, which enhances the dye's fluorescence. Binding of GR to single-stranded DNA (ssDNA) is much less efficient, yet the dye is still used for ssDNA staining in such applications as gel electrophoresis. The nature of GR interactions with ssDNA is not well understood. Here, preferential binding of GR to thymine-rich sequences was demonstrated, with ~20-fold increase in the dye's fluorescence in the presence of equimolar T 20 concentration. Based on pH and ionic strength dependences, electrostatic interactions with oligonucleotide backbone and hydrogen bonding between thymine and exocyclic amino groups of GR were proposed as likely stabilizing forces in GR-oligothymidylate binding. Lack of the C5-methyl group in dU 20 decreased GR affinity to the oligonucleotide ~2-fold. Molecular dynamic simulations were used to propose a possible structure of the GR-oligothymidilate complex. • Preferential binding of GelRed with oligothymidylate sequences. • Electrostatic interactions and hydrogen bonding stabilize the dye-oligothymidylate complexes. • Lack of the C5-methyl group decreases affinity of the oligonucleotide to GelRed. • Molecular dynamic simulation and docking shed light on GelRed-oligothymidylate complex. [ABSTRACT FROM AUTHOR]

Heteroarene-fused anthraquinone derivatives represent a class of perspective anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3- f indole-3- and anthra[2,3- b thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox , the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3- f indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused anthraquinones. Image 1 • A series of new anthrathiophene-3- and naphthoindole-3-carboxamides was synthesized. • Selected compounds were potent against wild type and drug resistant tumor cells. • Compound 8 binds DNA in vitro , inhibits topoisomerase 1 and induces apoptosis. • Antitumor potency in vivo demonstrates a prospect for lead optimization. [ABSTRACT FROM AUTHOR]