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A new class of potent and highly selective antitumor agents has been synthesized. Bisimidazoacridones, where the tetracyclic ring systems are held together by either a N2-methyl-diethylenetriamine or 3,3′-diamino-N- methyldipropylamine linker, and related asymmetrical compounds, where one of the imidazoacridone ring system was replaced by a triazoloacridone ring system, were found to be cytostatic and cytotoxic in vitro. Some of these compounds, such as 5,5′-[(methylimino)bis(3,1-propanediylimino)]bis[6H- imidazo[4,5,1-de]acridin-6-one] (4b) showed remarkably high activity and selectivity for colon cancer in the National Cancer Institute screen. This antitumor effect was also apparent in colony survival assays utilizing the colon cancer line, HCT-116, and in in vivo assays involving xenografts of tumor derived from HCT-116 in nude mice. The tested compounds exhibited relatively low acute toxicity and were well-tolerated by the treated animals. The bisimidazoacridones interact with nucleic acids in vitro but preliminary experimental and modeling data indicate that in spite of their structure, they may not be bis-intercalators. While the precise mode of action of these compounds is not yet understood, they appear to be excellent candidates for clinical development.

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Metal catalyst and ligand design,
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In order to determine whether there is an orientation preference of pyrrole-imidazole (Py-Im) polyamide dimers with respect to the 5′-3′ direction of the backbone in the DNA helix, equilibrium association constants (K(a)) were determined for a series of six-ring hairpin polyamides which differ with respect to substitution at the N and C termini. Affinity cleaving experiments using hairpin polyamides of core sequence composition ImPyPy-gamma-PyPyPy with an EDTA·Fe(II) moiety at the C-terminus reveal a single binding orientation at each formal match site, 5′-(A,T)G(A,T)3-3′ and 5′-(A,T)C(A,T)3-3′. A positive charge at the C-terminus and no substitution at the N-terminus imidazole affords the maximum binding orientation preference, calculated from K(a)(5′-TGTTA-3′)/K(a)(5′-TCTTA-3′), with the N-terminal end of each three-ring subunit located toward the 5′ side of the target DNA strand. Removal of the positive charge, rearrangement of the positive charge to the N-terminus or substitution at the N-terminal imidazole decreases the orientation preference. These results suggest that second generation design principles superimposed on the simple pairing rules can further optimize the sequence-specificity of Py-Im polyamides for double helical DNA.

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Boc-protected L-phenylalanine has been connected to a spacer-armed ureido-acetic acid derivative, which can form multiple supramolecular complexes with urea-adamantyl modified poly(propylene imine) dendrimers in chloroform. Complexes of this guest with several generations of urea-adamantyl dendrimers were prepared. The dendrimer-guest complexes were characterized in detail by 1H-NMR, 1H-1H-NOESY spectroscopy and mass spectrometry to prove their formation. Optical rotation experiments performed on different generations of dendrimer-guest complexes showed a constant positive value. These observations indicate that, though guest molecules decrease the flexibility at the periphery of the dendrimer upon binding, the amino acid at the terminus of the guest molecule retains its high local conformational freedom. This is in agreement with values found for covalently modified spacer-armed dendrimers.

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Four new complexes of the general formula [Co(Ln)Cl] (where Lnis dianion of pentadentate Schiff base ligand N,N?-bis(2-hydroxybenzylidene)-1,6-diamino-3-azahexane = H2L1, N,N?-bis(2-hydroxy-3-methoxy-benzylidene)-1,6-diamino-3-azahexane = H2L2, N,N?-bis(3-ethoxy-2-hydroxy-benzylidene)-1,6-diamino-3-azahexane = H2L3or N,N?-bis(2-hydroxybenzylidene)-1,7-diamino-4-methyl-4-azaheptane = H2L4) have been synthesized and characterized by elemental analyses, IR, UV?VIS. The redox properties have been studied by cyclic voltammetry. Moreover, the crystal structures of 1, 2 and 3 have been determined by X-ray diffraction and 1H NMR spectrum of 4 has been obtained.

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The synthesis and characterisation of the new macrocyclic ligand 6-methyl-2,6,10-triaza-[11]-12,25-phenathrolinophane (L1), which contains a triamine aliphatic chain linking the 2,9 positions of 1,10-phenanthroline and of its derivative L2, composed by two L1 moieties connected by an ethylenic bridge, are reported. Their basicity and coordination properties toward Cu(ii), Zn(ii), Cd(ii), Pb(ii) and Hg(ii) have been studied by means of potentiometric and spectroscopic (UV-Vis, fluorescence emission) measurements in aqueous solutions. L1 forms 1: 1 metal complexes in aqueous solutions, while L2 can give both mono- and dinuclear complexes. In the mononuclear L2 complexes the metal is sandwiched between the two cyclic moieties. The metal complexes with L1 and L2 do not display fluorescence emission, due to the presence of amine groups not involved in metal coordination. These amine groups can quench the excited fluorophore through an electron transfer process. The ability of the Zn(ii) complexes with L1 and L2 to cleave the phosphate ester bond in the presence has been investigated by using bis(p-nitrophenyl)phosphate (BNPP) as substrate. The dinuclear complex with L2 shows a remarkable hydrolytic activity, due to the simultaneous presence within this complex of two metals and two hydrophobic units. In fact, the two Zn(ii) act cooperatively in substrate binding, probably through a bridging interaction of the phosphate ester; the interaction is further reinforced by pi-stacking pairing and hydrophobic interactions between the phenanthroline unit(s) and the p-nitrophenyl groups of BNPP. The Royal Society of Chemistry 2006.

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Metal catalyst and ligand design,
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Supramolecular string of pearls: Polycationic ligands are designed to self-assemble into spherical pseudo-dendrimers that are capable of binding polyanionic heparin with affinities and binding modes similar to covalent nanostructures such as dendrimers and proteins (see picture; purple: heparin, red/blue: self-assembling ligand). Binding of the ligands to heparin induces nanoscale organization of the formed nanostructures.

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The synthesis of new polyamine derivatives containing dimeric quinoline (3a-c), cinnoline (4a-c) and phthalimide (7a-c and 8a-c) moieties is described. Three different polyamines: (1,4-bis(3-aminopropyl)piperazine (a), 4,9-dioxa-1,12-dodecanediamine (b), 3,3?-diamino-N-methyldipropylamine (c) were used as linkers. The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A375. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. Mainly cytostatic activity exerted as altered cell cycle profiles was observed at the concentrations causing about 50% reduction of adherent cell proliferation. Based on their structure as well as their biological activity, we assume that some of the newly synthesized compounds may act as DNA bisintercalators. This study might be useful for further designing and developing anticancer drugs with potent activities.

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Metal catalyst and ligand design,
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The invention provides a programmed death receptor 1 gene inhibitor and its preparation method and application. In particular discloses a method for suppressing programmed death receptor 1 expression of the compound and its pharmaceutically acceptable salt, a structure shown in formula I wherein A is selected from C or N; R1 Is selected from H, CH3 , (CH2 )3 – N (CH3 )2 , (CH2 )2 – N (CH3 )2 , CH2 – N (CH3 )2 , (CH2 )3 – N (CH3 ) CH2 CH2 NHR3 ; R2 Is selected from H, CH3 , R3 Is selected from H, CH3 , The invention discloses a polyamide molecule belongs to the polypeptide small molecule, can realize the chemical synthesis, is conducive to large-scale production, is PD1 function inhibition to provide more method. (by machine translation)

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The coordination behaviour of ligands containing the vitamin B6 vitamers [pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM) and their 5′-phosphates] is reviewed in the light of the structural information derived from X-ray studies. The review includes the complexes of the simple vitamers themselves or simple derivatives thereof; those of the Schiff bases resulting from their condensation with each other or with amino acids or other amino derivatives; and the metal compounds formed by hydrazones that contain the PL moiety. Taken together, these ligands exhibit a wide variety of coordination possibilities, the vitamer moiety usually playing a significant role. The biological relevance and therapeutic potential of some of these compounds are also reviewed.

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Six specific compounds having human neutrophil elastase inhibitory activity are disclosed, one of which has the structural formula wherein A- is a pharmaceutically acceptable anion. The compounds are useful inter alia for the treatment of inflammatory respiratory disease, and may be administered by inhalation.

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