Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated IrIII Complex Conjugated to a Far‐Red Emitting Coumarin

Although cyclometalated Ir^III complexes have emerged as promising photosensitizers for photodynamic therapy, some key drawbacks still hamper clinical translation, such as operability in the phototherapeutic window and reactive oxygen species (ROS) production efficiency and selectivity. In this work, a cyclometalated Ir^III complex conjugated to a far‐red‐emitting coumarin, Ir^III–COUPY, is reported with highly favourable properties for cancer phototherapy. Ir^III–COUPY was efficiently taken up by HeLa cells and showed no dark cytotoxicity and impressive photocytotoxicity indexes after irradiation with green and blue light, even under hypoxia. Importantly, a clear correlation between cell death and intracellular generation of superoxide anion radicals after visible light irradiation was demonstrated. This strategy opens the door to novel fluorescent photodynamic therapy agents with promising applications in theragnosis.     

Graft polymerization from a silica surface initiated by adsorbed peroxide macroinitiators. I. Adsorption and structure of the adsorbed layer of peroxide macroinitiators on a silica surface

The adsorption features of two peroxide macroinitiators (PMIs) with various functionalities from their semi-dilute solutions on the silica surface were thoroughly investigated in the present work. These investigations include the study of the adsorption kinetics of PMI in diverse solvents and a detailed examination of the adsorbed layer structure with the aid of ellipsometry, scanning force microscopy (SFM), and contact angle measurements. Rearrangements of PMI macromolecules at the solid surface are supposed to be the main reason for the appearance of extremes on the kinetic curves and, besides, have a more pronounceable effect on adsorption rate than their diffusion rate to the surface even at the initial stage of the process. Both island-like and densely packed structures of absorbed layers were revealed by combining contact angle measurements and SFM. Surprisingly, even in the case when saturation of the adsorbed layer is reached, PMI does not completely occupy the substrate surface which is at least particularly reachable for the wetting liquids. PMIs adsorbed at the solid surface are intended for the formation of tethered polymer "brushes" via the initiation of "grafting from" polymerization.     

Preparation of bis(heteroaryl)iodonium salts via an iodonium transfer reaction between di(cyano)iodonium triflate and organostannes

Di(cyano)iodonium triflate 5 generated in situ from iodosyl triflate (0 = I-OTf) and cyanotrimethylsilane is a preferred reagent for the preparation of various bis(heteroaryl)iodonium triflate salts 11–15 via an iodonium transfer reaction with the corresponding tributyltin substituted heterocycles 6–10 . Novel heteroaromatic iodonium salts 3, 11–15 were isolated in good yields as relatively stable microcrystalline solids and characterized by multinuclear nmr, ir and hrms data.     

Electrochemical behavior of natural and biosynthetic polynucleotides at the pyrolytic graphite electrode A new probe for studies of polynucleotide structure and reactions

The electrochemical oxidation of natural and biosynthetic polynucleotides at a pyrolytic graphite electrode (PGE) has been studied under differential pulse voltammetric conditions. Denatured DNA, ribosomal and transfer RNA give two voltammetric peaks. The first (more negative peak, peak G) corresponds to electrochemical oxidation of guanine residues where-as the second, more positive peak (peak A) corresponds to electrochemical oxidation of adenine residues. Native DNA gives rise only to a small peak A, peak G being totally absent. Denatured DNA and its voltammetric oxidation product are both strongly adsorbed at the PGE. Differential pulse voltammetric oxidation of natural and biosynthetic polynucleotides may provide a valuable technique for probing A-T and G-C regions during structural and conformational changes of these molecules and for following their interactions with other solution species.     

Electron Density Shift in Imidazolium Derivatives upon Complexation with Cucurbit[6]uril

In this study, we have investigated the supramolecular interaction between series of 1‐alkyl‐3‐methylimidazolium guests with variable alkyl substituent lengths and cucurbit[6]uril (CB6) in the solution and the solid state. Correct interpretation of ¹H NMR spectra was a key issue for determining the binding modes of the complexes in solution. Unusual chemical shifts of some protons in the ¹H NMR spectra were explained by the polarization of the imidazolium aromatic ring upon the complexation with the host. The formation of 1:1 complex between 1‐ethyl‐3‐methylimidazolium and CB6 is in disagreement with previously reported findings describing an inclusion of two guest molecules in the CB6 cavity.     

Factors Affecting DNA–DNA Interstrand Cross‐Links in the Antiparallel 3′–3′ Sense: A Comparison with the 5′–5′ Directional Isomer

Reported herein is a study of the unusual 3′–3′ 1,4‐GG interstrand cross‐link (IXL) formation in duplex DNA by a series of polynuclear platinum anticancer complexes. To examine the effect of possible preassociation through charge and hydrogen‐bonding effects the closely related compounds [{trans‐PtCl(NH₃)₂}₂(μ‐trans‐Pt(NH₃)₂{NH₂(CH₂)₆NH₂}₂)]⁴⁺ (BBR3464, 1 ), [{trans‐PtCl(NH₃)₂}₂(μ‐NH₂(CH₂)₆NH₂)]²⁺ (BBR3005, 2 ), [{trans‐PtCl(NH₃)₂}₂(μ‐H₂N(CH₂)₃NH₂(CH₂)₄)]³⁺ (BBR3571, 3 ) and [{trans‐PtCl(NH₃)₂}₂{μ‐H₂N(CH₂)₃‐N(COCF₃)(CH₂)₄}]²⁺ (BBR3571‐COCF₃, 4 ) were studied. Two different molecular biology approaches were used to investigate the effect of DNA template upon IXL formation in synthetic 20‐base‐pair duplexes. In the “hybridisation directed” method the monofunctionally adducted top strands were hybridised with their complementary 5′‐end labelled strands; after 24 h the efficiency of interstrand cross‐linking in the 5′–5′ direction was slightly higher than in the 3′–3′ direction. The second method involved “postsynthetic modification” of the intact duplex; significantly less cross‐linking was observed, but again a slight preference for the 5′–5′ duplex was present. 2D [¹H, ¹⁵N] HSQC NMR spectroscopy studies of the reaction of [¹⁵N]‐ 1 with the sequence 5′‐d{TATACATGTATA}₂ allowed direct comparison of the stepwise formation of the 3′–3′ IXL with the previously studied 5′–5′ IXL on the analogous sequence 5′‐d(ATATGTACATAT)₂. Whereas the preassociation and aquation steps were similar, differences were evident at the monofunctional binding step. The reaction did not yield a single distinct 3′–3′ 1,4‐GG IXL, but numerous cross‐linked adducts formed. Similar results were found for the reaction with the dinuclear [¹⁵N]‐ 2 . Molecular dynamics simulations for the 3′–3′ IXLs formed by both 1 and 2 showed a highly distorted structure with evident fraying of the end base pairs and considerable widening of the minor groove.     

Unprecedented cyclisations of calix[4]arenes under the Mitsunobu protocol. Part 3: Thiacalix[4]crowns versus dimers

Intermolecular couplings versus intramolecular ring closures were observed in the reaction of p-tert-butylthiacalix[4]arene and diethylene glycols affording dimers 2 and/or the inherently chiral 1,2-thiacalix[4]crown-3 derivatives 5 under the Mitsunobu protocol. The enantiomeric separation of 5a was achieved by chiral HPLC. The reaction of thiacalix[4]monocrowns 1 with diethylene glycols failed to give crowned thiacalix-tubes 7, instead biscrowns 8 were formed. Partially alkylated double thiacalix[4]arenes 10, 11 were obtained via the base promoted alkylations of a thiacalixarene dimer 2a containing diethyleneoxy linkers.     

Syntheses and Structures of RE10Ni9+xIn20 (RE = Tb,Dy) and YbNiIn2

The ternary indides RE₁₀Ni_9+xIn₂₀ (RE = Tb, Dy) were synthesized from the elements by arc‐melting under argon and subsequent annealing. YbNiIn₂ was prepared in a sealed tantalum tube in a water‐cooled sample chamber of a high‐frequency furnace. X‐ray powder and single crystal data revealed isotypism with the tetragonal Ho₁₀Ni₉In₂₀ type structure, space group P4/nmm for the RE₁₀Ni_9+xIn₂₀ compounds: a = 1337.0(2), c = 909.5(2) pm, wR2 = 0.0527, 1795 F² values, 65 variables for RE = Tb, and a = 1333.63(7), c = 907.2(1) pm, wR2 = 0.0590, 1346 F² values, 65 variables for RE = Dy. Both indides show an additional nickel site (Ni4) with partial nickel occupancy leading to the refined compositions Tb₁₀Ni_9.34(2)In₂₀ and Dy₁₀Ni_9.32(2)In₂₀. YbNiIn₂ adopts the orthorhombic MgCuAl₂‐type structure: Cmcm, a = 430.67(9), b = 1033.0(2), c = 758.1(1) pm, wR2 = 0.0262, 424 F² values and 16 variable parameters. The crystal chemistry of the RE₁₀Ni_9+xIn₂₀ and RENiIn₂ compounds is briefly discussed.