Synthetic profile of thiadiazoloquinazolines

According to the biological screening reports, a thiadiazoloquinazoline scaffold constitutes a promising source of inspiration for the synthesis of novel bioactive molecules. The current review article summarizes the most recent synthetic routes toward thiadiazoloquinazoline derivatives. According to the position of fusion between the thiadiazole and quinazoline rings, thiadiazoloquinazoline derivatives are classified into three major types, thiadiazolo[2,3-b]quinazolines, thiadiazolo[3,2-a]quinazolines and thiadiazolo[3,2-c]quinazolines.     

Engineered modular heterocyclic-diamidines for sequence-specific recognition of mixed AT/GC base pairs at the DNA minor groove

This report describes a breakthrough in a project to design minor groove binders to recognize any sequence of DNA. A key goal is to invent synthetic chemistry for compound preparation to recognize an adjacent GG sequence that has been difficult to target. After trying several unsuccessful compound designs, an N-alkyl-benzodiimidazole structure was selected to provide two H-bond acceptors for the adjacent GG-NH groups. Flanking thiophenes provide a preorganized structure with strong affinity, DB2831, and the structure is terminated by phenyl-amidines. The binding experimental results for DB2831 with a target AAAGGTTT sequence were successful and include a high ΔT_m, biosensor SPR with a K_D of 4 nM, a similar K_D from fluorescence titrations and supporting competition mass spectrometry. MD analysis of DB2831 bound to an AAAGGTTT site reveals that the two unprotonated N of the benzodiimidazole group form strong H-bonds (based on distance) with the two central G-NH while the central –CH of the benzodiimidazole is close to the –C O of a C base. These three interactions account for the strong preference of DB2831 for a -GG- sequence. Surprisingly, a complex with one dynamic, interfacial water is favored with 75% occupancy.

This report describes a breakthrough in a project to design minor groove binders to recognize any sequence of DNA.     

Small Sequence-Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

A series of small diamidines with thiophene and modified N-alkylbenzimidazole σ-hole module represent specific binding to single G⋅C base pair (bp) DNA sequence. The variation of N-alkyl or aromatic rings were sensitive to microstructures of the DNA minor groove. Thirteen new compounds were synthesized to test their binding affinity and selectivity. The dicyanobenzimidazoles needed to synthesize the target diamidines were made via condensation/cyclization reactions of different aldehydes with different 3-amino-4-(alkyl- or phenyl-amino) benzonitriles. The final diamidines were synthesized using lithium bis-trimethylsilylamide (LiN[Si(CH₃)₃]₂) or Pinner methods. The newly synthesized compounds showed strong binding and selectivity to AAAGTTT compared to similar sequences AAATTT and AAAGCTTT investigated by several biophysical methods including biosensor-SPR, fluorescence spectroscopy, DNA thermal melting, ESI-MS spectrometry, circular dichroism, and molecular dynamics. The binding affinity results determined by fluorescence spectroscopy are in accordance with those obtained by biosensor-SPR. These small size single G⋅C bp highly specific binders extend the compound database for future biological applications.     

Copper(I) 3-methylsalicylate,an efficient catalyst for N-arylation of heterocycles under moderate reaction conditions

Copper(I) 3-methylsalicylate mediates N-arylation reactions of both aliphatic and aromatic heterocycles under moderate reaction conditions. Both electron rich and electron poor aryl bromides and a diverse set of N-heterocycles were allowed to react and gave N-arylation products in high yields which demonstrated the efficiency and utility of this catalyst.     

Cephalosporin antibiotics as new corrosion inhibitors for nickel in HCl solution

Inhibition of nickel corrosion in 1 M HCl solution in the absence and presence of some Cephalosporin antibiotics derivatives was investigated using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and electrochemical frequency modulation (EFM) techniques. The results obtained show that the inhibition efficiency of these compounds depends on their concentrations and chemical structures. The inhibitive action of these compounds was discussed in terms of blocking the electrode surface by adsorption of the molecules through the active centers contained in their structures following the Langmuir adsorption isotherm. The polarization measurement showed that these inhibitors are acting as mixed inhibitors for both anodic and cathodic reactions. The effect of temperature on the rate of corrosion in the absence and presence of these compounds was also studied. The efficiencies obtained from the potentiodynamic polarization technique were in good agreement with those obtained from EIS and EFM techniques. This proves the validity of these tools in the measurements of the investigated inhibitors.     

Water-mediated binding of agents that target the DNA minor groove

Small molecule complexes with DNA that incorporate linking water molecules are rare, and the DB921-DNA complex has provided a unique and well-defined system for analysis of water-mediated binding in the context of a DNA complex. DB921 has a benzimidazole-biphenyl system with terminal amidines that results in a linear conformation that does not possess the appropriate radius of curvature to match the minor groove shape and represents a new paradigm that does not fit the classical model of minor groove interactions. To better understand the role of the bound water molecule observed in the X-ray crystal structure of the DB921 complex, synthetic modifications have been made in the DB921 structure, and the interactions of the new compounds with DNA AT sites have been evaluated with an array of methods, including DNase I footprinting, biosensor-surface plasmon resonance, isothermal titration microcalorimetry, and circular dichroism. The interaction of a key compound, which has the amidine at the phenyl shifted from the para position in DB921 to the meta position, has also been examined by X-ray crystallography. The detailed structural, thermodynamic, and kinetic results provide valuable new information for incorporation of water molecules in the design of new lead scaffolds for targeting DNA in chemical biology and therapeutic applications.     

The homological dimension of an abelian group as a module over its ring of endomorphisms. III

LetA be an abelian group; we denote byd(A) the homological dimension ofA as a module over its ringE of endomorphisms. In the present note we exhibit a groupA for whichgl dimE= andd(A)1, we show that there is a class of torsion-free groupsA of rank>2 for whichd(A)= and we construct an indecomposable torsion-free group of rankr which isE-isomorphic toE.This research was carried out with the support of the National Research Council of Canada (Grant #A7259) during the summer of 1972.     

Novel 2′-substituted amino-3-methoxy-16α-bromo-17-oxoestra-3,5(10)-dieno[1,2-b]thiazoles

A novel series of steroidal[1,2-b]thiazoles was synthesized by cyclization of several thiourea derivatives with bromine according to Hugerschoff synthesis. The H-nmr spectral analyses elucidating the structure of the products and the orientation of ring closure are reported.