Siritron Samosorn

Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group

Conjugation of the NorA substrate berberine and the NorA inhibitor 5-nitro-2-phenyl-1H-indole via a methylene ether linking group gave the 13-substituted berberine-NorA inhibitor hybrid, 3. A series of simpler arylmethyl ether hybrid structures were also synthesized. The hybrid 3 showed excellent antibacterial activity (MIC Staphylococcus aureus, 1.7 microM), which was over 382-fold more active than the parent antibacterial berberine, against this bacterium. This compound was also shown to block the NorA efflux pump in S. aureus.

Dual Action-Based Approaches to Antibacterial Agents

This review collates and analyses recent work done on dual action approaches to tackling the mounting health problem of resistance by human pathogenic bacteria to antibacterial agents. In particular the areas reviewed include the use of two drugs in combination, dual action prodrugs, and dual action drugs (or hybrid drugs).

8-Allyldihydroberberine as an Alternative Precursor for the Synthesis of 13-Substituted Berberine Derivatives

An alternative route to 13-substituted derivatives of the biologically active alkaloid berberine has been developed based on the key synthetic precursor, 8-allyldihydroberberine.

Azepines and their Fused-ring Derivatives

Azepines and their benz-fused derivatives have commanded a considerable amount of synthetic interest. This is particularly true of the latter systems because of their continuing pharmacological significance. Ring synthesis by ring construction is the dominant general approach, although a number of new ring transformation strategies have been developed. Amongst the ring construction strategies a flowering of methods based on ring closing metathesis is evident for type c and type d processes. There is scope also for extension of this methodology to type b processes. A novel zirconium-mediated approach to substituted azepanes has been described and this reaction has considerable further synthetic potential. The synthetic power of sequential reactions has also been demonstrated, for example in the synthesis of tetrahydro-1H-1-benzazepine derivatives. A single crystal X-ray structure of the first reported 2-azatropone is also a significant development.

ESI-MS Investigation of an Equilibrium between a Bimolecular Quadruplex DNA and a Duplex DNA/RNA Hybrid

AbstractElectrospray ionization mass spectrometry (ESI-MS) conditions were optimized for simultaneous observation of a bimolecular qDNA and a Watson-Crick base-paired duplex DNA/RNA hybrid. The DNA sequence used was telomeric DNA, and the RNA contained the template for telomerase-mediated telomeric DNA synthesis. Addition of RNA to the quadruplex DNA (qDNA) resulted in formation of the duplex DNA/RNA hybrid. Melting profiles obtained using circular dichroism spectroscopy confirmed that the DNA/RNA hybrid exhibited greater thermal stability than the bimolecular qDNA in solution. Binding of a 13-substituted berberine (1) derivative to the bimolecular qDNA stabilized its structure as evidenced by an increase in its stability in the mass spectrometer, and an increase in its circular dichroism (CD) melting temperature of 10°C. The DNA/RNA hybrid did not bind the ligand extensively and its thermal stability was unchanged in the presence of (1). The qDNA–ligand complex resisted unfolding in the presence of excess RNA, limiting the formation of the DNA/RNA hybrid. Previously, it has been proposed that DNA secondary structures, such as qDNA, may be involved in the telomerase mechanism. DNA/RNA hybrid structures occur at the active site of telomerase. The results presented in the current work show that if telomeric DNA was folded into a qDNA structure, it is possible for a DNA/RNA hybrid to form as is required during template alignment. The discrimination of ligand (1) for binding to the bimolecular qDNA over the DNA/RNA hybrid positions it as a useful compound for probing the role(s), if any, of antiparallel qDNA in the telomerase mechanism. Graphical Abstractᅟ

Synthesis and Structural Characterization of 1-(2-(5-Nitro-1H-indol-2- yl)phenyl)methylpyridinium Chloride

In the course of studies on hybrid antibacterials incorporating 2-aryl-5-nitro-1H-indole moieties as potential bacterial NorA efflux pump inhibitors, the compound 1-[2-(5-nitro-1H-indol-2-yl)phenyl]methylpyridinium chloride (2) was synthesized and structurally characterized. This pyridinium chloride salt crystallized in the monoclinic space group P21/c with the following unit cell dimensions: a 10.274(3) Å, b 13.101(4) Å, c 13.439(4) Å, β 107.702(7)°, V 1723.2(9) Å3, Z (f.u.) = 4; R1 = 0.048, and wR2 = 0.13. Of interest in the single crystal X-ray structure is the (intramolecular) disposition of the pyridinium plane over the indole heterocyclic residue [interplanar dihedral angle 17.91(4)°].

Photochemistry and mechanism of designed pyrenyl probe towards promoted cleavage of proteins

A new photochemical reagent, succinic acid-1(1-pyrene)methylamide (PMA-SUC), was developed to recognize the specific binding sites on model proteins, egg-white lysozyme and avidin. The interaction of the photochemical reagent with the proteins was studied by UV-Vis, fluorescence spectroscopic methods and docking description. PMA-SUC was found to bind to lysozyme and avidin with binding constants (Kb) of 2.4×105 and 6.7×105 (M-1), respectively. The fluorescence intensity of PMA-SUC decreased with increasing concentration of both proteins. Quenching of PMA-SUC fluorescence, in the absence and presence of the protein by an electron acceptor (Hexaamminecobalt(III) chloride, Co(NH3)6Cl3) showed no significant changes in the Ksv values (Stern-Volmer quenching constant), indicating that PMA-SUC bound to the hydrophilic sites or near the surface of the proteins. Irradiation of protein-PMA-SUC mixture, at 342nm for a period of time, in the presence of Co(NH3)6Cl3 as an electron acceptor, resulted in the cleavage of both proteins with high specificity. Binding mechanisms were studied using Molecular docking method. Molecular docking study indicated the position of PMA-SUC upon binding to the proteins by hydrogen bonding interaction with donor-acceptor within the distance of less than 5Å in the minimum of binding free energy. The docking results have supported the results obtained from the spectroscopic methods and cleavage studies.

1,2-Oxazepines and 1,2-Thiazepines

Although there has only been a modest interest in 1,2-oxazepines and 1,2-thiazepines and their benz-fused derivatives, there is considerable potential for further chemical and pharmacological exploration of this structural space. Ring-closing metathesis reactions have provided access to both 1,2-oxazepine and 1,2-thiazepine derivatives. Ring transformation reactions from six- to seven-membered rings via an intermediate cyclopropane fused system have been utilized for 1,2-oxazepine synthesis. This transformation forms a platform for further functionalization of the seven-membered ring system. A five- to seven-membered ring expansion has also been described for the preparation of a 1,2-benzothiazepine 1,1-dioxide derivative. A 1,2-benzothiazepine 1,1-dioxide system was also used as a springboard for accessing a novel ten-membered ring system through reaction with an aminoazirine derivative.

Tuning the chain length of new pyrene derivatives for site-selective photocleavage of avidin

Rational design of photoreagents with systematic modifications of their structures can provide valuable information for a better understanding of the protein photocleavage mechanism by these reagents. Variation of the length of the linker connecting the photoactive moiety with the protein anchoring-group allowed us to investigate the control of the protein photocleavage site. A series of new photochemical reagents (PMA-1A, PMA-2A and PMA-3A) with increasing chain lengths is examined in the current study. Using avidin as a model system, we examined the interaction of these probes by UV-Vis, fluorescence spectroscopic methods, photocleavage and computational docking studies. Hypochromism of the absorption spectrum was observed for the binding of these new photochemical reagents with estimated binding constants (Kb) of 6.2 × 105, 6.7 × 105 and 4.6 × 105 M-1, respectively. No significant changes of Stern-Volmer quenching constant (Ksv) with Co(NH3)6Cl3 has been noted and the data indicated that the probes bind near the surface of the protein with sufficient exposure to the solvent. Photoexcitation of the probe-avidin complex, in the presence of Co(NH3)6Cl3, resulted in protein fragmentation, and the cleavage yield decreased with the increase in the linker length, and paralleled with the observed Ksv values. Amino acid sequencing of the photofragments indicated that avidin is cleaved between Thr77 and Val78, as a major cleavage site for all the three photoreagents. This site is proximate to the biotin binding site on avidin, and molecular docking studies indicated that the H-bonding interactions between the polar end-group of the photoreagents and hydrophilic amino acids of avidin were important in positioning the reagent on the protein. The major cleavage site, at residues 77-78, was within 5 Å of the pyrenyl moiety of the probe, and hence, molecular tuning of the linker provided a simple approach to position the photoreagent along the potential photocleavage site.

1,3-Oxazepines and 1,3-Thiazepines

The 1,3-oxazepines and 1,3-thiazepines and their benz-fused derivatives have attracted some synthetic interest. Ring synthesis by ring construction is still an important avenue to these heterocycles. Typical of this approach are C–C bond formations to complete the heterocyclic ring using palladium-based methodology or metal complex-mediated ring closing metathesis to benz-fused oxazepines. There is much scope for extension of these metal-ion based ring cyclization approaches to oxazepines. The formation of C–O and C–S bonds underpin other cyclization approaches to 1,3-oxazepines and thiazepines respectively. The first route to a 1,3-selenazepane derivative was also described with ring cyclization after amine addition to a isoselenocyanate precursor. The Baeyer–Villiger ring expansion reaction still attracts some research attention, while other ring expansion methodologies to 1,3-oxazepines have been described, including a potentially adaptable insertion approach in 1,2-oxazines involving a cobalt carbonyl complex and carbon monoxide. This insertion reaction has considerable potential for further chemical and pharmacological exploration of this structural space.