Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region

The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.     

Design of a new oligotriazole peptide nucleic acid analogue (oT-PNA)

We describe in this Letter the synthesis of an original thymine azido-heterotrimer generated by Click Chemistry. This trimer has been obtained from an azido-thymidine and a new chloroethyl-propargylated PNA monomer analogue, after two azidation/click-reaction cycles. Conformational preferences of a rotameric intermediate have also been studied     

a,a,a,b-ZnT(o-BocThr)APP对咪唑衍生物和氨基酸酯的分子识别研究

Molecular Recognition of α,α,α,β-ZnT（o-BocThr）APP （1） toward a series of imidazole derivatives and amino acid esters was investigated. Association constants were determined in chloroform by means of UV-Vis titration method. The association constants of 1 with imidazole derivatives are larger than those of 1 with amino acid esters. 1H NMR spectra were investigated to describe the binding mode of the recognition system, showing that all the protons of the guests were shifted to upfield. The circular dichroism spectra of 1-L-/D-ValOMe showed a split cotton effect in Soret region, while those of 1-L-/D-PheOMe showed no split cotton effect. Molecular modeling was performed to understand chiral recognition on a molecular level. Quantum chemical calculation was carried out based on the stable conformations of these recognition systems, which gave a reasonable explanation for the behavior of molecular recognition. The results indicated that the conformation of 1-D-ValOMe was more stable than that of 1-L-ValOMe.     

Influence of N(1) protonation on the orientation of the N(6) substituent in hypermodified nucleic acid base N6-(N-glycylcarbonyl) adenine

The influence of protonation at N(1) on the conformational preferences of the N(6) substituent in the modified nucleic acid base N⁶-(N-glycylcarbonyl) adenine, gc⁶Ade, was investigated by the quantum chemical perturbative configuration interaction using localized orbitals (PCILO) method. The preferred orientation of the glycylcarbonyl substituent changes on the protonation of N(1). In the preferred conformation, the carbonyl oxygen O(10) is placed on the same side as N(1)H and provides stabilization through intramolecular hydrogen bonding of O(10) with HN(1). The amino acid component is so oriented that the carboxyl oxygen O(13b) is aligned closely with the N(6)H direction. Thus, the preferred molecular orientation is further stabilized by intramolecular hydrogen bonding involving HN(6) with O(13b). The alternative conformation has 0.5 kcal/mol higher energy than has the preferred conformation. The preferred conformation is about 1 kcal/mol more stable than is the conformation obtained by the flipping of torsion angle β alone, from the favored orientation for the unprotonated gc⁶Ade. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 62: 551–556, 1997     

DNA-, RNA- and self-pairing properties of a pyrrolidinyl peptide nucleic acid with a (2′R,4′S)-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid backbone

A new pyrrolidinyl peptide nucleic acid (PNA) comprising of an alternate sequence of 4′-nucleobase-modified proline with (2′R,4′S) configuration and a (1S,2S)-2-aminocyclopentanecarboxylic acid [(2′R,4′S)-acpcPNA] backbone was synthesized and its DNA-, RNA- and self-pairing properties studied. T_m and CD studies suggested that the (2′R,4′S)-acpcPNA forms antiparallel hybrids to DNA and RNA with high sequence and direction specificity. The stability of these hybrids is comparable to those of the (2′R,4′R)-acpcPNA hybrids previously reported by our group. On the other hand, experiments with a self-complementary sequence indicated that the new (2′R,4′S)-acpcPNA forms a more stable antiparallel self-hybrid than (2′R,4′R)-acpcPNA.     

The use of 3,3-bis(2-imidazolyl) propionic acid (bip-OH) as a new chelating ligand for Re(CO)3 and Ru complexes: Formation of organometallic PNA oligomers with (bip)Re(CO)3 and their interaction with complementary DNA

We report the use of 3,3-bis(2-imidazolyl) propionic acid (bip-OH, 1) as a new chelating bis(imidazole) ligand. The synthesis and full characterization of complexes Re(bip-O)(CO)₃2 and [Ru(bpy)₂(bip-OH)]²⁺3 is reported. Both complexes show interesting spectroscopic properties, namely IR for compound 2 and ¹H NMR for 3, respectively. The free carboxylic acid functionality of 1 may be used for the coupling to biomolecules. We have prepared two peptide nucleic acid (PNA) decamers to which the rhenium complex 2 is coupled. All reactions were carried out by solid phase synthesis methods. The Re-PNA oligomer conjugates Re(CO)₃(bip- tgt cta gca a -NH₂) 4 and Re(CO)₃(bip- agg agc aac t-Lys-NH₂) 5 were obtained in good yield and high purity after HPLC purification and identified by their mass spectra. The interaction of 5 with complementary DNA yields a melting temperature of (53.9 ± 1) °C. This is the first DNA melting temperature reported for an organometallic metal-PNA conjugate.     

Four Ni(II), Co(III), Cd(II) complexes based on 5-(pyrazol-1-yl)nicotinic acid: synthesis,X-ray single crystal structure,in vitro cytotoxicity,apoptosis and molecular docking studies

We have developed complexes [Ni₂(L)₂(H₂O)₄]_n (1), [Co₂(L)₂(H₂O)₄]_n (2), [Cd₂(L)₂(H₂O)₂Cl₂]n (3) and [Cd₂(L)₂(H₂O)₂]_n (4), where HL = 5-(pyrazol-1-yl) nicotinic acid. All complexes were characterized by elemental analysis, IR spectroscopy and single crystal X-ray diffraction, showing monoclinic crystal lattice with space group P2₁/c (1), P2₁/c (2), P2₁/c (3), and triclinic crystal lattice with space group P-1 (4), separately. In vitro antitumor screening (MTT method) revealed that 3 exhibited better inhibitory activities than the commercial anticancer drug cisplatin against HeLa tumor cell lines, with IC50 values 9?±?2. The bindings of these complexes with Fish Sperm DNA were measured by electronic absorption spectra and fluorescence spectroscopy, showing K_sq 0.1867 (1), 0.1589 (2), 0.2332 (3), and 0.1411 (4), with the binding affinities ranked 3?>?1 > 2?>?4. The experimental result showed that these complexes could bind DNA via intercalation. The ability of 1–4 to cleave the pBR322 plasmid DNA was demonstrated by gel electrophoresis assay. The experiment verified that these complexes could induce DNA damage. In addition, flow cytometric analysis showed that 1–4 induced apoptosis of HeLa tumor cell lines; as time increases, the apoptotic impact becomes increasingly significant. The potential of 1–4 as anticancer agents were examined using molecular docking of the complexes with DNA.

     

Protonated silanoic acid HSi(OH)2+ and its neutral counterpart: a tandem mass spectrometric and CBS-QB3 computational study

Protonated silanoic acid, HSi(OH)₂⁺, 1a ⁺, is cleanly generated by the dissociative electron ionization of triethoxysilane, HSi(OC₂H₅)₃, and tetraethoxysilane, Si(OC₂H₅)₄. This follows from tandem mass spectrometric experiments and CBS-QB3 model chemistry calculations. The calculations predict that 1a ⁺ (ΔH_f(298 K) = 205 kJ mol⁻¹) is separated by high barriers from its isomers HOSiOH₂⁺, 1b ⁺ and HSi(O)OH₂⁺, 1c ⁺. Low-energy (metastable) ions 1a ⁺ dissociate by loss of H₂O via the pathway 1a ⁺ → 1b ⁺ → SiOH⁺ + H₂O. Analysis of the metastable peak for this process confirms that the isomerization step 1a ⁺ → 1b ⁺ is rate determining. The calculations further predict that the incipient ions 1b ⁺ communicate via a low barrier with the proton-bound dimer SiO···H···OH₂⁺, 1d ⁺. This dimer ion is much lower in energy than its counterpart OSi···H···OH₂⁺, 1e ⁺, which is calculated to be only marginally stable. A comparison of the potential energy diagram for the silicon-containing ions 1a ⁺– 1e ⁺ with that of their carbon analogues reveals that the dissociation chemistries of HSi(OH)₂⁺ and HC(OH)₂⁺ are only superficially similar. Neutralization–reionization experiments confirm the theoretical prediction that the HSi(OH)₂^• radical (ΔH_f(298 K) = −455 kJ mol⁻¹) is a stable species in the rarefied gas phase. However, owing to a mismatch of Franck–Condon factors a large fraction of the neutralized ions dissociates by loss of H^• yielding Si(OH)₂. Copyright © 2004 John Wiley & Sons, Ltd.     

3-Aza-8,10-dioxa-bicyclo[5.2.1]decane (9-exo BTKa) carboxylic acid as a new reverse turn inducer: synthesis and conformational analysis of a model peptide

Dipeptide isostere 5, belonging to the class of 9-exo BTKa, was synthesised starting from R,R-tartaric acid and 4-nitro-1-(3-nitrophenyl)butan-1-one. The nine-membered lactam showed interesting structural features and was inserted in a 5-residue model peptide. The conformational properties of this modified peptide have been studied by NMR and molecular modelling, indicating that compound 5 acted as a reverse turn inducer.     

Diastereo- and enantioseparation of a N-Boc amino acid with a zwitterionic quinine-based stationary phase: Focus on the stereorecognition mechanism

A chiral chromatography method enabling the simultaneous diastereo- and enantioseparation of N^α-Boc-N⁴-(hydroorotyl)-4-aminophenylalanine [Boc-Aph(Hor)-OH, 1] was optimized with a quinine-based zwitterionic stationary phase. The polar-ionic eluent system consisting of ACN:MeOH:water—49.7:49.7:0.6 (v/v/v) with formic acid (4.0 mM) and diethylamine (2.5 mM), allowed the successful separation of the four acid stereoisomers: α_d,d-/d,l-1 = 1.08; α_d,l-/l,d-1 = 1.08; α_l,d-/l,l-1 = 1.40.     

Conformational change of proline residues observed in swollen and shrunken phases: γ‐Ray synthesis and variable temperature circular dichroism spectra of a thermo‐responding polymer,poly(acryloyl‐Pro‐OMe)

Poly(acryloyl‐L ‐proline‐methyl ester) ( 1 ) has optically active side chain, and constitutes thermoresponsive hydrogels upon crosslinking. In this study, we have prepared uncrosslinked polymer of 1 with a 10‐kGy irradiation dose of γ‐ray. For this polymer, 1 , variable temperature circular dichroism (CD) and ¹H NMR spectra have been studied in the range of 0–30 °C. The intense CD spectrum at 0 °C suggests that the side chains in 1 have an ordered orientation. The CD intensity decreases gradually with increasing temperature. The decreased intensity of CD spectra indicates that the disordering occurs for the side‐chain orientation. The CD band shape changes discontinuously at 20 °C. In the ¹H NMR spectra, signals disappear above 20 °C. These spectral change at 20 °C indicate that the phase transition occurs at around 20 °C from swollen to shrunken phase. Even after the phase transition, the CD spectra are still changing with isochromic point at 212 nm. It appears that the side‐chain conformation is still changing from one state to the other state in the shrunken phase polymers. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4524–4530, 2000     

The effect of amino acid backbone length on molecular packing: crystalline tartrates of glycine, β‐alanine, γ‐aminobutyric acid (GABA) and dl‐α‐aminobutyric acid (AABA)

We report a novel 1:1 cocrystal of β‐alanine with dl ‐tartaric acid, C₃H₇NO₂·C₄H₆O₆, (II), and three new molecular salts of dl ‐tartaric acid with β‐alanine {3‐azaniumylpropanoic acid–3‐azaniumylpropanoate dl ‐tartaric acid–dl ‐tartrate, [H(C₃H₇NO₂)₂]⁺·[H(C₄H₅O₆)₂]⁻, (III)}, γ‐aminobutyric acid [3‐carboxypropanaminium dl ‐tartrate, C₄H₁₀NO₂⁺·C₄H₅O₆⁻, (IV)] and dl ‐α‐aminobutyric acid {dl ‐2‐azaniumylbutanoic acid–dl ‐2‐azaniumylbutanoate dl ‐tartaric acid–dl ‐tartrate, [H(C₄H₉NO₂)₂]⁺·[H(C₄H₅O₆)₂]⁻, (V)}. The crystal structures of binary crystals of dl ‐tartaric acid with glycine, (I), β‐alanine, (II) and (III), GABA, (IV), and dl ‐AABA, (V), have similar molecular packing and crystallographic motifs. The shortest amino acid (i.e. glycine) forms a cocrystal, (I), with dl ‐tartaric acid, whereas the larger amino acids form molecular salts, viz. (IV) and (V). β‐Alanine is the only amino acid capable of forming both a cocrystal [i.e. (II)] and a molecular salt [i.e. (III)] with dl ‐tartaric acid. The cocrystals of glycine and β‐alanine with dl ‐tartaric acid, i.e. (I) and (II), respectively, contain chains of amino acid zwitterions, similar to the structure of pure glycine. In the structures of the molecular salts of amino acids, the amino acid cations form isolated dimers [of β‐alanine in (III), GABA in (IV) and dl ‐AABA in (V)], which are linked by strong O—H…O hydrogen bonds. Moreover, the three crystal structures comprise different types of dimeric cations, i.e. (A…A)⁺ in (III) and (V), and A⁺…A⁺ in (IV). Molecular salts (IV) and (V) are the first examples of molecular salts of GABA and dl ‐AABA that contain dimers of amino acid cations. The geometry of each investigated amino acid (except dl ‐AABA) correlates with the melting point of its mixed crystal.     

Preparation of a new chiral stationary phase for HPLC based on the (R)- 1-phenyl-2-(4-methylphenyl)ethylamine amide derivative of (S)-valine and 2-chloro-3,5-dinitrobenzoic acid: enantioseparation of amino acid derivatives and pyrethroid insecticides

A novel chiral stationary phase (CSP) for HPLC was prepared by bonding (R)-1-phenyl-2-(4-methylphenyl)ethylamine amide derivative of (S)-valine to aminopropyl silica gel through a 2-amino-3,5-dinitro-1-carboxamido-benzene unit. The CSP was used for the separation of some amino acid derivatives and pyrethroid insecticides by chiral HPLC. Satisfactory baseline separation required optimization of the variables of mobile phase composition. Use of dichloromethane as modifier in the mobile phase gave baseline separations of amino acid derivatives. The two enantiomers of fenpropathrin and four stereoisomers of fenvalerate were baseline separated using hexane-dichloromethane-ethanol as mobile phase. The results show that the enantioselectivity of the new CSP is better than Pirkle type 1-A column for these compounds. Only partial separations were observed for the stereoisomers of cypermethrin and cyfluthrin, which gave even and eight peaks, respectively.     

The first structurally analysed nucleic acid building block containing the Reese protecting group: 2′‐O‐[1‐(2‐fluorophenyl)‐4‐methoxypiperidin‐4‐yl]‐β‐D‐(1′R,2′R,3′R,4′R)‐uridine

The title compound, C₂₁H₂₆FN₃O₇, is assembled by N—H...O and O—H...O hydrogen bonds into well‐separated two‐dimensional layers of about 15 Å thickness. The crescent conformation of the molecules is stabilized by weak intramolecular C—H...O and C—H...F hydrogen bonds. The uridine moiety adopts an anti conformation. The ribofuranose ring exists in an envelope conformation. All the endocyclic uracil bonds are shorter than normal single C—N and C—C bonds, and five of them have comparable lengths, which implies a considerable degree of delocalization of the electron density within this ring.     

Gel‐to‐Sol and Sol‐to‐Gel Transitions Utilizing the Interaction of α‐Cyclodextrin with Dodecyl Side Chains Attached to a Poly(acrylic acid) Backbone

Summary: By utilizing the interaction of α‐cyclodextrin (α‐CD) with dodecyl side chains in polymers of x mol‐% dodecyl‐modified poly(acrylic acid) (p(AA/C₁₂(x))), systems that undergo gel‐to‐sol and sol‐to‐gel transitions were successfully constructed. Rheological experiments indicated that addition of α‐CD to the hydrogel of p(AA/C₁₂(5)) caused a drastic decrease in the viscosity, while addition of oligo(α‐CD) to the solution of p(AA/C₁₂(2)) led to a remarkable increase in the viscosity.

Photographs for a gel‐to‐sol transition upon addition of α‐CD to 5.0 g · L⁻¹ p(AA/C₁₂(5)).     

An unexpected skeletal transformation of 1,4-dihydroxythioxanthen-9-one on treatment with iodic acid: the first construction of the 2-(5-oxofuran-2-ylidene)-1-benzothienyl-3-one core

Treatment of 1,4-dihydroxythioxanthen-9-one with iodic acid gives, depending on the reaction conditions, predominantly either thioxanthen-1,4,9-trione or, unexpectedly, 2-(5-oxofuran-2(5H)-yliden)-1-benzothienyl-3(2H)-one. The latter is obtained in 60% yield.     

Effect of a copolymer poly(4-styrenesufonic acid-co-maleic acid) sodium salt on aggregation behavior of surface active ionic liquid 1-tetradecyl-3-methylimidazolium bromide and structurally similar conventional surfactant tetradecyltrimethylammonium bromide in aqueous media

The complex formation of anionic copolymer poly(4-styrenesufonic acid-co-maleic acid) sodium salt (PSSA-co-MA) with surfactant tetradecyltrimethylammonium bromide (TTAB) and surface active ionic liquid (SAIL) 1-tetradecyl-3-methylimidazolium bromide ([C₁₄mim][Br]) has been studied in aqueous media by utilizing various techniques such as tensiometry, conductometry and fluorimetry. Conductometric and tensiometric curve of all the investigated systems demonstrate four break points corresponding to four transition states. All the thermodynamic and surface properties of surfactant-polyelectrolyte systems have been determined by conductance and surface tension measurements respectively. The value of cmc decreases with increasing the concentration of polyelectrolyte for studied systems. But it has been observed that, the lowering in cmc values is more in [C₁₄mim][Br]-PSSA-co-MA system than TTAB-PSSA-co-MA system, although the differences in cmc are not much significant. The lowering in cmc of [C₁₄mim][Br]-PSSA-co-MA system shows that ionic attractions between cationic head group [C₁₄mim]⁺ and anionic parts (SO₃^? and COOH), are stronger than those in TTA⁺ and anionic parts (SO₃^? and COOH). The results indicated that the [C₁₄mim][Br]-PSSA-co-MA complexes are comparatively more surface active than TTAB-PSSA-co-MA complexes. The fluorescence probe behaviour also confirms cmc value and provides aggregation number (N_agg). Finally all the findings of [C₁₄mim][Br] and TTAB have been compared.     

A new protocol to synthesize 1,4-dihydropyridines by using 3,4,5-trifluorobenzeneboronic acid as a catalyst in ionic liquid: synthesis of novel 4-(3-carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines

3,4,5-Trifluorobenzeneboronic acid catalysed, ionic liquid mediated facile synthesis of 4-pyrazolyl 1,4-dihydropyridines at room temperature by the cyclocondensation of ethyl 3-aminocrotonate, pyrazole aldehyde and a β-keto ester is reported. The procedure adopted was found to be eco-benign, facile at room temperature and better than the conventional, [bmim]Cl mediated and InCl₃ catalysed, [bmim]Cl mediated 1,4-dihydropyridine syntheses.     

Chemical synthesis and structural elucidation of a new serotonin metabolite: (4R)-2-[(5′-hydroxy-1′H-indol-3′-yl)methyl]thiazolidine-4-carboxylic acid

A new serotonin (5-hydroxytryptamine) metabolite, (4R)-2-[(5′-hydroxy-1′H-indol-3′-yl)methyl]thiazolidine-4-carboxylic acid (5′-HITCA), was synthesized in 30% overall yield. The key step involved oxidation of protected 5-hydroxytryptophol using IBX followed by spontaneous cyclization with l-cysteine. The stereochemistry of condensation product thiazolidine-4-carboxylic acid was studied using NMR spectroscopy techniques.