Purine Ring Research Articles

A Novel Tautomeric Polymorph of Anhydrous Guanine and Its Reversible Water Harvesting Property

Tautomeric isomerism is very important in DNA/RNA research, especially base-pair mismatches. However, the tautomeric polymorph of anhydrous guanine (AG) composed of a N7-G purine ring has never been reported in the literature. Herein, a novel crystal phase of anhydrous guanine consisting of a N9-G purine ring was obtained by dehydration of guanine monohydrate (GM) at 111 °C, termed dehydrated-GM, the first reported tautomeric polymorph of AG (N7-G). The dehydration/hydration transformation between GM and dehydrated-GM can be repeated more than 10 times without any observable phase damage. The dehydrated-GM can harvest 8 wt % water within 30 min at relative low humidity (below 20%). Furthermore, dehydrated-GM has long-term stability in a very dry environment when the temperature is in between RT and 150 °C. The channel structure of dehydrated-GM can enlighten the design of materials to harvest water from atmospheric air. The tautomeric polymorphism of N7-G and N9-G purine rings provides a new insight in nu...

Hydrophobic alkyl chains substituted to the 8-position of cyclic nucleotides enhance activation of CNG and HCN channels by an intricate enthalpy - entropy compensation

Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are tetrameric non-specific cation channels in the plasma membrane that are activated by either cAMP or cGMP binding to specific binding domains incorporated in each subunit. Typical apparent affinities of these channels for these cyclic nucleotides range from several hundred nanomolar to tens of micromolar. Here we synthesized and characterized novel cAMP and cGMP derivatives by substituting either hydrophobic alkyl chains or similar-sized more hydrophilic heteroalkyl chains to the 8-position of the purine ring with the aim to obtain full agonists of higher potency. The compounds were tested in homotetrameric CNGA2, heterotetrameric CNGA2:CNGA4:CNGB1b and homotetrameric HCN2 channels. We show that nearly all compounds are full agonists and that longer alkyl chains systematically increase the apparent affinity, at the best more than 30 times. The effects are stronger in CNG than HCN2 channels which, however, are constitutively more sensitive to cAMP. Kinetic analyses reveal that the off-rate is significantly slowed by the hydrophobic alkyl chains. Molecular dynamics simulations and free energy calculations suggest that an intricate enthalpy - entropy compensation underlies the higher apparent affinity of the derivatives with the longer alkyl chains, which is shown to result from a reduced loss of configurational entropy upon binding.

Metal-cation regulation of enzyme dynamics is a key factor influencing the activity of S-adenosyl-l-homocysteine hydrolase from Pseudomonas aeruginosa

S-adenosyl-l-homocysteine hydrolase from Pseudomonas aeruginosa (PaSAHase) coordinates one K+ ion and one Zn2+ ion in the substrate binding area. The cations affect the enzymatic activity and substrate binding but the molecular mechanisms of their action are unknown. Enzymatic and isothermal titration calorimetry studies demonstrated that the K+ ions stimulate the highest activity and strongest ligand binding in comparison to other alkali cations, while the Zn2+ ions inhibit the enzyme activity. PaSAHase was crystallized in the presence of adenine nucleosides and K+ or Rb+ ions. The crystal structures show that the alkali ion is coordinated in close proximity of the purine ring and a 23Na NMR study showed that the monovalent cation coordination site is formed upon ligand binding. The cation, bound in the area of a molecular hinge, orders and accurately positions the amide group of Q65 residue to allow its interaction with the ligand. Moreover, binding of potassium is required to enable unique dynamic properties of the enzyme that ensure its maximum catalytic activity. The Zn2+ ion is bound in the area of a molecular gate that regulates access to the active site. Zn2+ coordination switches the gate to a shut state and arrests the enzyme in its closed, inactive conformation.

Abstract LB-271: Antitumor activity of new epidermal growth factor receptor inhibitors in non-small cell lung and breast cancer

Abstract Non-small cell lung cancer (NSCLC) and breast cancer (BrCa) are two of the most common forms of cancer. Since EGFR and HER2 are proven to be key targets in cancer therapy, we have designed and synthesized new molecules, belonging to a distinct chemical category of the existing drugs. Lapatinib was selected as an ideal prototype compound for the design of new analogues with potential action against EGFR and HER2 due to its ability to target and inhibit both receptors with great selectivity and efficiency. Structural analogues of lapatinib were synthesized by replacing the central ring of quinazoline by purine or bioisosteric rings aiming to investigate and potentially ameliorate the biological and pharmacological action. For the preparation of the target molecules, synthetic pathways have been designed and developed, which allow their high yielding preparation. The potency of the various analogues was evaluated in vitro using the following methodologies: MTT cytotoxic assay, Western Blot and ELISA assays to evaluate the ability of the analogues to inhibit EGFR phosphorylation in comparison with the activity of lapatinib and cell uptake studies based on mass spectrometry techniques. From a pool of 12 different analogues, two compounds, an imidazopyridine and an imidazopyrimidine derivative had the highest potencies, which were comparable to lapatinib in the NSCLC cell line A549 and in the BrCa cell line HCC-1954 (using MTT cytotoxic assays average IC50 values of 3 μM & 30 μM, respectively versus 11 μM for lapatinib). The same compounds were also tested in the NSCLC cell line NCI-H1975, which harbours the L858R + T790M mutations responsible for resistance (average IC50 values of 10 μM & 30 μM, respectively versus 9 μM for lapatinib). In addition, by using Western Blot and ELISA assays the two agents were the most potent compared to lapatinib, as they caused 50% inhibition of pEGFR at a 10 μM concentration. We have shown that the imidazopyridine derivative enters the A549 cells at a relatively slower rate in comparison to lapatinib. Presumably the physicochemical properties of the analogue are responsible for its higher accumulation (at 48 h incubation intracellular concentration of 17 ng/100.000 cells versus 10 ng/100.000 cells for lapatinib). Encouraged by the preliminary results two key molecules with similar potency to lapatinib will undergo further evaluation in vivo to determine their pharmacokinetic characteristics using advanced mass spectrometric approaches and their efficacy in clinically relevant mouse models. Citation Format: ARIS DOUKATAS, Efthymios-Spyridon Gavriil, Theodoros Karampelas, Panagiotis Marakos, Nicole Pouli, Constantin Tamvakopoulos. Antitumor activity of new epidermal growth factor receptor inhibitors in non-small cell lung and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-271.

Structural Features of DNA G-Quadruplexes Revealed by Surface-Enhanced Raman Spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) has been successfully used for the label-free detection of single-stranded oligonucleotides. However, the detection of complex DNA secondary structures remains a challenge. Structural features of diverse DNA G-quadruplexes were investigated via a novel SERS method. As a result, a series of highly reproducible and sensitive SERS signatures featuring the structures of G-quadruplexes were obtained. For the first time, we reported remarkably enhanced SERS bands corresponding to purine ring breathing vibrations. Moreover, we observed that by measuring the intensity of the bands corresponding to intramolecular hydrogen bonds, we could quantitatively assess the stability of the G-quadruplexes. Because no labels on DNA strands were present as the experiments were carried out in the solution, the fingerprint peaks reflect the native, internal structure of the G-quadruplexes accurately. The method here detailed provides new insights into the promising applications of diverse DNA structural studies.

Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery.

Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites’ viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 μM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.

Chemistry of the 8-Nitroguanine DNA Lesion: Reactivity, Labelling and Repair.

The 8-nitroguanine lesion in DNA is increasingly associated with inflammation-related carcinogenesis, whereas the same modification on guanosine 3',5'-cyclic monophosphate generates a second messenger in NO-mediated signal transduction. Very little is known about the chemistry of 8-nitroguanine nucleotides, despite the fact that their biological effects are closely linked to their chemical properties. To this end, a selection of chemical reactions have been performed on 8-nitroguanine nucleosides and oligodeoxynucleotides. Reactions with alkylating reagents reveal how the 8-nitro substituent affects the reactivity of the purine ring, by significantly decreasing the reactivity of the N2 position, whilst the relative reactivity at N1 appears to be enhanced. Interestingly, the displacement of the nitro group with thiols results in an efficient and specific method of labelling this lesion and is demonstrated in oligodeoxynucleotides. Additionally, the repair of this lesion is also shown to be a chemically feasible reaction through a reductive denitration with a hydride source.

Raman spectroscopy and density functional theory study of energetically closely separated C2′‐endo and C3′‐endo pentose forms in purine nucleoside analogue drug‐gold conjugates

AbstractWe performed a vibrational analysis of a cyclin‐dependent kinase inhibitor as an anticancer drug using Raman spectroscopy and quantum mechanical calculations. BMK‐Y101, a purine nucleoside analogue cyclin‐dependent kinase inhibitor, was found to adsorb on gold nanoparticles as evidenced by ultraviolet–visible absorption spectroscopy. Density functional theory (DFT) calculations were introduced to examine the energetic stabilities of the tautomeric amino and imino purine rings as well as C3′‐endo and C2′‐endo pentose forms for the possible binding geometries to 6‐atom gold clusters. DFT calculations predicted that the N9 binding mode of the C2′‐endo amino purine conformer would be the most stable in coordination with the gold atoms, despite very small energy differences of 0.026 kcal/mol to the second stable conformer of the N1 coordinated state. Surface‐enhanced Raman scattering (SERS) spectra were analyzed with appropriate vibrational assignments according to the DFT calculations and potential energy distribution analysis. The vibrational band at ~1,460 cm−1, which can be ascribed to the ν(N9–C4)(20%) + ν(N3–C4)(13%) + ν(C10–C7)(12%) + ν(C7–C8)(12%) + ν(N3–C2)(11%) mode for the N9‐coordination on Au6, appeared to be the most prominent in the SERS spectra, as predicted from the DFT calculations. BMK‐Y101 appeared to be detached from gold nanoparticles efficiently not in cell culture media but in hepatocarcinoma cells. Our findings indicate that quantum mechanical DFT calculations can be successfully implemented to interpret the SERS spectral features of the nucleoside drug on Au surfaces.

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products.

Marine secondary metabolites with a purine motif in their structure are presented in this review. The alkylpurines are grouped according to the size of the alkyl substituents and their location on the purine ring. Aspects related to the marine source, chemical structure and biological properties are considered together with synthetic approaches towards the natural products and bioactive analogues. This review contributes to studies of structure–activity relationships for these metabolites and highlights the potential of the sea as a source of new lead compounds in diverse therapeutic fields.

When nucleoside chemistry met hypervalent iodine reagents.

There has been increasing use of hypervalent iodine reagents in the field of nucleoside chemistry. Applications span: (a) synthesis of nucleoside analogues with sulfur and seleno sugar surrogates, (b) synthesis of unusual carbocyclic and ether ring-containing nucleosides, (c) introduction of sulfur and selenium into pyrimidine bases of nucleosides and analogues, (d) synthesis of isoxazole and isoxazoline ring-containing nucleoside analogues, (e) involvement of purine ring nitrogen atoms for remote C-H bond oxidation, and (f) metal-catalyzed and uncatalyzed synthesis of benzimidazolyl purine nucleoside analogues by intramolecular C-N bond formation. This review offers a perspective on developments involving the use of hypervalent iodine reagents in the field of nucleoside chemistry that have appeared in the literature in the 2003-2017 time frame.

Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors.

Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor.

Ultrafast Nuclear Dynamics of Photoexcited Guanosine-5'-Monophosphate in Three Singlet States.

We report measurement of resonance Raman (RR) spectra of guanosine-5'-monophosphate (GMP), a DNA nucleotide at excitation wavelengths throughout its ππ* absorption band (Bb) in the 210-230 nm range. From these data, we constructed wavelength-dependent Raman intensity excitation profiles (REPs) for all observed modes. These profiles and the absorption spectrum were then modeled using self-consistent simulations based on the time-dependent wave packet propagation formalism. We inferred the initial structural dynamics of GMP immediately after photoexcitation in terms of dimensionless displacements. The simulations also provide linewidth-broadening parameters that in turn report on the time scale of dynamics. We compared deduced structural changes in the purine ring upon photoabsorption into the Bb state with those deduced for the two lowest lying ππ* (La and Lb at 280 and 248 nm, respectively) excited states of GMP. We find that excitation to the Lb state lengthens C6-N1 and C2═N3 bonds, which lie along the formation coordinate of various oxidative adducts but Bb excitation does not. We also find that photoabsorption by the Bb state weakens the C8-N9 bond and thus might assist imidazole ring opening via cleavage of the same bond. Electronic excitation to different ππ* states of the guanine chromophore results in contrasting structural changes; although absorption by the La and Lb states induces expansion of pyrimidine and contraction of imidazole rings, excitation results in overall shrinkage of both the rings. Computed absolute changes in internal coordinates imply that photoexcitation to any of the three singlet states of GMP does not lead directly to the formation of a cation radical of guanine.

A Simple Isomerization of the Purine Scaffold of a Kinase Inhibitor, Roscovitine, Affords a Four- to Seven-Fold Enhancement of Its Affinity for Four CDKs. Could This Be Traced Back to Conjugation-Induced Stiffenings/Loosenings of Rotational Barriers?

Roscovitine is an antitumor purine inhibitor of cyclin-dependent kinase CDK5, for which it displays submicromolar affinity. It reached phase IIb clinical trials in 2007. The search for analogues with improved kinase affinities led recently to an isomer, finisterine, having a nearly 10-fold greater affinity for both CDK5 and CDK9. It solely differs by the displacement of one nitrogen atom in the purine ring, from position 6 to position 9. This has no incidence on the intermolecular interaction of either drug with the neighboring sites that anchor the ring in the recognition site. Quantum chemistry calculations combined with conformational and topological analyses of the impact of the purine ring isomerization of roscovitine and finisterine on its conformational stability show that the modified electronic conjugation, on the other hand, results in a stiffening of the rotational barrier around the extracyclic C–NH bond of finisterine, vicinal to N9, and to which an aryl ring is connected, along with a loosening of the barrier around an extracyclic C6–C bond connecting to a shorter, hydrophobic arm. The first effect is proposed to lead to a lesser hydration entropy of solvation in the case of finisterine, thus to a facilitated desolvation term in the overall energy balances.

Progress of nitrogen-phosphorus bond biosynthesis study of naturally occurring phosphoramidates

Naturally occurring phosphoramidates, which contain nitrogen-phosphorus (N−P) bonds, show high structure similarity with cytoplasmic carboxylates and phosphates. Phosphoramidates exhibit wide bioactivity spectrum attributed to the role as inhibitor of certain necessary enzymes in cell cycle. Three N−P bond biosynthetic pathways, which are respectively catalyzed by MccB, adenylyl sulphate: ammonia adenylyltransferase (APSAT) and Pyruvate phosphate dikinase (PPDK) homologues, are reviewed here. (1) MccB, a homologue of E1 ubiquitin ligase, catalyzed the phosphorylation of the asparagine residue of Microcin C7 precursor peptide. It consumed one molecule of ATP for the cyclization of the asparagine residue to give a succinimide. Then, the succinimidyl nitrogen atom attacked the Pα of a second ATP molecule to create an adenosine monophosphate- N -succinimide moiety. Agrocin 84, dinogunellin and phosmidosine shared identical AMP-NHR structural moiety with Microcin C7. Unfortunately, the biosynthetic gene clusters of dinogunellin and phosmidosine have not been identified yet. Agrocin 84 contains two N-P bonds, the first one linked the amino group of 2,3-dihydroxy-4-methyl-pentanamide with the phosphate group of 3′dAMP, and the second one bridged the amino group of the 3′dAMP purine ring with the phosphate group on the phosphorylated D-glucofuranosyloxy- phosphoryl. Analysis of Agrocin 84 biosynthetic gene cluster showed that agnA is homologous to mccB gene. Based on structural similarity and gene homology, it was proposed that the first N−P bond biosynthetic pathway of agrocin 84 is similar to that of Microcin C7. (2) APSAT catalyzed ammonolysis of adenosine-5′-phosphosulfate to give adenosine- 5′-phosphoramidate (AMP-NH2) and sulfate. AMP-NH2 was discovered from the extracts of Chlorella pyrenoidosa , Dictyostelium discoideum , Euglena gracilis var. bacillaris , spinach, barley and Escherichia coli . This APSAT protein was isolated from Chlorella pyrenoidosa and the biochemical characters were investigated. To eukaryotes, human Fhit (Fragile Histidine Triad) showed adenylyltransferase activity as well. It not only catalyzed the hydrolysis of diadenosine triphosphate (ApppA) to form AMP and ADP, but also catalyzed the ammonolysis of ApppA to form AMP-NH2 and ADP. In the hydrolysis of ApppA to AMP and ADP catalyzed by Fhit, first, ApppA and Mg2+ covalently bound to the 96th histidine residue of Fhit to form Fhit-AMP covalent intermediate and released ADP; then Fhit-AMP was further hydrolyzed to form AMP and Fhit. The Fhit-AMP could also be aminolyzed to give AMP-NH2. A possible mechanism for Fhit-catalysed ammonolysis involving nucleophilic attacks of NH3 to the covalent histidine-bound enzyme- nucleosidyl intermediate. (3) PPDK catalyzed the phosphorylation of pyruvate with an intermediate in which a phosphate group was loaded on the conserved histidine residue of PPDK. PPDK homologues PhtL and AgnD were proposed to catalyze the N-P bonds formation of Phaseolotoxin and Agrocin 84, respectively. The Walsh group of Harvard University have hypothesized that the Phaseolotoxin N-P bond was formed by nucleophilic attack of ornithine free amino to the phosphate group attached to the histidine residue of PhtL. Similarly, it can be assumed that the amino group of 3′dAMP purine ring attacking the phosphate group of AgnD1 (or AgnD2) histidine residue, makes the second N-P bond of Agrocin 84. This is a novel hypothesis of the biosynthesis of the N-P bonds in naturally occurring phosphoramidates, while the detailed enzymatic reactions remain to be studied further.

Structural and biochemical characterization of the nucleoside hydrolase from C. elegans reveals the role of two active site cysteine residues in catalysis.

Nucleoside hydrolases (NHs) catalyze the hydrolysis of the N-glycoside bond in ribonucleosides and are found in all three domains of life. Although in parasitic protozoa a role in purine salvage has been well established, their precise function in bacteria and higher eukaryotes is still largely unknown. NHs have been classified into three homology groups based on the conservation of active site residues. While many structures are available of representatives of group I and II, structural information for group III NHs is lacking. Here, we report the first crystal structure of a purine-specific nucleoside hydrolase belonging to homology group III from the nematode Caenorhabditis elegans (CeNH) to 1.65Å resolution. In contrast to dimeric purine-specific NHs from group II, CeNH is a homotetramer. A cysteine residue that characterizes group III NHs (Cys253) structurally aligns with the catalytic histidine and tryptophan residues of group I and group II enzymes, respectively. Moreover, a second cysteine (Cys42) points into the active site of CeNH. Substrate docking shows that both cysteine residues are appropriately positioned to interact with the purine ring. Site-directed mutagenesis and kinetic analysis proposes a catalytic role for both cysteines residues, with Cys253 playing the most prominent role in leaving group activation.

Supra-molecular hydrogen-bonding patterns in a 1:1 co-crystal of the N(7)-H tautomeric form of N6-benzoyl-adenine with 4-hy-droxy-benzoic acid.

The asymmetric unit of the title co-crystal, C12H9N5O·C7H6O3, contains one mol-ecule of N6-benzoyl-adenine (BA) and one mol-ecule of 4-hy-droxy-benzoic acid (HBA). The N6-benzoyl-adenine (BA) has an N(7)-H tautomeric form with nonprotonated N-1 and N-3 atoms. This tautomeric form is stabilized by a typical intra-molecular N-H⋯O hydrogen bond between the carbonyl (C=O) group and the N(7)-H hydrogen on the Hoogsteen face of the purine ring, forming a graph-set S(7) ring motif. The primary robust R22(8) ring motif is formed in the Watson-Crick face via N-H⋯O and O-H⋯N hydrogen bonds (involving N1, N6-H and the carboxyl group of HBA). Weak inter-actions, such as, C-H⋯π and π-π are also observed in this crystal structure.

Submolecular Structure and Orientation of Oligonucleotide Duplexes Tethered to Gold Electrodes Probed by Infrared Reflection Absorption Spectroscopy: Effect of the Electrode Potentials.

Unique electronic and ligand recognition properties of the DNA double helix provide basis for DNA applications in biomolecular electronic and biosensor devices. However, the relation between the structure of DNA at electrified interfaces and its electronic properties is still not well understood. Here, potential-driven changes in the submolecular structure of DNA double helices composed of either adenine-thymine (dAdT)25 or cytosine-guanine (dGdC)20 base pairs tethered to the gold electrodes are for the first time analyzed by in situ polarization modulation infrared reflection absorption spectroscopy (PM IRRAS) performed under the electrochemical control. It is shown that the conformation of the DNA duplexes tethered to gold electrodes via the C6 alkanethiol linker strongly depends on the nucleic acid sequence composition. The tilt of purine and pyrimidine rings of the complementary base pairs (dAdT and dGdC) depends on the potential applied to the electrode. By contrast, neither the conformation nor orientation of the ionic in character phosphate-sugar backbone is affected by the electrode potentials. At potentials more positive than the potential of zero charge (pzc), a gradual tilting of the double helix is observed. In this tilted orientation, the planes of the complementary purine and pyrimidine rings lie ideally parallel to each other. These potentials do not affect the integral stability of the DNA double helix at the charged interface. At potentials more negative than the pzc, DNA helices adopt a vertical to the gold surface orientation. Tilt of the purine and pyrimidine rings depends on the composition of the double helix. In monolayers composed of (dAdT)25 molecules the rings of the complementary base pairs lie parallel to each other. By contrast, the tilt of purine and pyrimidine rings in (dGdC)20 helices depends on the potential applied to the electrode. Such potential-induced mobility of the complementary base pairs can destabilize the helix structure at a submolecular level. These pioneer results on the potential-driven changes in the submolecular structure of double stranded DNA adsorbed on conductive supports contribute to further understanding of the potential-driven sequence-specific electronic properties of surface-tethered oligonucleotides.

Cysteine-based 3-substituted 1,5-benzoxathiepin derivatives: Two new classes of anti-proliferative agents

Two distinct series of the 3-amino-1,5-benzoxathiepin scaffold, derived from L-cysteine, were synthesized and evaluated for their anti-proliferative activity in the breast cancer MDA-MB-231 and MCF-7 cells, and in the ovarian carcinoma SKOV-3 cell line. (3R)-Amino-3,4-dihydro-2H-1,5-benzoxathiepin [(R)-10] was diversified into two forms: (a) by incorporating different amino acids at its position 3, through an amide bond; and (b) by construction of the purine ring to give 6-chloro-9-[2-(3,4-dihydro-2H-1,5-benzoxathiepin-(3R)-yl)]-9H-purine [(R)-28]. Nevertheless, when the introduction of iodine was tried at position 2 of the purine ring of (R)-28, 2-{[2-(6-chloro-2-iodo-9H-purin-9-yl)prop-2-en-1-yl]thio}phenol (34) was obtained. Compound 34 shows activity against cancer cells. Interestingly, 34 inhibits mammosphere formation at the micromolar range, demonstrating activity against cancer stem cells. Although further studies of its targets and mechanism of action are needed, these findings support the therapeutic potential of this compound in cancer.

Thermally prepared ultrabright adenosine monophosphate capped gold nanoclusters and the intrinsic mechanism.

Gold nanoclusters (AuNCs) have been widely applied in fluorescence sensing, bioimaging and phototherapy. Although great progress has been made, the relatively low quantum yield (QY, <10%) in most currently reported AuNCs limits their application greatly. In the present study, adenosine monophosphate (AMP) capped gold nanoclusters (AuNC@AMP) are prepared by using a newly developed heating method in a short time (within 60 min), and are found to show a strong and stable luminescence emission in a relative high QY (14.52%). In addition, an in-depth investigation by employing infrared, 1H and 31P NMR spectroscopy has attributed the origin of such a high luminescence to both the binding of the purine ring and/or the phosphate moiety of AMP as well as their orientations at the gold core surface. In addition, electron-rich atoms such as nitrogen and oxygen, or group moieties such as -NH2 in the ligands can largely promote the luminescence emission of AuNCs. The present study reveals the intriguing generation of ultrabright luminescence from metal nanoclusters, and it will stimulate more research both on the fabrication and practical applications of luminescent metal NCs. With regard to the high QY of these AuNCs, they have great potential for biological applications as adenine is crucially important in life sciences.

Analysis of the [CuL n ]2+ and [CuG n ]2+ (n = 2–4) complex structures: Comparison with CID experiment and DFT calculation

The collision-induced dissociation (CID) of the copper-cytidine complex [CuL n ]2+ (L is cytidine, n = 2–4) shows that the inter-ligand proton transfer (PT) is the dominating process. This is quite different from the CID of copper-guanosine complex [CuG n ]2+ (G is guanosine, n = 2–4), in which the inter-electron transfer (ET) dominates. The possible structures and zero-point energies for the majority of these structures were calculated using density functional theory (DFT) methods, and the ΔG Gibbs energy analysis of the CID processes also demonstrated the difference between the two complex structures. The results show that the steric hindrance effects and the intermolecular hydrogen bonds are the main reasons that cause the coordination between Cu(II) and the ligands of the cytidine and guanosine molecule. Cu(II) coordinates 4 ligands for [CuL n ]2+, forming the primary order sphere and presenting non-covalent bonding of the ligands. A greater steric effect was observed in the purine ring, which could be unstable if the guanosine molecules distributed around the copper ions to form coordination compounds. The [CuG n ]2+ complex tends to form intermolecular hydrogen bonds to enhance its structural stability by amino N and carbonyl O of purine ring.