Purine Position Research Articles

Synthesis of 6-Selanyl-2-triazolylpurine Derivatives Using 2,6-Bistriazolylpurines as Starting Materials.

Two pathways toward 6-selanyl-2-triazolylpurine derivatives were designed. The first method involved the synthesis of 2-chloro-6-selanylpurine derivatives, further SNAr reaction with NaN3, and following CuAAC using different alkynes. The second method was based on the synthesis of 2,6-bistriazolylpurine derivatives as starting materials followed by SNAr reaction with commercial or in situ generated selenols as nucleophiles. A series of 2-chloro-6-selanylpurine derivatives were obtained in yields up to 84%. It was found that in the latter compounds, 6-selanyl moiety was the better leaving group compared to 2-chlorosubstituent in SNAr reactions. On the other hand, the SNAr reaction between 2,6-bistriazolylpurines and selenols or diselenides was successful, and 13 examples of 6-selanyl-2-triazolylpurine derivatives were obtained in yields up to 87%. This direct approach for the Se-C bond formation proved the ability of the 1,2,3-triazolyl ring at the C6 position of purine to act as a good leaving group.

Cisplatin-based combination therapy for cancer.

Cisplatin, that is, cis-diamminedichloroplatinum is a coordinate compound that is mainly preferred as prior treatment against several solid tumors and malignancies like ovaries, head and neck, testicular, and lung cancers because of its anticancer activity. Cisplatin binds at the N7 position of purine and forms adducts, leading to altered activity of DNA that triggers apoptosis. DNA damage is followed by several signaling pathways like induced oxidative stress, upregulated p53, mitogen-activated protein kinase (MAPK), and Jun N-terminal kinases (JNK) or Akt pathways along with induced apoptosis. Additionally, cisplatin treatment comes with few disadvantages such as toxic effects, that is, hepatotoxicity, cardiotoxicity, neurotoxicity, etc., and drug resistance. Furthermore, to overcome cisplatin resistance and toxicological effects, combination drug therapy has been considered. The aim of the review is to focus on the molecular mechanism of action of cisplatin and combination drug therapy to reduce the side effects in cancer therapy.

Metal‐Free, Light‐Mediated, Site‐Specific, Radical C6−H Alkylation of Purines with Alcohols Intervened by Oxalates without Catalysts

AbstractHerein, we report the development of a radical deoxy‐functionalization strategy for the direct C−H alkylation of purines and purine nucleosides with alcohols (1°, 2°, 3°) intervened by oxalates under 12 W blue LED irradiation. The reaction shows high regioselectivity at C6−H position of purine and is suitable for N9‐, N7‐substitued purines. The process accommodates purines and alcohols to deliver a wide range of products (31 examples) in 41–91 % yields, which avoids transition metal catalysts and organometallic reagents, and is not sensitive to moisture and air. Besides, the mild protocol displays broad functional groups tolerance and is easily up scalable to gram scale and can be used for late‐stage C−H alkylation of purine to synthesize pharmaceutical 6‐cyclopentyl nebularine with anti‐CEM activity or natural d‐menthol modification.

Hydrogen-bond locked purine chromophores with high photostability for lipid droplets imaging in cells and tissues

Recently, hydrogen-bonding has attracted extensive attention in the design of chromophores. Here, a new class of hydrogen-bond locked purine chromophores (HOPs) were reported by introducing a hydroxyphenyl group into the C(6) position of purine. The intramolecular hydrogen bond plays a dominant role to light up these probes. As a bonus, HOPs show high photostability. Moreover, HOPs exhibit remarkable capability for the specific lipid droplets imaging in living cells with excellent biocompatibility and are also potential for diagnosing fatty liver diseases. These results bring important new insights into the photophysics of the purine-based chromophores and provide a new scaffold with high photostability for bioimaging.

Structure-Based Design of 2-Aminopurine Derivatives as CDK2 Inhibitors for Triple-Negative Breast Cancer.

Cyclin-dependent kinase 2 (CDK2) regulates the progression of the cell cycle and is critically associated with tumor growth. Selective CDK2 inhibition provides a potential therapeutic benefit against certain tumors. Purines and related heterocycle (e.g., R-Roscovitine) are important scaffolds in the development of CDK inhibitors. Herein, we designed a new series of 2-aminopurine derivatives based on the fragment-centric pocket mapping analysis of CDK2 crystal structure. Our results indicated that the introduction of polar substitution at the C-6 position of purine would be beneficial for CDK2 inhibition. Among them, compound 11l showed good CDK2 inhibitory activity (IC50 = 19 nM) and possessed good selectivity against other CDKs. Further in vitro tests indicated that compound 11l possesses anti-proliferation activity in triple-negative breast cancer (TNBC) cells. Moreover, molecular dynamics simulation suggested the favorable binding mode of compound 11l, which may serve as a new lead compound for the future development of CDK2 selective inhibitors.

6-Morpholino- and 6-amino-9-sulfonylpurine derivatives. Synthesis, computational analysis, and biological activity

The synthesis of novel 6-chloro/morpholino/amino/-9-sulfonylpurine derivatives was accomplished in two ways, either (i) involving the condensation reaction of 6-chloropurine with commercially available arylsulfonyl chlorides in acetone and the presence of aqueous KOH at 0 °C, followed by the substitution of C6-chlorine with morpholine, or (ii) employing a reversed synthetic approach where 6-morpholinopurine and commercially available adenine bases were reacted with the corresponding alkyl, 2-arylethene and arylsulfonyl chlorides giving the N9 sulfonylated products, the latter particularly used where prior nonselective sulfonylation was observed. In both approaches, the sulfonylation reaction occurred regioselectively at the purine N9 position lacking any concurrent N7 derivatives, except in the case of a smaller methyl substituent on SO2 and the free amino group at C6 of the purine ring. The tautomeric features of initial N9 unsubstituted purines, as well as stability trends among the prepared N-9-sulfonylpurine derivates, were investigated using DFT calculations with an important conclusion that electron-donating C6 substituents are beneficial for the synthesis as they both promote the predominance of the desired N9 tautomers and help to assure the stability of the final products. The newly synthesized 6-morpholino and 6-amino-9-sulfonylpurine derivatives showed antiproliferative activity on human carcinoma, lymphoma, and leukemia cells. Among the tested compounds, 6-morpholino 17 and 6-amino 22 derivatives, with trans-β-styrenesulfonyl group attached at the N9 position of purine, proved to be the most effective antiproliferative agents, causing accumulation of leukemia cells in subG0 cell cycle phase.

1,2,3-Triazoles as leaving groups: SNAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles.

A new approach was designed for the synthesis of C6-substituted 2-triazolylpurine derivatives. A series of substituted products was obtained in SNAr reactions between 2,6-bistriazolylpurine derivatives and O- and C-nucleophiles under mild conditions. The products were isolated in yields up to 87%. The developed C–O and C–C bond forming reactions clearly show the ability of the 1,2,3-triazolyl ring at the C6 position of purine to act as leaving group.

Posttranscriptional modifications at the 37th position in the anticodon stem-loop of tRNA: structural insights from MD simulations.

Transfer RNA (tRNA) is the most diversely modified RNA. Although the strictly conserved purine position 37 in the anticodon stem–loop undergoes modifications that are phylogenetically distributed, we do not yet fully understand the roles of these modifications. Therefore, molecular dynamics simulations are used to provide molecular-level details for how such modifications impact the structure and function of tRNA. A focus is placed on three hypermodified base families that include the parent i6A, t6A, and yW modifications, as well as derivatives. Our data reveal that the hypermodifications exhibit significant conformational flexibility in tRNA, which can be modulated by additional chemical functionalization. Although the overall structure of the tRNA anticodon stem remains intact regardless of the modification considered, the anticodon loop must rearrange to accommodate the bulky, dynamic hypermodifications, which includes changes in the nucleotide glycosidic and backbone conformations, and enhanced or completely new nucleobase–nucleobase interactions compared to unmodified tRNA or tRNA containing smaller (m1G) modifications at the 37th position. Importantly, the extent of the changes in the anticodon loop is influenced by the addition of small functional groups to parent modifications, implying each substituent can further fine-tune tRNA structure. Although the dominant conformation of the ASL is achieved in different ways for each modification, the molecular features of all modified tRNA drive the ASL domain to adopt the functional open-loop conformation. Importantly, the impact of the hypermodifications is preserved in different sequence contexts. These findings highlight the likely role of regulating mRNA structure and translation.

Probing the DNA Reactivity and the Anticancer Properties of a Novel Tubercidin-Pt(II) Complex.

Herein, we reported on the synthesis of a novel Pt(II) neutral complex having as ligand the nucleoside tubercidin, a potent anti-tumor agent extracted from the bacterium Streptomyces Tubercidicus. In detail, the chelation of the metal by a diamine linker installed at C6 purine position of tubercidin assured the introduction of a cisplatin-like unit in the molecular scaffold. The behavior of the synthesized complex with a double-strand DNA model was monitored by CD spectroscopy and compared with that of cisplatin and tubercidin. In addition, the cell viability was evaluated against HeLa, A375 and WM266 human cancer cell lines using the MTT test. Lastly, the results of the apoptotic assay (FITC Annexin V) performed on the HeLa cancer cell line are also reported.

Discovery of Hybrid Purine-quinoline Molecules and Their Cytotoxic Evaluation

Background: Apart from the “hit drugs”, there are many others being studied for their potent activity against several hostilities. To date, anticancer research has been exploited on the inherent versatility and active core skeleton of the compounds. Literature suggests that nitrogen rich molecules are most active and found in their potent cancer activity. Purine-based compounds such as olomoucine and roscovitine, which contain other heterobicyclic ring systems, are useful for the cell proliferation inhibitors in the treatment of many types of cancer. Methods: We put forward the novel purine based compounds, aryl amino-quinoline-purine by a two-step procedure. In the first step, nitrogen rich molecule was synthesized by the coupling of 2,6- dichloropurine with 3-aminoquinoline in an acidic reaction conditions at the C-6 position of purine. Aryl amines were introduced at the C-2 position by acid catalyst and using polar solvent at comparatively higher reaction conditions to furnish the desired products. Results: Stereochemical aspect was introduced for the identification of attachment of 3- aminoquinoline at the C-2/ C-6 position of purine and it was concluded by the spectral analysis (HMBC spectrum). The spectral data revealed that the first chloro-amine coupling was directed at the C-6 position rather than C-2 and the second chloro-amine coupling by various aryl amines were directed at the C-2 position. The applications of synthesized compounds were identified by their cytotoxic study against NCI-60 cell-lines. Out of nine selected molecules by NCI, 5a has shown promising response in a single dose study and GI50 value, 7.57 µM indicated that it has 7.57% lethality over HOP-92 cell-line (non-small cell lung cancer panel). Conclusion: Two straightforward novelties were introduced, first stereochemical identification for chloro-amine coupling in purine either at the C-2 or C-6 position on the basis of HMBC spectrum. And a second type of uniqueness was to identify better anti-cancer agents out of synthesized scaffolds. Overall study shows that compound 5a is a novel therapeutic agent after modification for the treatment of non-small cell lung and it satisfied determined threshold growth inhibition criteria at a single dose level.

Synthesis and Evaluation of the Antiproliferative Properties of a Tethered Tubercidin–Platinum(II) Complex

AbstractHerein, the synthesis of a nucleoside platinum(II) complex in which a cisplatin‐like unit is joined to 7‐deazaadenosine through an amino alkyl chain installed at the C6 position of purine was explored. The capability of the new complex to react with DNA purine bases was confirmed by a model reaction with deoxyguanosine monophosphate, whereas its antiproliferative activity against A549 and Cal27 human cancer cell lines was studied by sulforhodamine B assay in comparison with its unplatinated precursor and cisplatin.

Structural and Mutational Analysis of Escherichia coli AlkB Provides Insight into Substrate Specificity and DNA Damage Searching

BackgroundIn Escherichia coli, cytotoxic DNA methyl lesions on the N1 position of purines and N3 position of pyrimidines are primarily repaired by the 2-oxoglutarate (2-OG) iron(II) dependent dioxygenase, AlkB. AlkB repairs 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions, but it also repairs 1-methylguanine (1-meG) and 3-methylthymine (3-meT) at a much less efficient rate. How the AlkB enzyme is able to locate and identify methylated bases in ssDNA has remained an open question.Methodology/Principal FindingsWe determined the crystal structures of the E. coli AlkB protein holoenzyme and the AlkB-ssDNA complex containing a 1-meG lesion. We coupled this to site-directed mutagenesis of amino acids in and around the active site, and tested the effects of these mutations on the ability of the protein to bind both damaged and undamaged DNA, as well as catalyze repair of a methylated substrate.Conclusions/SignificanceA comparison of our substrate-bound AlkB-ssDNA complex with our unliganded holoenzyme reveals conformational changes of residues within the active site that are important for binding damaged bases. Site-directed mutagenesis of these residues reveals novel insight into their roles in DNA damage recognition and repair. Our data support a model that the AlkB protein utilizes at least two distinct conformations in searching and binding methylated bases within DNA: a “searching” mode and “repair” mode. Moreover, we are able to functionally separate these modes through mutagenesis of residues that affect one or the other binding state. Finally, our mutagenesis experiments show that amino acid D135 of AlkB participates in both substrate specificity and catalysis.

Conformational effects of purine N3 electronic properties on drug design and cyclic nucleotide metabolism

The conformational effect of variations in electronic properties at the N3 position of purines, purine analogs, and cyclic AMP analogs are related to their biological properties. The effect of glycosidic conformation is demonstrated for the adenosine analogs 2-azaadenosine and 2-fluoroadenosine by both theoretical calculations and T1 relaxation measurements. For these two analogs there is increased preference for the high anti conformations. The high anti conformation is considered to be required of purine substrates by the enzymes adenosine kinase and deoxycytidine kinase as well as adenylate cyclase activating adenosine receptors. Protein kinase II is considered as requiring an anti conformation for activation by cyclic AMP analogs, and an anti conformation may also be required at adenylate cyclase inhibiting adenosine receptors. The selective activation approach for designing nucleoside analogs is described. Selective therapeutic potential as antiparasitic, antiviral, antibacterial, or anticancer agents can be achieved with nucleoside analogs. The successful implementation of the selective activation approach depends on a precise understanding of the conformation and electronic specificity of normal versus disease associated nucleoside kinases and deoxynucleoside kinases. The conformation specificity of normal adenosine kinase and deoxycytidine kinase enzymes appears to be established. Less specific or alternative pathways leading to the formation of toxic nucleotide analogs are known to exist in bacteria, parasites, virus infections, and cancer. If the conformational, electronic, and functional group requirements for normal enzyme activation are removed in a nucleoside analog, then it can be selectively activated to a toxic form by the enzyme mechanisms available to a target disease. The target disease, by converting a nucleoside analog to a toxic form, will destroy itself with little or no damage anticipated for the host.

The attachment of amino fragment to purine: inner-shell structures and spectra

The impact of the amino fragment (-NH(2)) attachment on the inner-shell structures and spectra of unsubstituted purine and the purine ring of adenine are studied. Density functional theory calculations, using the LB94/TZ2P//B3LYP/TZVP model, reveal significant site-dependent electronic structural changes in the inner shell of the species. A condensed Fukui function indicates that all of the N and C sites, except for N((1)) and C((5)), demonstrate significant electrophilic reactivity (f(-) > 0.5 in |e|) in the unsubstituted purine. Once the amino fragment binds to the C((6)) position of purine to form adenine, the electrophilic reactivity of these N and C sites is greatly reduced. As expected, the C((6)) position experiences substantial changes in energy and charge transfer, owing to the formation of the C-NH(2) bond in adenine. The present study reveals that the N1s spectra of adenine inherit the N1s spectra of the unsubstituted purine, whereas the C1s spectra experience significant changes although purine and adenine have geometrically similar carbon frames. The findings also indicate that the attachment of the NH(2) fragment to purine exhibits deeply rooted influences to the inner-shell structures of DNA/RNA bases. The present study suggests that some fragment-based methods may not be applicable to spectral analyses in the inner shell.

DNA−Protein Cross-links between Guanine and Lysine Depend on the Mechanism of Oxidation for Formation of C5 Vs C8 Guanosine Adducts

The reaction between N(alpha)-acetyllysine methyl ester (Lys) and 2'-deoxyguanosine (dGuo) was used to study structural aspects of DNA-protein cross-link (DPC) formation. The precise structure of DPCs depended on the nature of the oxidant and cross-linking reactions in which a series of different oxidation conditions generated a distribution of adducts, principally spirodiiminodihydantoins with lysine appended at the purine position of C5 (5-Lys-Sp), C8 (8-Lys-Sp), or both C5 and C8 (5,8-diLys-Sp). Singlet oxygen oxidation of dGuo produced 5-Lys-Sp exclusively when Rose Bengal or methylene blue was used to photochemically generate (1)O2 in the presence of Lys, whereas riboflavin or benzophenone-mediated photochemistry generated lysine radicals and led to C8 adduct formation, yielding 8-Lys-Sp and 5,8-diLys-Sp. Notably, the yield of dGuo modifications from riboflavin photooxidation increased dramatically in the presence of lysine. Oxidation of deoxyguanosine/lysine mixtures with Na2IrCl6 or sulfate radicals produced both 5-Lys-Sp and 8-Lys-Sp. The same adducts were formed in single and double-stranded oligodeoxynucleotides, and these could be analyzed after nuclease digestion. Adduct formation in duplex DNA was somewhat dependent on the accessibility of lysine to C5 vs C8 of the purine. No adduct formation was detected between lysine and the other nucleobases T, C, or A. Overall, the precise location of adduct formation at C5 vs C8 of guanine appears to be diagnostic of the oxidation pathway.

A Convenient Synthesis of New Purinyl‐homo‐carbonucleosides on a Cyclopentane Ring Fused with Pyridazine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Convenient Synthesis of New Purinyl-homo-carbonucleosides on a Cyclopentane Ring Fused with Pyridazine

The new purinyl homo-carbonucleosides 10 and 17a were prepared from 1,4-diphenyl-5,8-dihydro-5,8-methanophthalazine by one-pot ozonolysis and reductive cleavage, followed by monoprotection with an Ac or TBDMS group, mesylation of the resulting diol and replacement of the mesyl group with 6-chloropurine in the presence of NaH and 18-crown-6 ether. Homo-carbonucleosides 12 and 13 were then obtained from 10 by substitution of the chlorine in purine position 6. Compounds 17b and 19 were obtained from 17a in the same way.

Determinants of plant U12-dependent intron splicing efficiency.

Factors affecting splicing of plant U12-dependent introns have been examined by extensive mutational analyses in an in vivo tobacco (Nicotiana tabacum) protoplast system using introns from three different Arabidopsis thaliana genes: CBP20, GSH2, and LD. The results provide evidence that splicing efficiency of plant U12 introns depends on a combination of factors, including UA content, exon bridging interactions between the U12 intron and flanking U2-dependent introns, and exon splicing enhancer sequences (ESEs). Unexpectedly, all three plant U12 introns required an adenosine at the upstream purine position in the branchpoint consensus UCCUURAUY. The exon upstream of the LD U12 intron is a major determinant of its higher level of splicing efficiency and potentially contains two ESE regions. These results suggest that in plants, U12 introns represent a level at which expression of their host genes can be regulated.

Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid.

WE wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest. A structure for nucleic acid has already been proposed by Pauling and Corey1. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons: (1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other. (2) Some of the van der Waals distances appear to be too small. Another three-chain structure has also been suggested by Fraser

The influence of square planar platinum complexes on DNA base pairing. An ab initio DFT study

The energetics and structures of guaninecytosine (GC) and adeninethymine (AT) Watson–Crick base pairs metalated by the square planar platinum adducts trans-PtCl2(NH3), trans-PtCl(NH3)2+ and Pt(NH3)32+ at the N7 purine position have been investigated using advanced quantum chemical methods. The molecular complexes were optimized using Becke3LYP density functional theory (DFT) approach. For each base pair we evaluated two structures, one of them with and the other without the formation of intrasystem H bonds between the ligands attached to the metal and the exocyclic 6 position of the purine nucleobase. Interaction energies were evaluated and decomposed into individual pairwise and many-body terms. For some systems, the Becke3LYP approach provided biased interaction energy decomposition when including the correction for the basis set superposition error. Thus, these systems were re-evaluated with a second-order Møller–Plesset (MP2) perturbation approach resulting in correct decomposition. The calculations show, among other results, that the GC base pair is significantly strengthened by polarization effects when Pt(NH3)32+ is bound to its N7 position. This observation is in agreement with recent solution experiments on platinated base pairs. The calculations suggest that the effect exerted by Pt(NH3)32+ on the base pair stability is larger compared with the effect exerted by inner-shell binding of hydrated divalent cations of zinc and magnesium groups.