Guanine Derivatives Research Articles

Synthesis and biological evaluation of 9-(5′,5′-difluoro-5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine ( DFPP- G) and its hypoxanthine analogue ( DFPP- H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP- H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)- 4.

Understanding the structure–activity and structure–selectivity correlation of cyclic guanine derivatives as phosphodiesterase-5 inhibitors by molecular docking, CoMFA and CoMSIA analyses

Molecular docking and 3D-QSAR analyses were performed to understand how PDE5 and PDE6 interact with a series of (49) cyclic guanine derivatives. Using the conformations of the compounds revealed by molecular docking, CoMFA and CoMSIA analyses resulted in the first quantitative structure–activity relationship (QSAR) and first quantitative structure–selectivity relationship (QSSR) models (with high cross-validated correlation coefficient q 2 and conventional correlation coefficient r 2 values) for predicting the inhibitory activity against PDE5 and the selectivity against PDE6. The high q 2 and r 2 values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting both the inhibitory activity and selectivity of cyclic guanine derivatives for these protein targets. A set of 3D contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal some useful clues to improve both the activity and selectivity by modifying structures of the compounds. It has been demonstrated that both the steric and electrostatic factors should appropriately be taken into account in future rational design and development of more active and more selective PDE5 inhibitors for the therapeutic treatment of erectile dysfunction (ED).

Rotamer Stability in cis‐[Pt(diA)G2] Complexes (diA=Diamine Derivative and G=Guanine Derivative) Mediated by Carrier‐Ligand Amine Stereochemistry as Revealed by Circular Dichroism Spectroscopy

Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each guanine leaning towards the cis-G. Such a "six-in" canting of the two guanine ligands can be hampered by the steric interaction between the H8 of each guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of guanine O6 and the cis-amine N-H group. Such a guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each guanine further from the cis-guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.

Inhibition of human telomerase by diphosphates of acyclic nucleoside phosphonates

Diphosphates of the antiviral acyclic nucleoside phosphonates (ANPs) were evaluated in telomeric repeat amplification protocol (TRAP) for their ability to inhibit the extension of telomeres by human telomerase. Extracts from human leukaemia HL-60 cells were used as a source of the enzyme. Data show that the most effective compound studied was the guanine derivative PMEGpp (IC 50 12.7 ± 0.5 μmol L −1 at 125 μmol L −1 deoxynucleoside triphosphates (dNTPs)). The inhibitory effects of other PME, PMP and HPMP diphosphates on telomerase reverse transcriptase decreased in the order: ( R)-PMPGpp > ( R)-HPMPGpp > PMEDAPpp > ( S)-PMPGpp > ( S)-HPMPApp > PMEO-DAPypp > ( R)-6-cyprPMPDAPpp > ( R)-PMPApp > ( R)-PMPDAPpp ≥ PMEApp ≥ PMECpp > PMETpp > ( S)-PMPApp ∼ 6-Me 2PMEDAPpp. These results are consistent with the observed antineoplastic activities of the parental guanine (PMEG) and 2,6-diaminopurine (PMEDAP) PME-derivatives. Moreover, structure–activity relationship indicates enantioselectivity of some of these human telomerase inhibitors: ( R)-isomers of the PMP-derivatives possess stronger inhibitory potency towards the enzyme than ( S)-isomers. The data may contribute to the rational design of telomerase inhibitors based on the structure of acyclic nucleotide analogues.

Possibilities of magnetic modifications of DNA wires, sheets and related materials

Our theoretical efforts towards molecule-based magnetic conductors and superconductors on the basis of ab initio Hamiltonians and effective model Hamiltonians are summarized in relation to recently developed DNA-based molecular materials. Guanine and adenine derivatives coupling with organic radicals (R) are investigated as possible π–R components. In order to elucidate electronic and magnetic properties of these species, effective exchange integrals (Jab) for magnetic clusters are calculated by ab initio hybrid density functional methods. Theoretical possibilities of organic magnetic conductors and the organic solenoid are elucidated on the basis of these models in self-assembled DNA wires, sheets and related materials. Implications of the calculated results are finally discussed in order to obtain a unified picture of many p–d, π–d and π–R molecule-based systems with strong electron correlations.

Slowly Exchanging cis‐PtA2B2 Atropisomers with A2 = Chiral Diamine Ligands and B = 5,6‐Dimethylbenzimidazole

Abstractcis‐PtA2G2 complexes, in which A2 is a bidentate amine ligand and G is a unidentate guanine derivative bound to platinum through N7, are simple models of the G‐G cross‐link DNA lesion formed by the anticancer drug cisplatin. Rotation of the G bases about the Pt–N7 bonds is usually rapid except for bulky amine ligand(s). This paper concerns cis‐PtA2(Me2Bzm)2 adducts [A2 = 2,2'‐bipiperidine (Bip)and N,N,N',N'‐tetramethyl‐2,3‐diaminobutane (Me4DAB); Me2Bzm = 5,6‐dimethylbenzimidazole] for which the interconversion among possible rotamers (one HH and two HT) is slow on the NMR time scale. The amounts of the rarely observed HH conformer were 52 and 37 % at 5 °C for BipPt(Me2Bzm)2 and Me4DABPt(Me2Bzm)2, respectively, and increased to 60 and 44 % at 50 °C. This result represents the first reported clear evidence for the existence of the HH atropisomer in cis‐PtA2B2 adducts (B = G or Me2Bzm base) with fully substituted diamines, such as Me4DAB or Me4EN (Me4EN = N,N,N',N'‐tetramethyl‐1,2‐diaminoethane). The lack of an O‐substituent on the C4 atom of Me2Bzm (corresponding to C6 of G) undoubtedly allows for a relatively stable HH conformer. Thermodynamic parameters confirm the crucial role of the substituents in positions 4 and 6 of the base systems (for Me2Bzm and G derivatives, respectively) in determining the stability of different rotamers. The greater abundance of the HH rotamer for BipPt(Me2Bzm)2 than for Me4DABPt(Me2Bzm)2 indicates that an increase in the steric bulk of the carrier ligand favors the HT rotamers over the HH rotamer. For both BipPt(Me2Bzm)2 and Me4DABPt(Me2Bzm)2 adducts, the major HT rotamer has the six‐membered ring of each Me2Bzm ligand on the more crowded side of the cis amine with respect to the platinum coordination plane: the N–CH2– group in Bip and the N–Meeq (N–Meeq = quasi‐equatorial N–Me) in Me4DAB adducts. The latter result is in complete agreement with previous findings from our laboratories concerning BipPtG2 and Me4DABPtG2 compounds and gives further support to the view that the major HT rotamer is stabilized by the six‐membered ring of each base canted toward the cis base. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Platinum Complexes with Only One Purine Ligand (Guanine, Deoxyguanine, or Adenine) Flanked by Two cis‐NH(CH3) Groups – Informative Models for Assessing the Interaction of Purine C6 Substituents with cis‐Amines

Abstractsyn‐(R,S)‐Me3dienPtL complexes (Me3dien = N,N',N‐trimethyldiethylenetriamine; L = a guanine, a 6‐deoxyguanine, or an adenine derivative) represent useful models for assessing the influence of the purine C6 substituent on the rate of rotation about the Pt–N7 bond. Because of the unsymmetric nature of the syn‐(R,S)‐Me3dien carrier ligand with respect to the coordination plane (all N–Me groups on one side of this plane), two rotamers are possible; they are defined as endo or exo for the six‐membered ring of the purine on the same or opposite side of the coordination plane as the N–Me groups, respectively. The derivatives of guanine (Pen), 6‐deoxyguanine (deoxy‐Pen), and adenine (MeA) used are distinguished by their C6 substituent (O, H, or NH2, respectively). At ambient temperature the rate of rotation of the purine about the Pt–N7 bond is slow on the NMR time scale for all three complexes. However, for Pen and deoxy‐Pen, an increase of the temperature from 293 to 353 K led to coalescence of the 1H NMR signals, indicating fast interconversion between rotamers and allowing evaluation of the rate constants and activation parameters (ΔH≠ and ΔS≠) for rotation. In contrast, for MeA raising the temperature to 353 K caused only a very slight broadening of the NMR signals, thus precluding a kinetic analysis of this complex by NMR methods. The rate of interconversion between the rotamers was comparable for the Pen and deoxy‐Pen complexes, notwithstanding the greater bulk of the C6 substituent in the Pen complex. On the other hand, the far slower rate of rotation for MeA, as compared to Pen, cannot be explained solely on the basis of C6 substituent bulk. Activation parameters for rotation (average values for the two rotamers: ΔH≠ = 57 ± 4 and 108 ± 3 kJ·mol–1, ΔS≠ = –18 ± 11 and 170 ± 11 J·K–1·mol–1 for Pen and deoxy‐Pen, respectively) suggest a plausible explanation for the observed trend. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthetic Strategies Towards O6-Substituted Guanine Derivatives and their Application in Medicine

Synthetic Strategies Towards O6-Substituted Guanine Derivatives and their Application in Medicine

Mass Spectrometric Methodology for the Determination of Glyoxaldeoxyguanosine and O6-Hydroxyethyldeoxyguanosine DNA Adducts Produced by Nitrosamine Bident Carcinogens

N-Nitrosodiethanolamine (NDELA) is a bident carcinogen that undergoes both P-450 mediated alpha-hydroxylation and beta-oxidation, leading ultimately to the formation of two prominent DNA adducts, glyoxaldeoxyguanosine (gdG) and O6-2-hydroxyethyldeoxyguanosine (OHEdG), in rat liver. HPLC coupled with electrospray ionization (ESI) and tandem mass spectrometry was used for both detection and quantification of gdG and OHEdG. The method, which is fast, sensitive, and unambiguous, is a significant improvement over the previous 32P-postlabeling methodology. A rapid procedure for the enzymatic hydrolysis of the DNA under acidic conditions preserved the integrity of the pH sensitive gdG adducts. Glyoxal and 3-nitroso-2-oxazolidinone generated gdG and OHEdG adducts, respectively, in calf thymus DNA (ct-DNA) in a concentration (range of 10(4)) dependent manner permitting optimization. Isotopomeric internal standards were prepared from the modified guanine derivatives by enzymatic trans-glycosylation. Quantitative HPLC-ESI-MS/MS analysis employing selective reaction monitoring (SRM) for the loss of the deoxyribose fragment was utilized. Both adducts could be detected in the liver DNA of rats that were administered NDELA in a dose range of 0.4-0.8 mmol/kg. At the highest dose, gdG adducts (4.4-11 adducts/10(6) nuc.) were more abundant than OHEdG adducts (0.35-0.87 adducts/10(6) nuc.). Conversely, OHEdG adducts were produced in higher yields in ct-DNA than were gdG adducts at the same reagent concentrations.

A Regioselective Synthesis of Alkyl 2-(Guanin-9-yl)acetates as PNA Building Blocks from 7-(4-Nitrobenzyl)guanine Derivatives

Guanine derivatives substituted at N7 with 4-R-benzyl groups (R = H, MeO, NO2) have been evaluated in the regioselective N9-alkylation of guanine. Given the capricious removal of (substituted) benzyl groups from guanine derivatives and pent-4-enoylation of guaninium hydrochloride, an improved alternative approach has been elaborated consisting in the pent-4-enoylation and per-O-acetylation of guanosine (8), 4-nitrobenzylation at N7 followed by N-glycoside hydrolysis (10), N9-alkylation (13) and deprotection with sodium dithionite to afford the peptide nucleic acid building block tert-butyl [N2-(pent-4-enoyl)guanin-9-yl]- acetate (15) in 36% overall yield. This avoids N7 regioisomer formation, solubility problems and any chromatographic purification. A remarkable influence of the O- and/or N2-acyl groups on the stability of N-glycosidic bond and reactivity of 2-amino group was observed. The structure of a pyrimidine by-product 12 arising from the imidazole ring-opening of guaninium salt 4d in alkaline medium has been elucidated by 2D NMR.

Possibilities of molecule‐based spintoronics of DNA wires, sheets, and related materials

AbstractOur theoretical efforts toward molecule‐based magnetic conductors and superconductors on the basis of ab initio Hamiltonians and effective model Hamiltonians are summarized in relation to recently developed DNA‐based molecular materials. Guanine and adenine derivatives coupling with organic radicals (R) are investigated as possible π–R components. To elucidate electronic and magnetic properties of these species, effective exchange integrals (Jab) for magnetic clusters are calculated by ab initio hybrid density functional (HDFT) methods. The ab initio Jab values are numerically reproduced by using model Hamiltonians such as the t‐J, Kondo, Anderson, and RKKY models. The theoretical possibilities of organic magnetic conductors are elucidated on the basis of these models for self‐assembled DNA wires, sheets, and related materials. The use of these materials for nanoscale molecular electronic devices is also elucidated theoretically in relation to an important role of electron–electron repulsion effect for quantum electron transport, together with the electron‐exchange interaction in the Kondo effect. The implications of the calculated results are finally discussed to obtain a unified picture of many p–d, π–d, and π–R molecule‐based systems with strong electron correlations. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005

SERS studies of the adsorption of guanine derivatives on gold colloidal nanoparticles

Surface enhanced Raman scattering spectra of guanine, guanosine and 2'-deoxyguanosine adsorbed on gold colloidal nanoparticles were obtained. From the striking similarity of the SERS spectra of these compounds, it can be evidenced that guanosine and 2'-deoxyguanosine adsorb on gold nanoparticles through the guanine moiety. The molecular sites involved in the interaction with the gold surface are the same for the 3 compounds: the oxygen of the carbonilic group and the N(7) atom. Guanine, guanosine and 2'-deoxyguanosine adsorb on the gold substrates with a tilted orientation with respect to the metal surface. SERS data were interpreted taking into account density functional theoretical (DFT) calculations of guanine.

The Synthesis of [(β‐d‐Ribofuranosyloxy)‐methyl]nucleosides

The coupling reaction of acetoxymethoxy ribofuranoside 4 with nucleic acid bases 5a–f to synthesize novel (ribofuranosyloxy)methyl uracil, thymine, cytosine, adenine, guanine derivatives 6a–g respectively in preference to the expected formation of natural nucleosides 2′,3′,5′‐tri‐O‐benzoyl uridine, methyluridine, cytidine, adenosine and guanosine 7a–g is described. Detailed study of these reactions catalysed by Lewis acids TMSOTf and SnCl4 is described. TMSOTf exhibited selectivity for the formation of ribofuranosyloxy methyl derivatives 6a–g rather than 7a–g. Reason for formation of 6a–g is explained by HSAB principle.

The Synthesis of [(β‐D‐Ribofuranosyloxy)methyl]nucleosides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Effect of cell cycle inhibition on Cisplatin-induced cytotoxicity.

Pharmacological inhibitors of cyclin-dependent kinase (CDK)2 are currently in preclinical and clinical development. The purpose of our work was to evaluate a series of guanine derivatives for their ability to inhibit CDK2, affect cell cycle progression, and enhance the cytotoxic and apoptotic effects of cisplatin. A panel of guanine derivatives, including O(6)-benzylguanine (O(6)-BG), S(6)-benzyl-6-thioguanine (S(6)-BG), S(6)-[(cyclohexyl)methyl]-6-thioguanine (S(6)-CMG), O(6)-[(cyclohexyl)methyl]guanine (O(6)-CMG), O(6)-benzyl-9-methylguanine (9-CH(3)-BG), O(6)-[(cyclohexyl)methyl]-9-methyl-guanine (9-CH(3)-CMG), and 7-benzylguanine (N7-BG), exhibited varying degrees of CDK2 inhibition with O(6)-CMG being the most potent and 9-CH(3)-BG, 9-CH(3)-CMG, and N7-BG the least potent compounds. Treatment with S(6)-CMG and O(6)-CMG significantly decreased the percentage of cells in S phase. In SQ20b and SCC61 head and neck cancer cell lines, the most potent CDK2 inhibitor, O(6)-CMG, was also the most effective at enhancing cisplatin-induced cytotoxicity and apoptosis. Cisplatin-induced DNA platination increased in SQ20b cells pretreated with S(6)-BG, S(6)-CMG, and O(6)-CMG. Treatment with both O(6)-BG and trichostatin A, an indirect cell cycle inhibitor, demonstrated additive effects on cisplatin-induced cytotoxicity. In summary, we have identified a group of guanine derivatives that were effective modulators of cisplatin-induced cytotoxicity and apoptosis.

Inhibition of O6-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O(6)-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O(6)-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O(6)-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared O(6)-benzylguanine, O(6)-2-fluoropyridinylmethylguanine (O(6)FPG), O(6)-3-iodobenzylguanine, O(6)-4-bromothenylguanine, and O(6)-5-iodothenylguanine with the corresponding C8-linker beta-d-glucose derivatives. All glucose conjugated inhibitors were 3- to 5-fold less effective than the corresponding nonconjugated drugs as to MGMT inhibition that was measured in cell extracts (in vitro) and cultivated HeLaS3 cells (in vivo). Except for O(6)FPG, IC(50) values of the guanine derivatives applied in vitro and in vivo were correlated. A similar correlation was not obvious for the corresponding glucosides, indicating differences in cellular uptake. C8-alpha-d-glucosides were less effective than beta-glucosides. From the newly developed glucose-conjugated inhibitors tested, O(6)-4-bromothenylguanine-C8-beta-d-glucoside (O(6)BTG-C8-betaGlu) was most potent in inhibiting MGMT both in vitro and in vivo. At a concentration of 0.1 microM, it inhibited cellular MGMT to completion. It was not toxic, even when applied chronically to cells at high dose (up to 20 microM). O(6)BTG-C8-betaGlu strongly potentiated the killing effect of fotemustine and temozolomide, causing reversal from MGMT+ to MGMT- phenotype. Therefore, O(6)BTG-C8-betaGlu seems to be especially suitable for approaching MGMT inhibitor targeting in tumor therapy.

A novel fluorescent guanine derivative distinguishable of three structures, single strand, duplex, and quadruplex

We have constructed a pyrene-labeled guanine base, 8PyG. 8PyG is a novel fluorescent probe for monitoring the secondary structure of G-rich DNA. The fluorescence emitted from 8PyG-labeled oligodeoxynucleotide clearly distinguished three structural states, single strand–duplex–quadruplex. Thus, the technique, which monitors the fluorescence of 8PyG-labeled oligodeoxynucleotide, is a powerful tool for the investigation of DNA structural changes.

Synthese von 6-O-Benzylguanin und seinen Anker-Konjugaten / Synthesis of 6-O-Benzyl Guanine and its Conjugations with Linkers

An improved synthesis of 6-O-benzyl guanine which is an important inhibitor of O6-alkyl-guanine DNA alkyltransferase (AGT) is described. In addition the conjugation of this guanine derivative was achieved with a functionalised hydrophilic linker which is of interest for immobilisation of this inhibitor and its conjugation with targeting components.

SAR Development of Polycyclic Guanine Derivatives Targeted to the Discovery of a Selective PDE5 Inhibitor for Treatment of Erectile Dysfunction.

SAR Development of Polycyclic Guanine Derivatives Targeted to the Discovery of a Selective PDE5 Inhibitor for Treatment of Erectile Dysfunction.

Nitroxide-labeled guanine as an ESR spin probe for structural study of DNA

A guanine derivative with a covalently linked nitroxide spin label has been devised. The spin label was incorporated into oligodeoxynucleotides by post-synthetic modification. The local environment of a variety of G-rich DNA is detectable by ESR using this spin probe.