Substituted Purine Derivatives Research Articles

Asymmetric Construction of Substituted Purine Esters with Tunable N‐9/N‐7 Regioselectivity via Enzymatic Dynamic Kinetic Resolution

AbstractWe report an enzyme‐catalyzed dynamic kinetic resolution protocol for the one‐pot asymmetric synthesis of substituted purine derivatives. The controllable N‐9/N‐7 substitution, which posed formidable challenges in organic synthesis, could be accomplished by choosing different types of enzymes as catalysts. This method was proved scalable and was used to prepare a series of prodrugs of medicinally active acids. In addition, the recyclability test of the biocatalysts indicated the potential of this strategy for applications in the pharmaceutical industry.

Synthesis, Characterization and Antimicrobial Activity of Novel Substituted Purine Derivatives

In the present work, three new compounds were synthesized (49a, 49b, 51). Compounds were synthesized as the reaction sequences outlined in scheme1. Nitration of the theophylline was carried out as per the literature method. In this theophylline was reacted with the 65% HNO3 in presence of the acetic anhydride at the 0-5oC. Acetic anhydride was used as a dehydrating agent in the nitration reactions. Reaction was carried out at a controlled temperature because; the high temperature may cause polynitration and oxidative breakdown of aromatic ring. Product was characterized by the FTIR, 1H NMR and mass spectra. The N-alkylation of 8-nitro theophylline can be done by using 1-chloro3-iodopropane as alkylating agent and K2CO3 as base, at controlled temperature condition to prevent polymerization and get better yield. Then the reaction of 7(2-chloro ethyl) 8-nitro theophylline, substituted aryl amines and KI was carried out in microwave oven at 140W for 15 minutes to obtain 1,3-dimethyl-7-{2-[(4-aryl amino] ethyl}-8-nitro-3, 7-dihydro-1H-purine-2, 6-dione. Keywords: Purine, Theophylline, 8-nitrotheophylline, Anti-microbial activity.

Synthesis, Characterisation and Biological Evaluation of Some New Aryl Substituted Purine Derivatives

Synthesis, Characterisation and Biological Evaluation of Some New Aryl Substituted Purine Derivatives

Design, synthesis and ability of non-gold complexed substituted purine derivatives to inhibit LPS-induced inflammatory response

In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1–10 and W1–10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1β, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1β, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2–5 h, and W4 was the most effective at 3–5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.

2D QSAR studies of the inhibitory activity of a series of substituted purine derivatives against c-Src tyrosine kinase

A series of 34 substituted purine analogues derivatives were subjected to quantitative structure-activity relationship analyses as inhibitors of c-Src tyrosine kinase. Partial least squares regression was applied to derive QSAR models, which were further validated for statistical significance by internal and external validation. The best QSAR model developed had a good predictive correlation coefficient (r2) of 0.8319, a significant cross-validated correlation coefficient (q2) of 0.7550, and an r2 for the external test set (pred_r2) of 0.7983. It was developed from the PLS method with descriptors including the SsCH3E-index, H-Donor Count, T_2_Cl_3, and negative correlation with SsOHcount. The current study provides better insight into the future design of more potent c-Src tyrosine kinase inhibitors prior to synthesis.

Synthesis and Antibacterial Activity of Novel Substituted Purine Derivatives

A series of novel N‐substituted‐2‐(6‐morpholino‐9H‐purin‐9‐yl)acetamide and 4‐(9‐((5‐substituted‐1,3,4‐oxadiazole/thiadiazole‐2‐yl)methyl)‐9H‐purin‐6‐yl)‐morpholine derivatives were synthesized and evaluated their antibacterial activities against rice bacterial leaf blight and tobacco bacterial wilt caused by Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the turbidimeter test in vitro. Antibacterial bioassay indicated that most compounds demonstrated good inhibitory effect against Xoo and R. solanacearum. Especially, compound 6a demonstrated the best inhibitory effect against Xoo with half‐maximal effective concentration (EC50) value of 8.39 μg/mL, which was even better than those of commercial agents Bismerthiazol and Thiodiazole copper. The synthesized purine derivatives containing amide and 1,3,4‐oxadiazole/thiadiazole moieties exhibited excellent antibacterial activities against Xanthomonas oryzae pv. oryzae and R. solanacearum in vitro.

Synthesis of Novel N9-Substituted Purine Derivatives from Polymer Supported α-Amino Acids.

Solid-phase synthesis of purine derivatives bearing an α-amino acid motif in position 9 is described herein. Polymer supported amines were acylated with various Fmoc-α-amino acids and, after cleavage of the protecting group, arylation with 4,6-dichloro-5-nitropyrimidine or 2,4-dichloro-5-nitropyrimidine was performed. The second chlorine atom was replaced with various amines. Subsequent reduction of the nitro group, followed by reaction with aldehydes, afforded the purine scaffold. After cleavage from the polymer support, the target compounds were obtained in very good crude purity, good overall yields, and excellent enantiomeric purity. The anticancer activity of prepared compounds was tested in vitro against human cancer cell lines MCF7 and K562, and they were found to have mild, but clear dose-dependent effects.

The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.

Synthesis of novel substituted purine derivatives and identification of the cell death mechanism.

Novel 9-(substituted amino/piperazinoethyl)adenines (4-12), 6-(substituted piperazino/amino)purines (15-27), 9-(p-toluenesulfonyl/cyclopentyl/ethoxycarbonylmethyl)-6-(substituted amino/piperazino)purines (28-34, 36, 37, 38-41) were synthesized and evaluated initially for their cytotoxic activities on liver Huh7, breast T47D and colon HCT116 carcinoma cells. N(6)-(4-Trifluoromethylphenyl)piperazine derivative (17) and its 9-(p-toluene-sulfonyl)/9-cyclopentyl analogues (28, 36) had promising cytotoxic activities. Compounds 17, 28 and 36 were further analysed for their cytotoxicity in a panel of a liver cancer cell lines. The compound 36 had better cytotoxic activities (IC50 ≤ 1 μM) than the nucleobase 5-FU and nucleosides fludarabine, cladribine, and pentostatine on Huh7 cells. Cytotoxicity induced by 36 was later identified as senescence associated cell death by SA-β-Gal assay.

ChemInform Abstract: One‐Pot Build‐Up Procedure for the Synthesis of Variously Substituted Purine Derivatives.

AbstractA convenient and simplified route to the title purine derivatives (III) can be carried out in a single step by using commercially available pyrimidine precursors.

C6 -substituted purine derivatives: an experimental and theoretical 1 H, 13 C and 15 N NMR study

We measured the (1)H, (13)C and (15)N chemical shifts for a series of purine derivatives bearing a norbornane substituent in position 9 and various substituents in position 6. The experimental data were complemented with density functional theory (DFT) calculations. The comparison of the calculated and experimental chemical shifts provided us with information about the tautomer and conformational equilibria of the studied compounds.

One-pot build-up procedure for the synthesis of variously substituted purine derivatives

In this article, we report a one-pot build-up procedure leading to 6-chloro- or 2-amino-6-chloropurines bearing various alkyl or aryl substituents in position N-9. This reaction is simple, fast and effective with up to 96% yields depending on the starting amine. This reaction may be easily combined with further nucleophilic displacement of the C-6 chlorine atom using various reagents, making this procedure very attractive in the field of medicinal chemistry pertaining to compounds based on a purine scaffold.

Abstract A171: Cytotoxicity of novel substituted purine derivatives against liver cancer cells

Abstract Cytotoxic purine and purine nucleoside analogs (PNA) are widely used in cancer treatment (1). In this study, three newly synthesized substituted purine derivatives, AUM18, AUM23 and AUM32* were evaluated for their cytotoxicities by Sulforhodamine B (SRB) assay initially on Hct116 (colon), T47D (breast), and Huh7 (liver) human carcinoma cell lines (2). The IC50 values for the cell lines analyzed were ∼2.0µM for AUM18, ∼0.5µM for AUM23 and ∼5nM for AUM32. The growth inhibitory effects that we observed with these PNAs were comparable to those of the known anticancer agents Camptothecin (IC50 ∼ 10 nM) and 5-Fluorouracil (IC50 ∼10µM). Subsequently, the cytotoxicity of each molecule was tested on the HCC cell line panel composed of Huh7, HepG2, Hep3B, Mahlavu, PLC, SkHep1, Focus, SNU-182 and SNU-475 cells. The IC50 values were again in micromolar varying between 0.1 to 10 µM range. However, we did not observe significant cytotoxic effect on SNU-182 cells with AUM18 PNA and on SNU-475 with AUM32. The differential inhibition that we observe, can be considered as an indication of the specificity of these inhibitors against their target. They might interfere with the activity of certain kinases rather than acting as a multi-kinase inhibitor. Furthermore, we evaluated the protein kinase activity inhibition potential of these novel purine analogs. Therefore, the kinase assay based on the detection of the amount of ATP in the reaction mixture through bioluminescence was performed with Huh7 and Mahlavu cells. Cells incubated with these novel kinase inhibitor candidates and Staurosporine (STS), a multi-kinase inhibitor used as positive control (4). The relative light units that we observed with novel PNAs were comparable to that of STS. Based on our observations, the newly synthesized PNAs, AUM18, AUM23 and AUM32 can be identified as protein kinase inhibitor candidates which must be further analyzed at the molecular level. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A171.

Synthesis and antimicrobial evaluation of some new substituted purine derivatives

A series of 8,9-disubstituted adenines ( 4, 5, 8), 6-substituted aminopurines ( 10–13) and 9-( p-fluorobenzyl/cyclopentyl)-6-substituted aminopurines ( 16, 17, 19–30) have been prepared and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolate), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. 6-[( N-phenylaminoethyl)amino]-9 H-purine ( 12) which has no substitution at N-9 position and 9-cyclopentyl-6-[(4-fluorobenzyl)amino]-9 H-purine ( 24) exhibited excellent activity against C. albicans with MIC 3.12 μg/mL. These compounds displayed better antifungal activity than that of standard oxiconazole. Furthermore, compound 22 carrying 4-chlorobenzylamino group at the 6-position of the purine moiety exhibited comparable antibacterial activity with that of the standard ciprofloxacin against both of the drug-resistant bacteria (MRSA, standard and clinical isolate).

Synthesis of Some Novel Substituted Purine Derivatives as Potential Anticancer, anti‐HIV‐1 and Antimicrobial Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Mitsunobu Coupling of Nucleobases and Alcohols: An Efficient, Practical Synthesis for Novel Nonsugar Carbon Nucleosides

A simple facile synthesis of substituted purine derivatives has been developed by using Mitsunobu conditions for an alcohol and a respective nucleobase. A wide range of alcohols produces good to excellent yield (>90%). The resulting purine analogues show good regioselectivity with N-9 substitution as the dominant products in most of the cases. Application of diastereospecific alcohols reveals a complete inversion of the carbon stereogenic center giving a single diastereomer. More than two dozen novel nucleobase derivatives have been prepared in high yield.

Synthesis of Some Novel Substituted Purine Derivatives As Potential Anticancer, Anti‐HIV‐1 and Antimicrobial Agents

In search of novel purine antimetabolites, a series of 8-substituted methylxanthine derivatives was prepared in order to explore their in vitro anticancer, anti-HIV-1 and antimicrobial activities. The target compounds include: 8-[(3-substituted-4-oxo-thiazolidin-2-ylidene)hydrazino]-1,3-dimethyl (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 5a-e, 8-[(3,4-disubstituted 2,3-dihydrothiazol-2-ylidene)hydrazino]-1,3,7-trimethyl-3,7-dihydropurine-2,6-diones 6a-d and 8-(5-amino-3-arylpyrazol-1-yl)-1,3-dimethyl- (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 7a-g. The in vitro anticancer results revealed that compound 5d exhibited a super sensitivity profile towards leukemia K-562 with a GI(50) value of <0.01 microM. Compound 7c showed significant activity against colon cancer HCT-15 and renal cancer CAKI-1 (GI(50) values of 0.47 and 0.78 microM, respectively). Compound 7a displayed high activity against colon cancer HCT-15 (GI(50 )= 0.8 microM). The anti-HIV-1 results indicated that compound 6b displayed a good reduction of viral cytopathic effect (56.69%). The antimicrobial results showed that compound 5a was four times more active than ampicillin against P. aerugenosa (MIC =or< 25 microg/mL), compound 5b had twice the activity of ampicillin, while compounds 5d, 7c and 7f were equipotent to ampicillin. On the other hand, compound 7a was equipotent to ampicillin against P. vulgaris (MIC = 50 microg/mL).

Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors

Because of its essential role in HIV replication and lack of human counterpart, HIV integrase is an attractive target for the development of novel anti-AIDS agents. Among the recently developed integrase inhibitors, only the α,γ-diketo acid (DKA) compounds were biologically validated as potent and selective integrase inhibitors. The general structure of DKAs contains a diketo acid moiety as the Mg 2+ chelating pharmacophore, and an adjacent aryl group to provide selectivity. Numerous structure–activity relationship (SAR) studies on DKAs have been conducted, which generally involved substituting the carboxylate group or the aryl group. Our objective was to investigate the SARs of the DKA molecule by incorporating a purine ring in the aryl moiety and replacing the labile diketo acid moiety with other divalent metal (Me 2+) chelating ligands. A series of amide substituted purine derivatives were synthesized via palladium-catalyzed amidation reactions, and their biological activities against HIV integrase were evaluated. These purine derivatives showed anti-integrase activity at low micromolar range. The biological results indicated that the type of Me 2+ ligands, two-point ligand picolinamide or three-point ligand 8-hydroxy-quinoline-7-carboxamide, affected inhibitory potency depending on the substitution position of the para-fluorobenzyl group. The C 6-,C 8-dipicolinamide substituted purine ( 32) exhibited the best potency among this series.

N7‐ and N9‐substituted purine derivatives: a 15N NMR study

AbstractThe 15N NMR chemical shifts of N7‐ and N9‐substituted purine derivatives were investigated systematically at the natural abundance level of the 15N isotope. The NMR chemical shifts were determined and assigned using GSQMBC, GHMBC, GHMQC and GHSQC experiments in solution. 15N cross‐polarization magic angle spinning data were recorded for selected compounds in order to study the principal values of the 15N chemical shifts. Geometric parameters obtained by using RHF/6–31G** and single‐crystal x‐ray structural analysis were used to calculate the chemical‐shielding constants (GIAO and IGLO) which were then used to assign the nitrogen resonances observed in the solid‐state NMR spectra and to determine the orientation of the principal components of the shift tensors. Copyright © 2002 John Wiley &amp; Sons, Ltd.

Structural features of substituted purine derivatives compatible with depletion of human O6-alkylguanine-DNA alkyltransferase

A series of O6- and S6-substituted purine derivatives were tested for their ability to deplete the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in cell-free extracts from HT29 colon tumor cells and intact HT29 cells. The order of potency was O6-(p-Y-benzyl)-guanine (Y = H, F, Cl, and CH3) > O6-benzyl-2'-deoxyguanosine > O6-(p-Y-benzyl)guanosine (Y = H, Cl, and CH3) > or = a series of 9-substituted O6-benzylguanine derivatives > or = O6-allylguanine > O6-benzylhypoxanthine > O6-methylguanine. A series of 7-substituted O6-benzylguanine derivatives, 2-amino-6-(p-Y-benzylthio)purine (Y = H, CH3), 2-amino-6-[(p-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, and 7-benzylguanine were inactive. It is concluded that for efficient AGT depletion, an allyl or benzyl group attached through exocyclic oxygen at position 6 of a 2-aminopurine derivative is required. Activity is preserved with a variety of substituent groups attached to position 9 while substitution at position 7 leads to a complete loss of activity.