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Journal of Enzyme Inhibition and... Feb 20149-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition...
9-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et3N under MW or from hydrazinoylchloride and Et3N under reflux. The coupling of new 6-chloropurines with amines in H2O under microwaves resulted quantitatively to modified pyrazol-5-yl- or 2-pyrazolin-5-yl adenine homo-N-nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity.
Topics: Drug Evaluation, Preclinical; Magnetic Resonance Spectroscopy; Purine Nucleosides; Pyrazoles; Spectrometry, Mass, Electrospray Ionization
PubMed: 23339428
DOI: 10.3109/14756366.2012.755623 -
Current Medicinal Chemistry 2008This review will describe the recent advances in the field of aza-C-nucleosides with a particular emphasis on immucillins and related compounds. The review will cover... (Review)
Review
This review will describe the recent advances in the field of aza-C-nucleosides with a particular emphasis on immucillins and related compounds. The review will cover both chemical and biological aspects concerning their preparation and/or occurrence in Nature as well as their biological properties which include glycosidase, glycosyl transferase, and nucleoside hydrolase and phosphorylase inhibition, among others. These enzymatic inhibitory properties are the basis for the potential use of the title compounds in viral and parasitic infections, cancer and genetic disorders.
Topics: Adenine; Adenosine; Aza Compounds; Glycoside Hydrolases; N-Glycosyl Hydrolases; Nucleosides; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones; Pyrroles; Pyrrolidines
PubMed: 18393853
DOI: 10.2174/092986708784049612 -
Bioorganic & Medicinal Chemistry Aug 2009The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid...
The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabolizing enzymes is possible. Given the increasing reports of the development of resistance in many enzymatic systems, a drug that could be recognized by more than one enzyme could prove highly advantageous in overcoming resistance mechanisms related to binding site mutations. In that regard, the design, synthesis and results of preliminary biological activity for a series of carbocyclic uracil derivatives with either a fused imidazole or thiazole ring are presented herein.
Topics: Adenosylhomocysteinase; Enzyme Inhibitors; Imidazoles; Molecular Structure; Purine Nucleosides; Pyrimidine Nucleosides; Thiazoles; Uracil
PubMed: 19592260
DOI: 10.1016/j.bmc.2009.06.039 -
The Journal of Organic Chemistry Mar 2008Novel C6-phosphonated purine nucleosides were obtained in good to excellent isolated yields by the simple and catalyst-free SNAr-Arbuzov reaction of trialkyl phosphite...
Novel C6-phosphonated purine nucleosides were obtained in good to excellent isolated yields by the simple and catalyst-free SNAr-Arbuzov reaction of trialkyl phosphite with 6-choloropurine nucleosides, including a series of nonsugar carbon nucleosides. Shorter reaction times were needed, and substantially higher yields were obtained under microwave irradiation conditions compared with conventional heating conditions.
Topics: Mass Spectrometry; Microwaves; Organophosphonates; Purine Nucleosides
PubMed: 18307357
DOI: 10.1021/jo702680p -
Biopolymers Jan 2021The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible... (Review)
Review
The notion of using synthetic heterocycles instead of the native bases to interface with DNA and RNA has been explored for nearly 60 years. Unnatural bases compatible with the DNA/RNA coding interface have the potential to expand the genetic code and co-opt the machinery of biology to access new macromolecular function; accordingly, this body of research is core to synthetic biology. While much of the literature on artificial bases focuses on code expansion, there is a significant and growing effort on docking synthetic heterocycles to noncoding nucleic acid interfaces; this approach seeks to illuminate major processes of nucleic acids, including regulation of transcription, translation, transport, and transcript lifetimes. These major avenues of research at the coding and noncoding interfaces have in common fundamental principles in molecular recognition. Herein, we provide an overview of foundational literature in biophysics of base recognition and unnatural bases in coding to provide context for the developing area of targeting noncoding nucleic acid interfaces with synthetic bases, with a focus on systems developed through iterative design and biophysical study.
Topics: Base Pairing; DNA; Hydrogen Bonding; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Synthetic Biology
PubMed: 32969496
DOI: 10.1002/bip.23399 -
Journal of Medicinal Chemistry Jan 1993In order to study the structure-activity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl...
In order to study the structure-activity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl pyrimidine and purine nucleosides were synthesized and evaluated for anti-HIV-1 activity in human peripheral blood mononuclear (PBM) cells. The key intermediate 8 was synthesized starting from L-gulose via 1,6-thioanhydro-L-gulopyranose. The acetate 8 was condensed with thymine, 5-substituted uracils and cytosines, 6-chloropurine, and 6-chloro-2-fluoropurine to give pyrimidine and purine nucleosides. Upon evaluation of these final nucleosides, the 5-fluorocytosine derivative 51 was found to be the most potent compound among those tested. In the case of 5-substituted cytosine analogues, the antiviral potency was found to be in the following decreasing order: cytosine (beta-isomer) > 5-iodocytosine (beta-isomer) > 5-fluorocytosine (alpha-isomer) > 5-methylcytosine (alpha-isomer) > 5-methylcytosine (beta-isomer) > 5-bromocytosine (beta-isomer) > 5-chlorocytosine (beta-isomer). Among the thymine, uracil, and 5-substituted uracil derivatives, thymine (alpha-isomer) and uracil (beta-isomer) derivatives exhibited moderate anti-HIV activity. In the purine series, the antiviral potency is found to be in the following decreasing order: adenine (beta-isomer) > 6-chloropurine (beta-isomer) > 6-chloropurine (alpha-isomer) > 2-NH2-6-Cl-purine (beta-isomer) > guanine (beta-isomer) > N6-methyladenine (alpha-isomer) > N6-methyladenine (beta-isomer). The cytotoxicity was also determined in human PBM cells as well as Vero cells. None of the synthesized nucleosides was toxic up to 100 microM in PBM cells.
Topics: Antiviral Agents; Blood; Cells, Cultured; HIV-1; Heterocyclic Compounds; Humans; Magnetic Resonance Spectroscopy; Purine Nucleosides; Pyrimidine Nucleosides; Structure-Activity Relationship; Thiophenes
PubMed: 8423591
DOI: 10.1021/jm00054a001 -
Comparative Biochemistry and... Jun 2008Venoms of Heloderma horridum and Heloderma suspectum were analyzed for the possible presence of purine and pyrimidine nucleosides. Adenosine, cytidine, guanosine,...
Venoms of Heloderma horridum and Heloderma suspectum were analyzed for the possible presence of purine and pyrimidine nucleosides. Adenosine, cytidine, guanosine, hypoxanthine, inosine, and uridine were found in mug quantities. These amounts are much smaller than those seen in many elapid or viperine venoms, but greater and more varied than those found in crotaline venoms. While their contribution to the hypotension induced by Heloderma venoms may be minor, venom nucleosides nonetheless act in concert with kallikreins/hemorrhagins, alkaline phosphomonoesterase, 5'-nucleotidase, helodermin, helospectins, helothermine, and serotonin. The use of nucleosides as toxins is therefore a generalized squamate strategy, rather than the exclusive province of snakes. Both Heloderma venoms were found to be devoid of NADase and phosphodiesterase activities. Enzymes to release endogenous purines in the prey, are not significant components of Heloderma venoms.
Topics: Animals; Chromatography, Gel; Lizards; Purine Nucleosides; Pyrimidine Nucleosides; Venoms
PubMed: 18430599
DOI: 10.1016/j.cbpb.2008.02.012 -
Current Cancer Drug Targets Sep 2005The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic... (Review)
Review
The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkin's lymphomas, including Waldenström's macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.
Topics: Antineoplastic Agents; Hematologic Neoplasms; Humans; Purine Nucleosides
PubMed: 16178817
DOI: 10.2174/1568009054863618 -
Zeitschrift Fur Naturforschung. Section... 1975With the use of PMR the ribose conformations have been studies in the temperature range -60 to +40 degrees C in ND3 solutions of adenosine (A), guanosine (G), inosine... (Comparative Study)
Comparative Study
With the use of PMR the ribose conformations have been studies in the temperature range -60 to +40 degrees C in ND3 solutions of adenosine (A), guanosine (G), inosine (I), xanthsine (X), purineriboside (PR), 2-aminopurineriboside (2amPR), N6-isopentenyladenosine (N6ipA), 8-bromoadenosine (iA), and isopropylideneguanosine (iG). The aanlysis is based on the two-state S in equilibrium N model of the ribose moiety proposed by Altona and Sundaralingam. The compounds studied can be classified into two groups: 1. A, I, G, X, PR, 2amPR, N6ipA, and T show a small temperature dependence of thnd F have a stronger temperature dependence and [S] approximately 0.8. Within these two groups the similarities observed are greater than observed in the solid state. Some thermodynamic conclusions about the S in equilibrium N and the syn in equilibrium anti equilibria are presented. The results support the previously proposed correlation of the S state of the ribose with the syn conformation of the base and of the N state of the ribose with the anti conformation of the base. Furthermore, it is derived that the gg rotamer is correlated with the S state of the ribose and therefore stabilizes the syn conformation of the base.
Topics: Adenosine; Guanosine; Inosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Purine Nucleosides; Ribonucleosides; Ribose; Xanthines
PubMed: 125961
DOI: 10.1515/znc-1975-3-401 -
Advances in Experimental Medicine and... 1991
Topics: Adenosine; Animals; Biological Transport; Chromatography, High Pressure Liquid; Duodenum; In Vitro Techniques; Kinetics; Perfusion; Purine Nucleosides; Pyrimidine Nucleosides; Rats
PubMed: 1789253
DOI: 10.1007/978-1-4899-2638-8_92