Influence of the Nucleobase and Anchimeric Assistance of the Carboxyl Acid Groups in the Hydrolysis of Amino Acid Nucleoside Phosphoramidates (original) (raw)
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European Journal of Biochemistry, 1990
A theoretical study is presented, where, by using both ab initio and semi-empirical methodologies, the properties of benzoadenine derivatives as substrates of adenosine deaminase are discussed. The results suggest that lin-benzoadenine and lin-benzoadenosine can be recognized with an affinity similar to that of adenosine, but only if they are introduced about 0.12 nm deeper inside the active site of the enzyme than the natural substrate adenosine. This fact implies the existence of non-linear hydrogen bonds inside the active site of adenosine deaminase. Ab initio molecular electrostatic potential values suggest that these hydrogen bonds can exist, and have stability similar to that of linear hydrogen bonds. Finally, the great rate of deamination of lin-benzoadennie, comparable with that of adenosine despite the absence of the ribose, is explained in the context of the hypothesis that the protonation at the N1 atom is the rate-determining step of the whole deamination reaction.
Zeitschrift für Naturforschung C, 1979
The syn-anti equilibrium about the glycosidic bond in adenosine and some related analogues was studied by means of *H NMR spectroscopy, with the aid of several model analogues fixed in given conformations either by intramolecular bonding, or by introduction of a bulky substituent. A model unambiguously and exclusively in the syn conformation is 8-(a-hydroxyisopropyl) adenosine; while one fixed in the a n ti conformation is 8,5'-anhydro-8-oxoadenosine. A new analogue, fixed in the high an ti conformation, is 8,2'-0-isopropylidenearabinofuranosyladenine. Several additional new model compounds were synthesized and their properties are described. With the aid of these models, the syn-anti dynamic equilibrium was examined for adenosine and some related compounds in different solvent systems, and the conformer populations evaluated quantitatively. The validity of the procedure applied, and the accuracy of the results, are critically examined, and compared with findings obtained by other procedures. Available literature data on the syn-anti equilibrium in other 8-substituted adenosines are re analyzed in the light of the present results. An analysis is also presented of the interdependence of the various conformational parameters, i. e. conformation about the glycosidic bond and those of the sugar ring and exocyclic carbinol group, in adenosine and 2',3'-0-isopropylideneadenosine.
A quantum chemical study of the enzymatic deamination of benzoadenine derivatives
European Journal of …, 1990
A theoretical study is presented, where, by using both ab initio and semi-empirical methodologies, the properties of benzoadenine derivatives as substrates of adenosine deaminase are discussed. The results suggest that linbenzoadenine and lin-benzoadenosine can be recognized with an affinity similar to that of adenosine, but only if they are introduced about 0.1 2 nm deeper inside the active site of the enzyme than the natural substrate adenosine. This fact implies the existence of non-linear hydrogen bonds inside the active site of adenosine deaminase. Ab initio molecular electrostatic potential values suggest that these hydrogen bonds can exist, and have stability similar to that of linear hydrogen bonds. Finally, the great rate of deamination of lin-benzoadenine, comparable with that of adenosine despite the absence of the ribose, is explained in the context of the hypothesis that the protonation at the N1 atom is the rate-determining step of the whole deamination reaction.
Synthesis of 3-Guaninyl- and 3-Adeninyl-5-hydroxymethyl-2-pyrrolidinone Nucleosides
The Journal of Organic Chemistry, 2011
Human immune-deficiency virus type 1 (HIV-1) is the causative organism for acquired immune-deficiency syndrome (AIDS), 1 and despite great progress in chemotherapeutic treatment and prevention, 2 millions have lost their lives. The World Health Organization estimates that as of 2009 33.3 million people were living with AIDS, and 1.8 million died in 2009. 3 Several forms of chemotherapy are based on key events in the life cycle of HIV-1, including interception of the viral enzyme, reverse transcriptase (RT). 4 The HIV-RT enzyme converts the viral RNA to proviral DNA, and there are two general classes of RT inhibitors: nucleoside-based reverse transcriptase inhibitors (NRTI's) 5 and non-nucleoside reverse transcriptase inhibitors (NNRTI's). 6 Significant toxicity is associated with many NRTIs, and there is evidence that much of this toxicity results from the inhibition of mitochondrial DNA replication. AZT (1), for example, is known to cause bone marrow suppression, but the delay of disease progression often outweighs the complications caused by treatment with AZT. 7 One FDA-approved anti-HIV NRTI treatment is abacavir (2), 8 which after the intracellular monophosphorylation, is converted to carbovir monophosphate, which is further phosphorylated to the biologically active carbovir triphosphate. Carbovir (3), 8 an anti-HIV drug marketed by GlaxoSmithKline, was first identified as a potent anti-HIV agent in 1990. It has comparable activity to the clinically used AZT and lower toxicity. There have been several syntheses of carbovir, with the first in 1990 by Vince and co-workers, 9a,d the discoverers of carbovir. In the scheme reported by Vince and co-workers, a guanine derivative was structurally modified to incorporate the cyclopentene unit, rather than begin with a cyclopentene and then attach a guanine unit. Analyses of 1À3 (see Scheme 1), as well as other related antiviral drugs, show that a nucleobase and a hydroxymethyl unit are attached to a relatively flat five-membered ring. The synthesis of such compounds remains an area of interest with respect to ' RESULTS AND DISCUSSION L-Glutamic acid is an attractive starting material due to its commercial availability, low cost, and widespread use. In a study that is highly relevant to our targeted compounds, Nielsen and co-workers reported a synthesis of conformationally restricted peptide nucleic acid (PNA) derivatives from D-glutamic acid (6). 11 As shown in Scheme 2, formation of 2-pyrrolidinone-5carboxylic acid (pyroglutamic acid) was followed by reduction to the hydroxymethyl derivative and protection of the alcohol and nitrogen to give the O-TBDPS, N-Boc derivative 7. R-Hydroxylation with MoOPH, via the lactam enolate anion, gave 8 as a key intermediate. The PNA monomer was prepared by conversion of 8 to 9 in several steps, followed by a Mitsunobu coupling that incorporated adenine, with clean inversion of configuration
The Many Facets of Adenine: Coordination, Crystal Patterns, and Catalysis
Accounts of Chemical Research, 2010
C anonical purine-pyrimidine base pairs, the key to the complementary hydrogen bonding in nucleic acids, are fundamental molecular recognition motifs crucial for the formation and stability of double-helical DNA. Consequently, focused study and modeling of nucleobase hydrogen-bonding schemes have spawned a vast array of chemical and biophysical investigations. The Watson-Crick, reverse Watson-Crick, Hoogsteen, and reverse Hoogsteen hydrogen-bonding schemes stabilize various nucleic acid structures. As a result, numerous modified bases have been designed to maximize such interactions, addressing specific problems related to base pairing and giving rise to supramolecular ensembles in solution or in the solid state. It is also important to realize that suitably predisposed imino nitrogens and other functional groups present in heterocyclic nucleobases present a versatile molecular framework for the construction of coordination architectures, which may be harnessed to mimic base polyads and higher order nucleic acid structures. Adenine, a purine nucleobase, is an important naturally occurring nitrogen heterocycle present in nucleic acids. It is notable that the adenine unit is also frequently encountered as an inextricable part of enzyme cofactors and second messenger systems, such as NAD + , FADH 2 , and cAMP, which are essential for certain catalytic reactions and biochemical processes. In addition, a crucial catalytic role of the adenine moiety is also observed in group II intron catalysis and at the ribosomal peptidyltransferase center. Such versatile functional roles of the adenine framework serve as an inspiration for addressing research problems, ranging from classical coordination chemistry to the development of new materials. In this Account, we begin by describing the emerging use of adenine nucleobase for the design of metal-nucleobase frameworks. The coordination of metal ions affords a variety of oligomeric and polymeric species; we focus on silver-and copperbased structures and also discuss ferrocenylated adenine tetrads. We then consider the use of supramolecular adenine coordination complexes for transferring molecular properties onto surfaces. This technique is particularly useful for transferring noncovalent interactions, such as van der Waals forces, electrostatic interactions, and hydrogen bonding, to designed architectures in nanoscale applications. Finally, we explore the issue of adenine-based catalytic entities. Here, adenine moieties are first fixed in a polymeric matrix, followed by metalation of the matrix. These metalated adenine-containing polymers are then assayed for catalytic assistance in various chemical and biochemical reactions. Taken together, the versatile coordination abilities and hydrogenbonding capacity of adenine offer a novel entry point for a natural ligand into materials synthesis.
The Journal of Physical Chemistry B, 2015
Non-natural (synthetic) nucleobases, including 7-ethynyl-and 7-triazolyl-8-aza-7-deazaadenine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7deaza modification of the adenine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanine when paired to cytosine. To stress further the H-bonding pairing in the modified adenine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.
Bioorganic & Medicinal Chemistry, 2015
The phosphoramidites of DNA monomers of 7-(3-aminopropyn-1-yl)-8-aza-7-deazaadenine (Y) and 7-(3aminopropyn-1-yl)-8-aza-7-deazaadenine LNA (Z) are synthesized, and the thermal stability at pH 7.2 and 8.2 of anti-parallel triplexes modified with these two monomers is determined. When, the anti-parallel TFO strand was modified with Y with one or two insertions at the end of the TFO strand, the thermal stability was increased 1.2°C and 3°C at pH 7.2, respectively, whereas one insertion in the middle of the TFO strand decreased the thermal stability 1.4°C compared to the wild type oligonucleotide. In order to be sure that the 3-aminopropyn-1-yl chain was contributing to the stability of the triplex, the nucleobase X without the aminopropynyl group was inserted in the same positions. In all cases the thermal stability was lower than the corresponding oligonucleotides carrying the 3-aminopropyn-1-yl chain, especially at the end of the TFO strand. On the other hand, the thermal stability of the anti-parallel triplex was dramatically decreased when the TFO strand was modified with the LNA monomer analog Z in the middle of the TFO strand (DT m = À9.1°C). Also the thermal stability decreased about 6.1°C when the TFO strand was modified with Z and the Watson-Crick strand with adenine-LNA (A L). The molecular modeling results showed that, in case of nucleobases Y and Z a hydrogen bond (1.69 and 1.72 Å A 0 , respectively) was formed between the protonated 3-aminopropyn-1-yl chain and one of the phosphate groups in Watson-Crick strand. Also, it was shown that the nucleobase Y made a good stacking and binding with the other nucleobases in the TFO and Watson-Crick duplex, respectively. In contrast, the nucleobase Z with LNA moiety was forced to twist out of plane of Watson-Crick base pair which is weakening the stacking interactions with the TFO nucleobases and the binding with the duplex part.