Tricyclic Base Research Articles

Radical mediated ring formation in the biosynthesis of the hypermodified tRNA base wybutosine

Wyosine and its derivatives are highly modified, acid labile tricyclic bases found at position 37 of tRNA(Phe) in archaea and eukarya. The formation of the common 4-demethylwyosine structural feature entails condensation of pyruvate and N-methylguanosine catalyzed by TYW1. This review will focus on the mechanism of this complex radical mediated transformation.

Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases

A series of 3,9-dihydro-9-oxo-5 H-imidazo[1,2- A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (−)-β-D-(2 R,4 R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG) 7, and 2′- C-methylguanosine 8. Their in vitro activity against HIV and HCV was evaluated and correlated to their ability to degrade to their purine counterpart.

A Computational Study of Expanded Heterocyclic Nucleosides in DNA

The first molecular dynamics study of a series of heterospacer-expanded tricyclic bases in DNA using modified force field parameters in AMBER is detailed. The expanded purine nucleoside monomers have been designed to probe the effects of a heteroaromatic spacer ring on the structure, function, and dynamics of the DNA helix. The heterobase scaffold has been expanded with a furan, pyrrole, or thiophene spacer ring. This structural modification increases the polarizability of the bases and provides an additional hydrogen bond donor with the amine hydrogen of the pyrrole ring or hydrogen bond acceptor with the furan or thiophene ring free electron pairs. The polarizability of the expanded bases were determined by AM1 calculations and the results of the MD simulations of 20-mers predict that the modified curvature of the expanded base leads to a much larger major groove, while the effect on the minor groove is negligible. Overall, the structure resembles A-DNA. MD simulations of 10-mers suggest that the balance between base pairing vs. base stacking and intercalation can be shifted towards the latter due to the increased surface area and polarizability of the expanded bases.

The base exchange reaction of NAD + glycohydrolase: Identification of novel heterocyclic alternative substrates

ADP-ribosyl cyclase and NAD + glycohydrolase (CD38, E.C.3.2.2.5) efficiently catalyze the exchange of the nicotinamidyl moiety of NAD +, nicotinamide adenine dinucleotide phosphate (NADP +) or nicotinamide mononucleotide (NMN +) with an alternative base. 4′-Pyridinyl drugs (amrinone, milrinone, dismerinone and pinacidil) were efficient alternative substrates ( k cat/ K M = 0.9–10 μM −1 s −1) in the exchange reaction with ADP-ribosyl cyclase. When CD38 was used as a catalyst the k cat/ K M values for the exchange reaction were reduced two or more orders of magnitude (0.015–0.15 μM −1 s −1). The products of this reaction were novel dinucleotides. The values of the equilibrium constants for dinucleotide formation were determined for several drugs. These enzymes also efficiently catalyze the formation of novel mononucleotides in an exchange reaction with NMN +, k cat/ K M = 0.05–0.4 μM −1 s −1. The k cat/ K M values for the exchange reaction with NMN + were generally similar (0.04–0.12 μM −1 s −1) with CD38 and ADP-ribosyl cyclase as catalysts. Several novel heterocyclic alternative substrates were identified as 2-isoquinolines, 1,6-naphthyridines and tricyclic bases. The k cat/ K M values for the exchange reaction with these substrates varied over five orders of magnitude and approached the limit of diffusion with 1,6-naphthyridines. The exchange reaction could be used to synthesize novel mononucleotides or to identify novel reversible inhibitors of CD38.

Трициклічна 1,2,4-триазинвмісна гетеросистема: спрямований синтез нових біологічно активних сполук

A new se ries of tricyclic heteroaromatic com pounds was pre pared by cyclization of N2-sub sti tuted-6-bromo-3-oxo(amino)-1,2,4-tri azin-5(4I)-ones with 2-aminobenzothiol. The struc ture of bioactive tricyclic glycosides, ob tained ear lier by the sim pli fied silylic method, was con firmed as well as ex pe di ence and ad e quacy of this method for di rected glycosylation of triazine bear ing tricyclic bases.

Structure of an archaeal TYW1, the enzyme catalyzing the second step of wye-base biosynthesis

Wye bases are tricyclic bases that are found in archaeal and eukaryotic tRNAs. The most modified wye base, wybutosine, which appears at position 37 (the 3'-adjacent position to the anticodon), is known to be important for translational reading-frame maintenance. Saccharomyces cerevisiae TYW1 catalyzes the tri-ring-formation step in wye-base biosynthesis, with the substrate tRNA bearing N(1)-methylated G37. Here, the crystal structure of the archaeal TYW1 homologue from Pyrococcus horikoshii is reported at 2.2 A resolution. The amino-acid sequence of P. horikoshii TYW1 suggested that it is a radical-AdoMet enzyme and the tertiary structure of P. horikoshii TYW1 indeed shares the modified TIM-barrel structure found in other radical-AdoMet enzymes. Radical-AdoMet enzymes generally contain one or two iron-sulfur (FeS) clusters. The tertiary structure of P. horikoshii TYW1 revealed two FeS cluster sites, each containing three cysteine residues. One FeS cluster site was expected from the amino-acid sequence and the other involves cysteine residues that are dispersed throughout the sequence. The existence of two FeS clusters was confirmed from the anomalous Fourier electron-density map. By superposing the P. horikoshii TYW1 tertiary structure on those of other radical-AdoMet enzymes, the AdoMet molecule, which is necessary for the reactions of radical-AdoMet enzymes, was modelled in P. horikoshii TYW1. Surface plots of conservation rates and electrostatic potentials revealed the highly conserved and positively charged active-site hollow. On the basis of the surface properties, a docking model of P. horikoshii TYW1, the tRNA, the FeS clusters and the AdoMet molecule was constructed, with the nucleoside at position 37 of tRNA flipped out from the canonical tRNA structure.

Inhibition of HIV integrase by novel nucleotides bearing tricyclic bases.

5'-Monophosphates of several novel dideoxynucleosides bearing tricyclic nucleobases were synthesized. Both linear and angular ring-extended analogs of isomeric dideoxyadenosine 5'-monophosphate were discovered to have moderate to good inhibition of the viral-encoded enzyme, HIV integrase. The results suggest that the nucleotide binding site of HIV integrase can accommodate major modifications in the nucleobase, which is in stark contrast to the nucleotide binding site on HIV reverse transcriptase.

3-beta-D-ribofuranosyl-6,7-dihydro-9H-thiazolo[3,2-a]purin-9-one hydrate.

The title molecule, C12H14N4O5S.H2O (I), has a syn-XCN glycosyl torsion angle, which is stabilized by an intramolecular hydrogen bond between N3 of the tricylic base and O5' of the ribose (in a C2'-endo pucker). [The purine base, including atoms S and O6, of the molecule is planar to within 0.043 (2) A.] The tricyclic bases are stacked along a with an interplanar distance of 3.602 (3) A.

ChemInform Abstract: SYNTHESIS OF 4H‐THIENO(2,3‐D)AZONINE AND THIENO(2,3‐D)AZECINE DERIVATIVES

AbstractDie mit Bromcyan induzierte Solvolyse der ausgehend von (I) und (II) erhaltenen Thienoheterocyclen (IV) liefert die Titelverbindungen (V), von denen die Verbindungen (Vb) zu den Ketonen (VI) oxidiert bzw. zu den N‐Methyl‐Derivaten (VII) und weiter zu den Ketonen (VIII) umgesetzt werden.

Synthesis of 4H-Thieno[2,3-d]azonine and Thieno[2,3-d]azecine derivatives

Derivatives of two new thieno medium-ring heterocyclic systems have been prepared by ring degradation using cyanogen bromide-induced solvolysis of tricyclic bases. Reaction of a hexahydrothieno[2,3-glindolizine (4a) and a hexahydro-7H-thieno[3,2-a]quinolizine (4b) with cyanogen bromide and magnesium oxide under solvolytic conditions yielded derivatives of hexahydro-4H-thieno[2,3-d]azonine (5a) (6a) and octahydrothieno[2,3-d]azecine (5b) (6b), respectively. Functional group interconversions of these medium-ring systems are described, including oxidations to cyclic ketones. The 9a-phenyl derivative of (4a) reacted similarly. By contrast 10b-phenyl derivatives (10a,b) of a hexahydropyrrolo[2,1-a]isoquinoline reacted under these conditions to give medium-ring elimination products, derivatives of tetrahydro-1H-3-benzazonines.

Biosynthesis of Thermopsis alkaloids from carbon-14 dioxide. Evidence for the formation of the pyridone bases from lupanine via 5,6-dehydrolupanine.

The observed relative rates and chronology of labelling of the alkaloids of Thermopsis rhombifolia and T. caroliniana following pulse feeding of 14CO2 were consistent with the formation of the pyridone bases from lupanine, via 5,6-dehydrolupanine. Rhombifoline appears to be the first of the tricyclic bases to be formed from the tetracyclic ones. No evidence was obtained for the formation of sparteine, casting doubt on its role in the formation of these alkaloids.