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This research presents the first example of the formation of a triplex via hydrogen bonding of a synthetic cyanuryl nucleoside (Cn) composed of a 6-membered ring compound (triazine-2,4,6-trione) which functions as a pyrimidine base. The Cn was able to form the triad via hydrogen bonding in two directions with two adenines, one in the antisense and one in the parallel chain. The thermal stability of the duplex between the antisense and sense chains was evaluated via its UV melting temperature. The melting curves of triplexes possessing the cyanuryl nucleoside (sense chain) and two adenines (antisense and parallel chains) were biphasic. To prove the formation of hydrogen bonding between the cyanuryl nucleoside and the adenine base toward the major groove, structural analysis via NMR was undertaken. A cyanuryl nucleoside containing three 15N in triazine-2,4,6-trione was synthesized first, and then the 15N cyanuryl nucleoside was incorporated into target sequences. The triplex containing the A·CnA triad was analyzed via 1H NMR, coupled and decoupled with 15N. This triad has two imino proton signals derived from the cyanuryl nucleoside, split according to the 15N coupling condition, at low field. These results are evidence of the formation of hydrogen bonds between the Cn and adenosine. The solution structure of the triplex was analyzed via NOE information from the imino proton. The cyanuryl nucleoside-containing triplex forms a right-handed helical structure similar to natural triplex DNA, albeit DNA having an enhanced pyrimidine analog in the sense chain capable of bidirectional hydrogen bonding with high sequence selectivity.

The present study provides an overview of the chemistry and biological significance of pyrimido[4,5-d]pyrimidine and pyrimido[5,4-d]pyrimidine analogs as types of bicyclic [6 + 6] systems. The main sections include: (1) synthesis methods; (2) the reactivities of the substituents linked to the ring carbon and nitrogen atoms; and (3) biological applications. A discussion demonstrating the proposed mechanisms of unexpected synthetic routes is intended. The aim of this study is to discuss the synthetic significance of the titled compounds and to establish the biological characteristics of this class of compounds as studied to date, where the compounds have been applied on a large scale in the medical and pharmaceutical fields. This survey will help researchers in the fields of synthetic organic and medicinal chemistry to undertake and improve new approaches for the construction of new standard biological components.

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines. crosscheck: This document is CrossCheck deposited related_data: Supplementary Information identifier: Klaas Verschueren (ORCID) identifier: Joachim Demaerel (ORCID) identifier: Arnout R. D. Voet (ResearcherID) identifier: Wim M. De Borggraeve (ORCID) identifier: Wim M. De Borggraeve (ResearcherID) copyright_licence: The Royal Society of Chemistry has an exclusive publication licence for this journal copyright_licence: This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) history: Received 2 December 2016; Accepted 31 January 2017; Accepted Manuscript published 9 February 2017; Advance Article published 15 February 2017; Version of Record published 23 March 2017 ispartof: MEDCHEMCOMM vol:8 issue:3 pages:640-646 ispartof: location:England status: published

The construction of carbocyclic nucleosides with a fixed 3E ring pucker in the Southern hemisphere of the pseudorotational cycle is achieved from a common precursor carbocyclic amine, (1S,3S,4R,5 S )-3-benzyloxy-4-benzyloxymethyl-1-aminobicyclo[3.1.0]hexane 20. This carbocyclic amine is efficiently assembled from optically pure 2-benzyloxymethylcyclopent-3-enol 11 in ten steps. The key cyclopropanation step is performed on (3R,4S )-1-cyano-4-benzyloxy-3-(benzyloxymethyl)cyclopentane 15, and proceeds regio- and stereo-selectively to give the critical cyanocarbocyclic intermediate 17 from which the amine 20 is subsequently obtained. Synthesis of the pyrimidine analogues 6–8 is accomplished via the intermediate acyclic acryloylureas 21 and 22. Preparation of purines 9 and 10 required prior N-formylation of the corresponding 4,6-dichloro-5-aminopyrimidine and 4,6-dichloro-2,5-diaminopyrimidine heterocyclic precursors for efficient coupling with amine 20. Except for (S)-2′-deoxy-methanocarba-A (9, the 2′-deoxyadenosine analogue), all Southern conformers appear to be devoid of antiviral activity.

The synthesis of 9-methylpyrrolo[4,3,2-de]pyrimido [4,5-c]dihydrooxazepine 34, a tricyclic pyrrolo[2,3-d]pyrimidine analogue of the mutagenic purine N6-hydroxyadenine, and several novel pyrrolo[2,3-d]pyrimidines is described. The presence of the third ring constrains the amino substituent of 34 to an anti orientation and is expected to improve dramatically the base-pairing characteristics of the analogue with both cytosine and thymine when present in DNA. An intramolecular cyclisation reaction of 5-(aminooxyethyl)-4-chloro-7-methyl-2-methylsulfonyl-7H -pyrrolo[2,3-d]pyrimidine 30 gave 33, which was converted into the target molecule 34 via the displacement of the methylsulfonyl group with hydrazine followed by oxidation of the hydrazino group with mercuric oxide. An analogous cyclisation with 5-(aminooxyethyl)-4-chloro-7-methyl-7H-pyrrolo [2,3-d]pyrimidine 31 was less effective, whilst the corresponding 2-amino derivative 32 failed to cyclise.

The chiral epoxide (6) has been converted in five stages into the thymidine analogue (14) of Neplanocin A and into the 6′α-(8) and 6′β-(10) hydroxy analogues of carbocyclic Thymidine.

The reaction of 5-bromouridine and its 4-thio derivative with both nitrile sulfides and oxides is described.

An adenine analogue of the nucleoside skeleton of the antibiotic polyoxins has been prepared from the natural pyrimidine nucleoside by an improved transglycosylation reaction.

Photolysis of 1-benzyl-2-imino-1,2-dihydropyrimidine (IIIa) was found to afford 2-benzylaminopyrimidine (IVa), a Dimroth rearrangement product, but the 1-methyl analogue (IIIb) does not give 2-methylaminopyrimidine (IVb). A similar photochemical 1,3-alkyl migration was observed for 1-alkyl-2-ethoxycarbonylmethylene-1,2-dihydropyridines (VI) giving ethyl α-alkyl-2-pyridylacetates (VII). For example, the 1 -benzyl compound (VIa) gives (VIIa) readily, but the 1 -methyl counterpart (VIc) yields (VIIc) inefficiently. A mechanism involving homolytic cleavage and recombination is postulated for the rearrangement.