Chemical Synthesis of Conformationally Constrained PNA Monomers

Merino, Pedro; Matute, Rosa

doi:10.1002/9781118498088.ch19

Cited by 23 publications

(24 citation statements)

References 83 publications

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“…A wide variety of synthetic nucleotides bearing nucleobase analogs have been reported, [8-10] and several have been identified that stably pair with one another within an otherwise natural duplex. [11-19] However, efficient and high fidelity replication of DNA containing a UBP has proven much more challenging, and early work from the Benner laboratory yielded what were for over a decade the only promising candidates.…”

Section: Introduction and Overviewmentioning

confidence: 99%

The Expanded Genetic Alphabet

2015

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All biological information, since the last common ancestor of all life on earth, has been encoded by a genetic alphabet consisting of only four nucleotides that form two base pairs. Long standing efforts to develop two synthetic nucleotides that form a third, unnatural base pair (UBP) have recently yielded three promising candidates, one based on alternate hydrogen bonding, and two based on hydrophobic and packing forces. All three UBPs are replicated and transcribed with remarkable efficiency and fidelity, and the latter two thus demonstrate that hydrogen bonding is not unique in its ability to underlie the storage and retrieval of genetic information. This review highlights these recent developments as well as the applications enabled by the UBPs, including the expansion of the evolution process to include new functionality and the creation of semi-synthetic life that stores increased information.

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Section: Introduction and Overviewmentioning

confidence: 99%

The Expanded Genetic Alphabet

2015

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“…The structures 4.1 and 4.2 shown in Fig 1 illustrate the concept of mechanism-based suicide-inhibition. Fig 2 shows a realistic functional derivative of the conceptual structure 4.1. in Fig 1 [ 26 , 27 ]. In essence, our mechanism-based inhibitor is designed to mimic the last elimination step in the catalytic cycle of DNA methyltransferases ( Fig 1 ).…”

Section: Transition-state Analogue As a Lead Compound For A Mechanismmentioning

confidence: 99%

“… ( A ) The figure shows our first prototype for a mechanism-based inhibitor of Dnmt1. The structure is derived from the structure 4.1 in Fig 1 as a reasonable challenge for organic synthesis that has a reasonable agreement with the Lipinski's rules [ 26 , 27 ]. The structure is designed to act as a transition state analogue and consists of four functional parts: adenine, ribose, tertiary amine linker and 1-methyl-pyrimidin-2-one as the target base ring.…”

Section: Transition-state Analogue As a Lead Compound For A Mechanismmentioning

confidence: 99%

In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1

et al. 2017

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BackgroundWe use our earlier experimental studies of the catalytic mechanism of DNA methyltransferases to prepare in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for analysis of human epigenome and for the creation of iPS cells.ResultsWe describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel mechanism-based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition-state analogues. Molecular dynamics studies showed that the lead compound can form between 6 to 9 binding interactions with Dnmt1. QM/MM analysis showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNA-free form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented analysis is described in detail using 69 modifications in the lead compound structure. In total 18 of the presented 69 modifications can be used to prepare a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases.ConclusionsPresented results can be used for preparation of some highly specific and potent inhibitors of mammalian DNA methylation with specific pharmacological properties.

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“…Moreover, several novel nucleoside analogs (including those embedded in versatile conjugate or pronucleotide scaffolds) are under clinical or preclinical trials [1]. Recent studies have also revealed a potential of nucleoside analogs as radiopharmaceuticals [2–6], antibiotics [7–9], anti-infective agents [10–12], or molecular probes [13–14]. Taking into account the importance of nucleoside analogs in medicine and biotechnology, there is a considerable interest in the development of simple and efficient synthesis of these compounds.…”

Section: Introductionmentioning

confidence: 99%

Multicomponent reactions in nucleoside chemistry

Koszytkowska‐Stawińska¹,

Buchowicz²

2014

Beilstein J. Org. Chem.

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SummaryThis review covers sixty original publications dealing with the application of multicomponent reactions (MCRs) in the synthesis of novel nucleoside analogs. The reported approaches were employed for modifications of the parent nucleoside core or for de novo construction of a nucleoside scaffold from non-nucleoside substrates. The cited references are grouped according to the usually recognized types of the MCRs. Biochemical properties of the novel nucleoside analogs are also presented (if provided by the authors).

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Chemical Synthesis of Conformationally Constrained PNA Monomers

Cited by 23 publications

References 83 publications

The Expanded Genetic Alphabet

The Expanded Genetic Alphabet

In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1

Multicomponent reactions in nucleoside chemistry

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