Synthesis of Peptide Nucleic Acid Monomers Containing the Four Natural Nucleobases: Thymine, Cytosine, Adenine, and Guanine and Their Oligomerization

Dueholm, K. L.; Egholm, Michael; Behrens, Carsten; Christensen, Leif; Hansen, Henrik F.; Vulpius, Tore; Petersen, Kenneth H.; Berg, Rolf H.; Nielsen, Peter E.; Buchardt, Ole

doi:10.1021/jo00098a042

Cited by 300 publications

(249 citation statements)

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“…Solvents and reagents were reagent-grade, purchased from commercial suppliers, and used without further purification unless otherwise stated. The following compounds were prepared according to literature procedures: 6-chloropyridine-2,3-diamine (47) [17], (naphthalene-1,4-diyl)dimethanol (60) [18], and benzyl (1,2-dihydro-2-oxopyrimidin-4-yl)carbamate (63) [19]. THF was freshly distilled from sodium benzophenone ketyl, CH 2 Cl 2 from CaH 2 .…”

Section: Experimental Partmentioning

confidence: 99%

Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF, an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis

Baumgartner

Eberle

Diederich

et al. 2007

Helvetica Chimica Acta

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In this paper, we describe the structure-based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C 5 precursors to isoprenoids, isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2; Scheme 1). The nonmevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non-mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs. 2 and 3), new cytosine derivatives and analogues (Fig. 1) were selected as potential drug-like inhibitors of IspF protein, and synthesized (Schemes 2 -5). Determination of the enzyme activity by 13 C-NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine-2,5-diamine derivatives in the upper micromolar range (IC 50 values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56', which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub-pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to Pocket III ) and rings that occupy the flexible hydrophobic region of Pocket II . The proposed binding mode remains to be further validated by X-ray crystallography.

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Section: Experimental Partmentioning

confidence: 99%

Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF, an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis

Baumgartner

Eberle

Diederich

et al. 2007

Helvetica Chimica Acta

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“…1 Following this landmark publication, in 1994 the details for the synthesis of the complete set of the PNA monomers of the four natural nucleobases and their oligomerization was disclosed. 2 Due to PNA's ability to bind strongly and selectively to complementary sequences, it has stimulated interest in a variety of applications from nucleic acid detection to supramolecular chemistry. 3 Concomitant with the high interest that PNA elicited, a variety of chemistries were developed for the synthesis of oligomers that spanned Boc, Fmoc and Mmt-based oligomerization strategies among others.…”

Section: Introductionmentioning

confidence: 99%

“…3 Concomitant with the high interest that PNA elicited, a variety of chemistries were developed for the synthesis of oligomers that spanned Boc, Fmoc and Mmt-based oligomerization strategies among others. 2,[4][5][6] Our own interest in developing PNA chemistry was driven by the need for orthogonal protecting groups for the synthesis of nucleobase modified PNAs. 7,8 PNA bearing modified nucleobases have been explored for endowing PNA oligomers with new biophysical properties, as a labeling strategy, or to incorporate expanded functionality such as fluorescence.…”

Section: Introductionmentioning

confidence: 99%

A solid-phase CuAAC strategy for the synthesis of PNA containing nucleobase surrogates

Amant

Engbers

Hudson

2013

Artificial DNA: PNA & XNA

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“…Potential triplex interactions were investigated using a homopyrimidine decamer, PNA-(T)10, hybridized with a poly(dA) strand. In addition, a number of PNAs, with specific sequences, or in which the backbone had been modified, were studied with respect to drug The PNA and DNA oligonucleotides were synthesised as described elsewhere (6,7,16). The synthetic polynucleotides poly(dA) and poly(dT) were purchased from Pharmacia.…”

Section: Introductionmentioning

confidence: 99%

Interactions of DNA binding ligands with PNA-DNA hybrids

et al. 1994

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The interactions of two representative mixed-sequence (one with an AT-stretch) PNA -DNA duplexes (10 or 15 base-pairs) and a PNA2/DNA triplex with the DNA binding reagents distamycin A, 4',6-diamidino-2-phenylindole (DAPI), ethidium bromide, 8-methoxypsoralen and the A and A enantiomers of Ru(phen)2-dppz2+ have been investigated using optical spectroscopic methods. The behaviour of these reagents versus two PNA -PNA duplexes has also been investigated. With triple helical poly(dA)/(H-T10-Lys-NH2)2 no significant intercalative binding was detected for any of the DNA intercalators, whereas DAPI, a DNA minor groove binder, was found to exhibit a circular dichroism with a positive sign and amplitude consistent with minor groove binding. Similarly, a PNA-DNA duplex containing a central AATA motif, a typical minor groove binding site for the DNA minor groove binders distamycin A and DAPI, showed binding for both of these drugs, though with strongly reduced affinity. No important interactions were found for any of the ligands with a PNA -DNA duplex consisting of a ten base-pair mixed purine-pyrimidine sequence with only two AT base-pairs in the centre. Nor did any of the ligands show any detectable binding to the PNA -PNA duplexes (one containing an AATT motif). Various PNA derivatives with extentions of the backbone, believed to increase the flexibility of the duplex to opening of an intercalation slot, were tested for intercalation of ethidium bromide or 8-methoxypsoralen into the mixed sequence PNA-DNA duplex, however, without any observation of improved binding. The importance of the ionic contribution of the deoxyribose phosphate backbone, versus interactions with the nucleobases, for drug binding to DNA is discussed in the light of these findings. INTRODUCTIONThe interactions of double stranded DNA with small as well as with large molecules are often divided into contributions from the deoxyribose phosphate backbone and from the nucleobases themselves, although this segregation of binding/recognition components is not easily made. The main electrostatic component of the binding energy of cationic ligands is generally attributed to the negative phosphates of the DNA backbone, whereas the nucleobases contribute hydrophobic and dispersive bonding components but also considerable electrostatic components in terms of hydrogen and dipolar bonding (1,2). Specific interactions with the nucleobases naturally determine the sequence specificity exhibited by a ligand, for proteins they are also assisted by 'textured' properties such as helical pitch, indirectly determined by the base-sequence (3,4). However, the relative importance of electrostatic and hydrophobic contributions in the recognition/ binding process is far from clear, even for rather simple ligands such as typical intercalators and minor groove binders.We recently prepared a DNA analog termed PNA (peptide nucleic acid) containing an uncharged pseudo-peptide backbone composed of N-(2-aminoethyl)glycine units to which the nucleobases are attached (Figure ...

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Synthesis of Peptide Nucleic Acid Monomers Containing the Four Natural Nucleobases: Thymine, Cytosine, Adenine, and Guanine and Their Oligomerization

Cited by 300 publications

References 0 publications

Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF, an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis

Structure‐Based Design and Synthesis of the First Weak Non‐Phosphate Inhibitors for IspF, an Enzyme in the Non‐Mevalonate Pathway of Isoprenoid Biosynthesis

A solid-phase CuAAC strategy for the synthesis of PNA containing nucleobase surrogates

Interactions of DNA binding ligands with PNA-DNA hybrids

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