α-cycloPNA: 1-Aminocylopentane-1-carboxylic acid-derived peptide nucleic acid

Article abstract of DOI:10.1081/NCN-120022963

All four diastereoisomers of 3-thymine-1-( ^tbutoxycarbonyl)aminocyclopentane-1-carboxylic acid have been synthesised from (S)-dimethyl malate and thymine monomer 12 has been incorporated into an α-cycloPNA oligomer.

Full text of DOI:10.1081/NCN-120022963

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α-cycloPNA: 1-Aminocylopentane-1-carboxylic Acid-
Derived Peptide Nucleic Acid
Nicola M. Howarth a c , Laurence P. G. Wakelin b & David M. Walker a
a Chemistry, School of Engineering and Physical Sciences , Heriot-Watt University ,
Riccarton, Edinburgh, UK
b School of Medical Sciences , University of New South Wales , Sydney, Australia
c Chemistry, School of Engineering and Physical Sciences , Heriot-Watt University , William
H. Perkin Building, EH14 4AS, Riccarton, Edinburgh, UK
Published online: 31 Aug 2006.
To cite this article: Nicola M. Howarth , Laurence P. G. Wakelin & David M. Walker (2003) α-cycloPNA: 1-Aminocylopentane-1-
carboxylic Acid-Derived Peptide Nucleic Acid, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1351-1353, DOI: 10.1081/
NCN-120022963
To link to this article: http://dx.doi.org/10.1081/NCN-120022963
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1351–1353, 2003
a-cycloPNA: 1-Aminocylopentane-1-carboxylic Acid-Derived
Peptide Nucleic Acid
2
1
Nicola M. Howarth,1, Laurence P. G. Wakelin, and David M. Walker
*
1Chemistry, School of Engineering and Physical Sciences,
Heriot-Watt University, Riccarton, Edinburgh, UK
2School of Medical Sciences, University of New South Wales,
Sydney, Australia
ABSTRACT
All four diastereoisomers of 3-thymine-1-(tbutoxycarbonyl)aminocyclopentane-
1-carboxylic acid have been synthesised from (S)-dimethyl malate and thymine
monomer 12 has been incorporated into an a-cycloPNA oligomer.
Key Words: PNA; Cyclic a,a-disubstituted amino acids.
Polyamide analogues of DNA (1), termed PNA, have attracted much interest as
potential regulators of gene expression as a consequence of their ability to invade ds-
DNA.[1] However, one limitation hindering the development of PNA is that strand
invasion by simple examples is generally restricted to homopurine and homopyrimi-
dine sequences.[1] Thus, there is the need to explore other PNA analogues for the
purpose of expanding the strand invasion alphabet. Recently, we have reported
the design and synthesis of a true peptide mimic of DNA, designated L-a-PNA
(2).[2] Surprisingly, despite molecular models indicating structural complementarity,
*Correspondence: Nicola M. Howarth, Chemistry, School of Engineering and Physical
Sciences, William H. Perkin Building, Heriot-Watt University, Riccarton, Edinburgh EH14
4AS, UK; Fax: þ44 131 4513180; E-mail: n.m.howarth@hw.ac.uk.
1351
DOI: 10.1081/NCN-120022963
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1352
Howarth, Wakelin, and Walker
L-a-PNA oligomers fail to hybridise to single-stranded target DNAs. We believe
that this is due to flexibility in the side chain linking the bases to the backbone
and so we are currently exploring side chain restricted analogues. One of the pro-
posed oligomers for study is a-cycloPNA (3).
Synthetic routes to all four diastereoisomers of the thymine monomer required
for construction of the a-cycloPNA oligomers have now been developed starting
from commercially available (S)-dimethyl L-malate (4) as outlined below.
Reagents: i. Ph3CCl, DBU, DCM; ii. LiBH4, B-methoxy-9-BBN, THF; iii. MsCl, Et3N, DCM; iv. NaI,
acetone; v. Ph2CNCH2CO2Et, LiHMDS, THF; vi. (a) 2M(aq) HCl (b) (Boc)2O, Na2CO3; vii.
BrC6H4SO2Cl, DMAP, Et3N, CHCl3; viii. N3-benzoylthymine, NaH, DMF; ix. NaOEt, EtOH; x.
2=3M(aq) NaOH, dioxane; xi. PPh3, DIAD, MeI, THF.

1-Aminocylopentane-1-carboxylic Acid-Derived PNA
1353
Finally, monomer 12 has been successfully incorporated into an a-cycloPNA
oligomer using our established manual solid phase protocol.[2]
REFERENCES
1. Uhlmann, E.; Peyman, A.; Breipohl, G.; Will, D.W. PNA: Synthetic polyamide
nucleic acids with unusual binding properties. Angew. Chem. Int. Ed.
1998, 37, 2796–2823.
2. Howarth, N.M.; Wakelin, L.P.G. a-PNA: A novel peptide nucleic acid anologue
of DNA. J. Org. Chem. 1997, 62, 5441–5450.