Chiral, charged peptide nucleic acid oligomers from cyclic monomers
AssigneeCouncil of Scientific and Industrial Research
InventorsVaijayanti A. Kumar, Moneesha D'Costa, Krishnarajanagar N. Ganesh
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Abstract
A novel class of peptide nucleic acid compounds, which are positively charged, chiral analogs based on cyclic monomeric units, bind to complementary ssDNA, dsDNA and RNA strands with more affinity than the corresponding achiral, linear peptide nucleic acids, without compromising the binding sequence specificity and the compounds of this invention are more soluble in water than the standard peptide nucleic acids.
Claims10
A compound having the formula
- wherein
- m and n are 1 to 2 and x=1-20;
- each of B is independently selected from the group consisting of naturally occurring nucleobases adenine (A), thymine (T), cytosine (C) and guanine (G), and non-naturally occurring nucleobases;
- each chiral monomeric unit is independently selected from the four possible diastereomers;
- and
- R1=H or Fluorophore or Biotin, R2=OH or NH(CH2)2COOH or NH(CH2)3NH(CH2)4NH(CH2)3NH2.
A compound having the formula
- that is heteropolymeric aepPNA III comprising non-chiral aeg unit of aminoethylglycyl PNA I and chiral aep monomeric unit IV
- wherein
- T is a nucleobase;
- each chiral monomer unit is independently selected from the four possible diastereomers;
- a, b, c, d, m, n are integers with independent values in the range 1 to 10;
- R1 is H, COCH3 or L (L=dansyl, carboxyfluoresceinyl);
- R2 is OH, NH2, NHCH2CH2COOH, or NH(CH2)3NH(CH2)4NH(CH2)3NH2, and
- each of B is independently selected from the group consisting of H, HO, NH2, naturally occurring nucleobases, non-naturally occurring nucleobases, DNA intercalators, heterocyclic moieties and reporter ligands.
A monomer precursor-synthon of formula IV
- wherein
- R1=H, Boc or Fmoc:
- R2=OMe, H, OEt or OBenzyl;
- chirality at positions 2 and 4 results in four diastereomers (2S,4R), (2R,4S), (2S,4S) and (2R,4R);
- and
- T is a nucleobase.
A process for preparing compounds of formulae 4a and 6a
- comprising the steps of
- A. a) synthesizing (N-Boc)-2-aminoethanol from 2-aminoethanol;
- b) synthesizing (N-Boc)-2-aminoethylbromide from (N-Boc)-2-aminoethanol;
- B. N-alkylation of 4-hydroxyprolinemethylester with (N-Boc)-2-aminoethanol prepared as in step A;
- (i) alkylation of 4R-hydroxy-2S-prolinemethylester with (N-Boc)-2-aminoethylbromide to obtain 1-(N-Boc-aminoethyl)-4R-hydroxy-2S-prolinemethyl ester;
- (ii) alkylation of 4R-hydroxy-2R-prolinemethylester with (N-Boc)-2-aminoethyl bromide to obtain 1-(N-Boc-aminoethyl)-4R-hydroxy-2R-prolinemethyl ester;
- (iii) alkylation of 4S-hydroxy-2R-prolinemethylester with (N-Boc)-2-aminoethyl bromide to obtain 1-(N-Boc-aminoethyl)-4S-hydroxy-2R-prolinemethylester;
- (iv) alkylation of 4S-hydroxy-2S-prolinemethylester with (N-Boc)-2-aminoethyl bromide to obtain —(N-Boc-aminoethyl)-4S-hydroxy-2S-prolinemethylester;
- C. Mitsunobu reaction of compounds 1-(N-Boc-aminoethyl)-4R-hydroxy-2S-prolinemethyl ester and (N-Boc)-2-aminoethanol prepared according to steps B(i) and B(ii) with N3-benzoylthymine, to produce monomer synthons of formulae 4a and 6a, respectively.
Dependencies are inferred from the claim text.