Conformationally-preorganized, MiniPEG-containing gamma-peptide nucleic acids

Patent metadata

Field	Value
Publication number	US-11279736-B2
Application number	US-202017003131-A
Country	US
Kind code	B2
Filing date	Aug 26, 2020
Priority date	Apr 8, 2011
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

Abstract

The present invention relates to γ-PNA monomers according to Formula I where substituent groups R1, R2, R3, R4, R5, R6, B and P are defined as set forth in the specification. The invention also provides methodology for synthesizing compounds according to Formula I and methodology for synthesizing PNA oligomers that incorporate one or more Formula I monomers.

First claim

What is claimed is:

1. A compound according to Formula I

wherein
B is a nucleic acid base;
R 1 , R 2 and R 5 each independently is selected from the group consisting of H, linear or branched (C 1 -C 8 )alkyl, and —CH 2 —(OCH 2 —CH 2 ) q OP 1 , provided that at least one of R 1 and R 2 independently is —CH 2 —(OCH 2 —CH 2 ) q OP 1 ;
R 3 and R 4 each independently is H;
R 6 is selected from the group consisting of H, linear or branched (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )aryl and (C 3 -C 8 )aryl(C 1 -C 6 )alkylene;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl, Boc, benzyloxycarbonyl, tosylate, benzyl, alloc, trityl, dimethoxytrityl and monomethoxytrityl;
P 1 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene;
n is an integer between 0 and 10 inclusive, and
q is an integer between 1 and 10 inclusive.

2. The compound according to claim 1 , wherein each of R 1 and R 2 is independently —CH 2 —O—(CH 2 -CH 2 —O) q P 1 .

3. The compound according to claim 2 , wherein R 1 is —CH 2 —(O—CH 2 —CH 2 ) n OP 1 and R 2 is selected from the group consisting of H and linear or branched (C 1 -C 8 )alkyl.

4. The compound according to claim 3 , wherein R 1 is —CH 2 —(O—CH 2 —CH 2 ) q OP 1 and R 2 is H.

5. The compound according to claim 4 , wherein P 1 is H or (C 1 -C 8 )alkyl.

6. The compound according to claim 1 , having stereochemical purity in the range from about 80% to about 99% at the Cγ-position.

7. The compound according to claim 6 , having stereochemical purity of at least 90% at the Cγ-position.

8. The compound according to claim 6 , having stereochemical purity of at least 99% at the Cγ-position.

9. A method for synthesizing a peptide nucleic acid (PNA) oligomer having a pre-determined sequence, comprising:
(a) activating the carboxylic acid group of an allyl linker according to Formula

(b) contacting a solid support with the activated allyl linker;
(c) activating the carboxylic acid group of a first amino protected PNA monomer or an amino protected γPNA monomer depending on the PNA oligomer sequence and then contacting the activated carboxylic acid monomer to the product from step (b);
(d) de-protecting the amino group of the product from step (c);
(e) contacting the product from step (d) with a second sequence specific PNA monomer or a γ-PNA monomer; and
(f) repeating steps (c), (d) and (e) to synthesize the peptide nucleic acid (PNA) oligomer comprising at least one PNA monomer;
wherein
the γ-PNA monomer is a compound according to Formula I

wherein
B is a nucleic acid base selected from adenine, guanine, cytosine, thymine or uracil;
R 1 R 2 and R 5 each independently is selected from the group consisting of H, linear or branched (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene, —CH 2 —(OCH 2 —CH 2 ) q —OP 1 , —CH 2 —(OCH 2 —CH 2 ) q —NHP1, —CH 2 —(OCH 2 —CH 2 ) q —SP 1 and —CH 2 —(SCH 2 —CH 2 ) q —SP 1 ;
R 3 and R 4 each independently is H;
R 6 is selected from the group consisting of H, linear or branched (C 1 -C 8 )alkyl, substituted or unsubstituted (C 3 -C 8 )aryl and (C 3 -C 8 )aryl(C 1 -C 6 )alkylene;
P is selected from the group consisting of H, 9-fluorenylmethyloxy carbonyl, Boc, benzyloxycarbonyl, tosylate, benzyl, alloc, trityl, dimethoxytrityl and monomethoxytrityl;
P 1 is selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )aryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )aryl(C 1 -C 6 )alkylene and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkylene; and
n and q each independently is an integer between 0 and 10 inclusive.

10. The method of claim 9 , wherein steps (a) through (f) are performed using an automated solid-phase synthesizer.

11. The compound of claim 1 , wherein B is adenine.

12. The compound of claim 1 , wherein B is guanine.

13. The compound of claim 1 , wherein B is cytosine.

14. The compound of claim 1 , wherein B is thymine.

15. The compound of claim 1 , wherein B is uracil.

Assignees

• Univ Carnegie Mellon

Inventors

• Ly Danith H
• Rapireddy Srinivas
• Sahu Bichismita

Classifications

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• C07K14/003 Primary

  Peptide-nucleic acids (PNAs) · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07K1/08

  using activating agents {(C07K1/003, C07K1/006 take precedence)} · CPC title