Alpha-morpholino ribonucleoside derivatives and polymers thereof

• US 5,235,033 A
• Filed: 12/20/1989
• Issued: 08/10/1993
• Est. Priority Date: 03/15/1985
• Status: Expired due to Term

• Current Assignee: AntiVirals, Inc. (Sarepta Therapeutics, Inc.)
• Original Assignee: Anti-Gene Development Group
• Inventors: Weller, Dwight D., Summerton, James E., Stirchak, Eugene P.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Datlow, Philip I.
• Application Number:
  US07/454,056
• Time in Patent Office: 1,329 Days
• Field of Search: 544/81, 544/82, 528/391, 528/403, 528/405, 528/406
• US Class Current: 528/391
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07K 14/003 Peptide-nucleic acids (PNAs)
• CPC Class Codes: C12Q 1/6813 Hybridisation assays
• CPC Class Codes: C12Q 1/682 Signal amplification

Abstract

Alpha-morpholino subunits and polymer compositions composed of alpha-morpholino subunits are disclosed. These subunits can be linked together by uncharged linkages, one to three atoms in length, joining the morpholino nitrogen of one subunit to the 5'"'"' exocyclic carbon of an adjacent subunit. Each subunit contains a purine or pyrimidine base-pairing moiety effective to bind by hydrogen bonding to a specific base or base-pair in a target polynucleotide. The polymers of the present invention can be used in place of standard RNA or DNA oligomers for a number of standard laboratory procedures, for example, as probes in solid-phase systems and nucleic acid hybridization analyses. Further, the polymers of the present invention have potential use as therapeutic agents in anti-sense-type technologies.

Claims

1. A polymer composition comprised of α

-morpholino subunit structures of the form;

##STR2## where (i) the structures are linked together by uncharged linkages, one to three atoms long, joining the morpholino nitrogen of one subunit to the 5'"'"', exocyclic carbon of an adjacent subunit, and (ii) P_i is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

2. The composition of claim 1, wherein P_i is selected from the group consisting of:

##STR3## where X is H, CH₃, F, Cl, Br, or I.

3. The composition of claim 1, wherein the linked structures have a form selected from the group consisting of:

##STR4##

4. The composition of claim 1, wherein the linkage is of the form:

##STR5## where P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

5. The composition of claim 1, wherein the linkage is of the form:

##STR6## where R is H, CH₃, or other alkyl; and

,

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

6. The composition of claim 1, wherein the linkage is of the form:

##STR7## where X is alkyl, alkoxy, thioalkoxy, or an unsubstituted, monosubstituted, or disubstituted nitrogen; and

,

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

7. The composition of claim 1, wherein the linkage is of the form:

##STR8## where X is alkyl, alkoxy, thioalkoxy, or an unsubstituted, monosubstituted, or disubstituted nitrogen;

R is H or CH₃ ; and

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

8. The composition of claim 1, wherein the linkage is of the form:

##STR9## where X is alkyl, alkoxy, thioalkoxy, or an unsubstituted, monosubstituted, or disubstituted nitrogen; and

,

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

9. The composition of claim 1, wherein the linkage is of the form:

##STR10## where X is alkyl, alkoxy, thioalkoxy, or an unsubstituted, monosubstituted, or disubstituted nitrogen;

R is H or CH₃ ; and

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

10. The composition of claim 1, wherein the linkage is of the form ##STR11## where R is H or CH₃, or other alkyl;

and

P_j is a purine or pyrimidine base-pairing moiety effective to bind by base-specific hydrogen bonding to a base in a polynucleotide.

11. The composition of claim 1, which further includes a moiety at one or both termini which is effective to enhance the solubility of the polymer in aqueous medium.

12. The composition of claim 11, wherein the terminal moiety is polyethylene glycol.

13. The composition of claim 1, composed of at least 3 morpholino subunits.

14. The composition of claim 1, wherein at least one of the P_i is a 2,6-diaminopurine.

15. The composition of claim 1, wherein at least one of the P_i is a 5-halouracil.

16. The composition of claim 1, wherein at least 70% of the P_i are 2-amine containing purines.