Thiol compounds and the use thereof for the synthesis of modified oligonucleotides

Patent metadata

Field	Value
Publication number	US-9896473-B2
Application number	US-201314390747-A
Country	US
Kind code	B2
Filing date	Apr 4, 2013
Priority date	Apr 4, 2012
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

The present invention relates to a thiol compound suitable for forming a chain of oligomers that can be grafted to an oligonucleotide. The invention also relates to an oligonucleotide grafted by such a compound, thus having one or more thiol functions, suitable for being immobilized on a gold surface or on a grafted surface.

First claim

The invention claimed is:

1. A compound corresponding to the following formula (I):

in which:
T is a group selected from —O—P(OR 1 )N(R 2 ) 2 , —O—PH(O)O—, —OC(O)JC(O)NH-□,
R 1 is selected from 2-cyanoethyl and R′ 1 R′ 2 R′ 3 SiCH 2 CH 2 groups and R′ 1 , R′ 2 , R′ 3 , which may be identical or different, represent a group selected from linear or branched alkyls comprising from 1 to 12 carbon atoms and the C6-C12 aryls,
R 2 is selected from linear or branched alkyl groups comprising from 1 to 12 carbon atoms and pyrrolidine,
J is selected from a single bond, a —CH 2 —, —CH 2 CH 2 —, —CH 2 OCH 2 — and —CH 2 OPhOCH 2 — group, where Ph is a benzyl,
□ represents a solid support,

D is a protective group of alcohols,
W is selected from C1-C12 alkane triyl groups, C6-C18 aryl triyl groups and C6-C18 aralkane triyl groups,
Z is selected from C1-C12 alkoxy groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups, C1-C12 NCO-alkyl groups, C1-C12 CON-alkyl groups,
Y is selected from linear or branched C1-C12 alkyl groups, C1-C12 aminoalkyl groups, C1-C12 alkoxy groups, C3-C12 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups,
X is selected from linear or branched C1-C12 alkyl groups, C1-C12 aminoalkyl groups, C1-C12 alkoxy groups, C3-C12 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups,
R is selected from C1-C12 acyl, C1-C12 S-alkyl, C6-C12 S-aryl, S-2-pyridine, oxygen-containing or nitrogen-containing C1-C12 S-heteroalkyl, C3-C12 S-cycloalkyl, oxygen-containing or nitrogen-containing C3-C12 S-cycloheteroalkyl groups.

2. The compound according to claim 1 , corresponding to one of the formulas (Ia), (Ib) and (Ic) below:

3. The compound according to claim 1 , wherein:
D is selected from 4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl or fluorenylmethoxycarbonyl;
W is selected from C1-C6 alkane triyl groups, a C6-C12 aryl triyl group, a C6-C12 aralkane triyl group, more particularly from CH, CCH 3 , CCH 2 CH 3 , cyclohexane triyl and benzene triyl groups; and/or
Z is selected from C1-C6 alkoxy groups, oxygen-containing or nitrogen-containing C3-C6 cycloheteroalkyl groups, C1-C6 NCO-alkyl groups, C1-C6 CON-alkyl groups; and/or
Y is selected from linear or branched C1-C6 alkyl groups, C1-C6 aminoalkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C6 cycloheteroalkyl groups; and/or
X is selected from linear or branched C1-C6 alkyl groups, C1-C6 aminoalkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C6 cycloheteroalkyl groups; and/or
R is selected from C1-C6 acyl, C1-C6 S-alkyl, C6-C6 S-aryl, oxygen-containing or nitrogen-containing C1-C6 S-heteroalkyl, C3-C6 S-cycloalkyl, oxygen-containing or nitrogen-containing C3-C6 S-cycloheteroalkyl groups, preferably R is a C1-C6 acyl group.

4. The compound according to claim 1 , wherein T is a group —O—P(OR 1 )N(R 2 ) 2 where R 2 is an isopropyl group and R 1 is chosen from 2-cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(triphenylsilyl)ethyl, 2-(diphenylmethylsilyl)ethyl groups.

5. The compound according to claim 1 , wherein T is a group —OC(O)JC(O)NH-□ where □ is a solid support selected from resins, in particular from resins based on polystyrene, polyacrylamide, polyethyleneglycol, cellulose, polyethylene, polyester, latex, polyamide, polydimethylacrylamide, hydrophilic natural or synthetic polymers, glass beads, silica gels.

6. An oligomer having the formula:
(Ic)-(Δ) k   (XVI) k

in which:
(Ic) has the following formula,

k represents an integer between 1 and 12,
(Δ) represents (I′a) or (I′b), with:

the formulae (Ic), (I′a) and (I′b) in which
□ represents a solid support,
D is a protective group of alcohols,
W is selected from C1-C12 alkane triyl groups, C6-C18 aryl triyl groups and C6-C18 aralkane triyl groups,
Z is selected from C1-C12 alkoxy groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups, C1-C12 NCO-alkyl groups, C1-C12 CON-alkyl groups,
Y is selected from linear or branched C1-C12 alkyl groups, C1-C12 aminoalkyl groups, C1-C12 alkoxy groups, C3-C12 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups,
X is selected from linear or branched C1-C12 alkyl groups, C1-C12 aminoalkyl groups, C1-C12 alkoxy groups, C3-C12 cycloalkyl groups, oxygen-containing or nitrogen-containing C3-C12 cycloheteroalkyl groups,
J is selected from a single bond, a —CH 2 —, —CH 2 CH 2 —, —CH 2 OCH 2 — and —CH 2 OPhOCH 2 — group, where Ph is a benzyl,
R is selected from C1-C12 acyl, C1-C12 S-alkyl, C6-C12 S-aryl, S-2-pyridine, oxygen-containing or nitrogen-containing C1-C12 S-heteroalkyl, C3-C12 S-cycloalkyl, oxygen-containing or nitrogen-containing C3-C12 S-cycloheteroalkyl groups being understood that R can further represent H, and
R 1 is selected from 2-cyanoethyl and R′ 1 R′ 2 R′ 3 SiCH 2 CH 2 groups, and R′ 1 , R′ 2 , R′ 3 , which may be identical or different, represent a group selected from linear or branched alkyls comprising from 1 to 12 carbon atoms and C6-C12 aryls.

7. The oligomer according to claim 6 , having the formula (XIV) k :

in which:
□, D, J, X, Y, W, Z, R and R 1 have the same definition as in claim 6 , and D can further represent H,
k is an integer comprised between 1 and 11.

Assignees

• Centre Nat Rech Scient
• Univ De Montpellier 1
• Francais Du Sang Ets
• Univ Clause Bernard Lyon 1
• Francais Du Sang Ets

Inventors

• Morvan François
• Meyer Albert
• Vasseur Jean Jacques
• Mayen Julie
• Chaix Carole
• Farre Carole
• Fournier Wirth Chantal
• CANTALOUBE Jean François
• Lereau Myriam

Classifications

• C07C323/52

  the carbon skeleton being acyclic and saturated · CPC title

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title

• C07F9/2408

  of hydroxyalkyl compounds · CPC title

• C08F257/02

  on to polymers of styrene or alkyl-substituted styrenes · CPC title

• C12N15/11

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title