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US 5,801,155 AGranted
Covalently linked oligonucleotide minor grove binder conjugates
AssigneeEpoch Pharmaceuticals, Inc.
InventorsIgor V. Kutyavin, Eugeny A. Lukhtanov, Howard B. Gamper, Rich B. Meyer, Jr.
Life of this patent
Estimating the term…
Abstract
Minor groove binding molecules are covalently bound to oligonucleotides which in their base sequence are complementary to a target sequence of single stranded or double stranded DNA, RNA or hybrids thereof. The covalently bound oligonucleotide minor groove binder conjugates strongly bind to the target sequence of the complementary strand.
Claims28
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binder moiety is a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that before attachment to said oligonucleotide binds in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybrids thereof with an association constant greater than approximately 10.sup.3 M.sup.-1 and wherein the minor groove binder is attached through the linking group to a site of the oligonucleotide which is selected from the group consisting of the 5'-end of the oligonucleotide, the 3'-end of the oligonucleotide and a heterocyclic base in an intermediate position within said oligonucleotide.
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binder moiety is a radical of a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that bind in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybdrids thereof with an association constant greater than approximately 10.sup.3 M.sup.-1 wherein the minor groove binding moiety including the linking group is represented by formula (b)
- R.sub.1 --(R.sub.6 N--Y.sub.2 --CO).sub.n --R.sub.2 (b)
- where Y.sub.2 is a ring system consisting of a 6-membered aromatic ring condensed with a 5-membered ring having one double bond, the condensed ring system having 0 to 3 heteroatoms selected from the group consisting of N, S and O, each of the R.sub.6 N and CO groups is attached to a ring carbon which is in a different ring of the condensed ring system, and which is the second ring atom, respectively, from one common bridgehead ring atom, the CO and NR.sub.6 groups thereby positioning 2 non-bridgehead ring atoms between themselves on one side and 3 non-bridgehead ring atoms on the other side of the condensed ring system, the two non-bridgehead ring atoms on the one side being optionally substituted with an R.sub.7 group, the three non-bridgehead ring atoms on the other side of the condensed ring system being optionally substituted with an R.sub.3 group;
- where R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.3 is selected from the group consisting of F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2 and R.sub.4 ;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- R.sub.6 is H, alkyl of 1 to 5 carbons;
- R.sub.7 is F, methyl or ethyl;
- --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --;
- m is an integer between 1 to 10;
- n is an integer between 1 to 10, and
- p is an integer between 1 to 5.
10 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binder moiety is a radical of a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that bind in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybdrids thereof with an association constant greater than approximately 10.sup.3 M.sup.-1 wherein the minor groove binding moiety including the linking group is represented by formula (c)
- R.sub.1 --(CO--Y.sub.3 --NH).sub.n --R.sub.2 (c)
- wherein Y.sub.3 is a 6-membered aromatic ring having 0 to 3N heteroatoms, and where each of the CO and NH groups is attached to a ring carbon, said ring carbons being in 1,4 position relative to one another, two ring atoms not occupied by the CO or NH groups on either one of the two sides of the 6-membered ring being optionally substituted with an R.sub.3 group, the two ring atoms not occupied on the other side of the 6 membered ring being optionally substituted with an R.sub.7 group;
- where R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.3 is selected from the group consisting of F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, and CON(R.sub.4).sub.2 ;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- R.sub.7 is F, methyl or ethyl;
- --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --;
- m is an integer between 1 to 10, and
- n is an integer between 1 to 10.
8 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binding moiety including the linking group has the formula ##STR20## where n is 2 to 5.
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binding moiety including the linking group has the formula ##STR21## where n is 2 to 5.
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, the combination having the formula ##STR24## where x is O or S;
- q is an integer between 3 to 100;
- R.sub.8 is H, OH, alkoxy having 1 to 6 carbons, O--C.sub.2 -C.sub.6 alkenyl, or F;
- B is an aglycon selected from a group consisting of a heterocyclic base naturally found in nucleic acids and hypoxanthine, 2-aminoadenine, 2-thiouracil, 2-thiothymine, 5-N.sup.4 -ethenocytosine, 4-aminopyrrazolo 3,4-d!pyrimidine, 6-amino-4-hydroxy-3,4-d!pyrimidine;
- W.sub.1 is H, PO(OH).sub.2 or a salt thereof, or a minor groove binder moiety attached to the 3' or 5' end of said oligonucleotide, including the linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms;
- W.sub.2 is absent or is a minor groove binder moiety attached to one of the aglycons B including the linking group which covalently binds the minor groove binder moiety to said aglycon, or W.sub.2 is a cross-linking functionality including a linker arm which covalently binds the cross-linking functionality to said aglycon,
- wherein the minor groove binder moiety is a radical of a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that bind in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybdrids thereof with an association constant greater than approximately M.sup.-1, with the proviso that at least one of said W.sub.1 and W.sub.2 groups is a minor groove binder moiety.
4 more elements
An oligonucleotide minor groove binder combination in accordance with claim 22 wherein the minor groove binder moiety including the linking group has the formula selected from the group consisting of groups (a), (b), (c), (d) and (e):
- R.sub.1 --(HN--Y.sub.1 --CO).sub.n --R.sub.2 (a)
- where Y.sub.1 represents a 5-membered ring having two double bonds and 0 to 3 heteroatoms selected from the group consisting of N, S and O, the NH and CO groups are attached respectively to two ring carbons which are separated by one ring atom from one another, the ring atom positioned between said two ring carbons is substituted only with H when it is carbon or nitrogen and not substituted when it is oxygen or sulfur, each of the remaining ring atoms may be optionally substituted with 1, 2 or 3 R.sub.3 groups;
- R.sub.1 --(R.sub.6 N--Y.sub.2 --CO).sub.n --R.sub.2 (b)
- where Y.sub.2 is a ring system consisting of a 6-membered aromatic ring condensed with a 5-membered ring having one double bond, the condensed ring system having 0 to 3 heteroatoms selected from the group consisting of N, S and O, each of the R.sub.6 N and CO groups is attached to a ring carbon which is in a different ring of the condensed ring system, and which is the second ring atom, respectively, from one common bridgehead ring atom, the CO and NR.sub.6 groups thereby positioning 2 non-bridgehead ring atoms between themselves on one side and 3 non-bridgehead ring atoms on the other side of the condensed ring system, the two non-bridgehead ring atoms on the one side being optionally substituted with an R.sub.7 group, the three non-bridgehead ring atoms on the other side of the condensed ring system being optionally substituted with an R.sub.3 group;
- R.sub.1 --(CO--Y.sub.3 --NH).sub.n --R.sub.2 (c)
- Y.sub.3 is a 6-membered aromatic ring having 0 to 3N heteroatoms, and where each of the CO and NH groups is attached to a ring carbon, said ring carbons being in 1,4 position relative to one another, two ring atoms not occupied by the CO or NH groups on either one of the two sides of the 6-membered ring being optionally substituted with an R.sub.3 group, the two ring atoms not occupied on the other side of the 6 membered ring being optionally substituted with an R.sub.7 group;
- R.sub.1 --(HN--Y.sub.4 --HN--CO--Y.sub.4 --CO).sub.p --R.sub.2(d)
- where Y.sub.4 is a 6-membered aromatic ring having 0 to 3N heteroatoms, and where each of the CO and NH groups is attached to a ring carbon, said ring carbons being in 1,4 position relative to one another in each ring, two ring atoms not occupied by the CO or NH groups on either one of the two sides of the 6-membered ring being optionally substituted with an R.sub.3 group, the two ring atoms not occupied on the other side of the 6 membered ring being optionally substituted with an R.sub.7 group;
- R.sub.1 --(Y.sub.5).sub.n --R.sub.2 (e)
- where Y.sub.5 is a ring system consisting of a 6-membered aromatic ring condensed with a 5-membered ring having one double bond, the condensed ring system having 0 to 3 heteroatoms selected from the group consisting of N, S and O, each of the R.sub.1 and R.sub.2 groups is attached to a ring carbon which is in a different ring of the condensed ring system, and which is the second ring atom, respectively, from one common bridgehead ring atom, the R.sub.1 and R.sub.2 groups thereby positioning 2 non-bridgehead ring atoms between themselves on one side and 3 non-bridgehead ring atoms on the other side of the condensed ring system, the two non-bridgehead ring atoms on the one side being optionally substituted with an R.sub.7 group, the three non-bridgehead ring atoms on the other side of the condensed ring system being optionally substituted with an R.sub.3 group;
- where R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONH.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.3 is selected from the group consisting of F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2 and R.sub.4, or the R.sub.3 groups may form a 3, 4, 5 or 6 membered ring condensed to the Y.sub.1 rings;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- R.sub.6 is H, alkyl of 1 to 5 carbons, or R.sub.6 and R.sub.7 jointly form a 4, 5, or 6 membered ring, optionally an --O--, --S--, --NH--, --NCH.sub.3 -- or N--lower alkyl group being part of said ring;
- R.sub.7 is F, methyl or ethyl;
- --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --;
- m is an integer between 1 to 10;
- n is an integer between 1 to 10, and
- p is an integer between 1 to 5.
17 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binder moiety is a radical of a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that bind in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybdrids thereof with an association constant greater than approximately 10.sup.3 M.sup.-1 wherein the minor groove binding moiety including the linking group is represented by formula (d)
- R.sub.1 --(HN--Y.sub.4 --HN--CO--Y.sub.4 --CO).sub.p --R.sub.2(d)
- where Y.sub.4 is a 6-membered aromatic ring having 0 to 3N heteroatoms, and where each of the CO and NH groups is attached to a ring carbon, said ring carbons being in 1,4 position relative to one another in each ring, two ring atoms not occupied by the CO or NH groups on either one of the two sides of the 6-membered ring being optionally substituted with an R.sub.3 group, the two ring atoms not occupied on the other side of the 6 membered ring being optionally substituted with an R.sub.7 group;
- where R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.3 is selected from the group consisting of F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2 and R.sub.4 ;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- R.sub.7 is F, methyl or ethyl;
- --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --;
- m is an integer between 1 to 10, and
- p is an integer between 1 to 5.
8 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binder moiety is a radical of a molecule having a molecular weight of approximately 150 to approximately 2000 Daltons that bind in a non-intercalating manner into the minor groove of double stranded DNA, RNA or hybdrids thereof with an association constant greater than approximately 10.sup.3 M.sup.-1 wherein the minor groove binding moiety including the linking group is represented by formula (e)
- R.sub.1 --(Y.sub.5).sub.n --R.sub.2 (e)
- Y.sub.5 is a ring system consisting of a 6-membered aromatic ring condensed with a 5-membered ring having one double bond, the condensed ring system having 0 to 3 heteroatoms selected from the group consisting of N, S and O, each of the R.sub.1 and R.sub.2 groups is attached to a ring carbon which is in a different ring of the condensed ring system, and which is the second ring atom, respectively, from one common bridgehead ring atom, the R.sub.1 and R.sub.2 groups thereby positioning 2 non-bridgehead ring atoms between themselves on one side and 3 non-bridgehead ring atoms on the other side of the condensed ring system, the two non-bridgehead ring atoms on the one side being optionally substituted with an R.sub.7 group, the three non-bridgehead ring atoms on the other side of the condensed ring system being optionally substituted with an R.sub.3 group;
- where R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.3 is selected from the group consisting of F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2 and R.sub.4, or the R.sub.3 groups may form a 3, 4, 5 or 6 membered ring condensed to the Y.sub.5 ring and substituted by one, two or three R.sub.4 ;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- R.sub.7 is F, methyl or ethyl;
- --CH.sub.2 --, or --CH.sub.2 CH.sub.2 --;
- m is an integer between 1 to 10, and
- n is an integer between 1 to 10.
8 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binding moiety including the linking group has the formula ##STR26## where n is 2 to 5.
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, wherein the minor groove binding moiety including the linking group is represented by formula (a)
- R.sub.1 --(HN--Y.sub.1 --CO).sub.n --R.sub.2 (a)
- wherein HN--Y.sub.1 --CO has the structure, ##STR27## and R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- m is an integer between 1 to 10, and
- n is an integer between 1 to 10.
4 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, the combination having the formula ##STR28## where X is O or S;
- q is an integer between 3 to 100;
- R.sub.8 is H, OH, alkoxy having 1 to 6 carbons, O--C.sub.2 -C.sub.6 alkenyl, or F;
- B is an aglycon selected from a group consisting of a heterocyclic base naturally found in nucleic acids and hypoxanthine, 2-aminoadenine, 2-thiouracil, 2-thiothymine, 5-N.sup.4 -ethenocytosine, 4-aminopyrazolo 3,4-d!pyrimidine, 6-amino-4-hydroxypyrazolo-3,4-d!pyrimidine;
- W.sub.1 is H, PO(OH).sub.2 or a salt thereof, or a minor groove binder moiety attached to the 3' or 5' end of said oligonucleotide, including the linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, with the proviso that at least one of the W.sub.1 groups is a minor group binder and a linking group and wherein the minor groove binding moiety including the linking group is represented by formula (a)
- R.sub.1 --(HN--Y.sub.1 --CO).sub.n --R.sub.2 (a)
- wherein HN--Y.sub.1 --CO has the structure, ##STR29## and R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- m is an integer between 1 to 10, and
- n is an integer between 1 to 10.
8 more elements
An oligonucleotide minor groove binder combination comprising an oligonucleotide having a plurality of nucleotide units, a 3'-end and a 5'-end, and
- a minor groove binder moiety attached to at least one of said nucleotides through a linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, the combination having the formula ##STR30## where X is O or S;
- q is an integer between 3 to 100;
- R.sub.8 is H, OH, alkoxy having 1 to 6 carbons, O--C.sub.2 -C.sub.6 alkenyl, or F;
- B is an aglycon selected from a group consisting of a heterocyclic base naturally found in nucleic acids and hypoxanthine, 2-aminoadenine, 2-thiouracil, 2-thiothymine, 5-N.sup.4 -ethenocytosine, 4-aminopyrrazolo 3,4-d!pyrimidine, 6-amino-4-hydroxypyrazolo-3,4-d!pyrimidine;
- W.sub.1 is H, PO(OH).sub.2 or a salt thereof, or a minor groove binder moiety attached to the 3' or 5' end of said oligonucleotide, including the linking group which covalently binds the minor groove binder moiety to the oligonucleotide through no more than 15 atoms, with the proviso that at least one of the W.sub.1 groups is a minor groove binder and a linking group and wherein the minor groove binding moiety including the linking group is represented by the formula
- R.sub.1 --(R.sub.6 N--Y.sub.2 --CO).sub.n --R.sub.2 (b)
- wherein R.sub.6 N--Y.sub.2 --CO has the formula ##STR31## and R.sub.1 and R.sub.2 independently are H, F, Cl, Br, I, NH.sub.2, NHR.sub.4, N(R.sub.4).sub.2, N(R.sub.4).sub.3.sup.+, OH, OR.sub.4, SH, SR.sub.4, COR.sub.4, CONHR.sub.4, CON(R.sub.4).sub.2, R.sub.4, H.sub.2 N(CH.sub.2).sub.m CO, CONH.sub.2, CONHR.sub.4 and H.sub.2 N(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, O(CH.sub.2).sub.m CO, O(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH, --O--, --S--, --HN(CH.sub.2).sub.m CO, --CONH--, --CONR.sub.4, --HN(CH.sub.2).sub.m COO(CH.sub.2).sub.m S(CH.sub.2).sub.m C.sub.6 H.sub.4 NNC.sub.6 H.sub.4, and --(CH.sub.2).sub.m CH(OH)(CH.sub.2).sub.m NHCO(CH.sub.2).sub.m NH-- or one of the R.sub.1 and R.sub.2 groups is absent;
- R.sub.4 is an alkyl or cycloalkyl group having 1 to 20 carbons, an alkenyl or cycloalkenyl group having 1 to 20 carbons and 1 to 3 double bonds, a carbocyclic aromatic group of no more than 25 carbons, a heterocyclic aromatic group of no more than 25 carbons, a carbocyclic or heterocyclic arylalkyl group of no more than 25 carbons, where R.sub.4 may be optionally substituted with 1, 2 or 3 F, Cl, Br, I, NH.sub.2, NHR.sub.5, N(R.sub.5).sub.2, N(R.sub.5).sub.3.sup.+, OH, OR.sub.5, SH, SR.sub.5, COR.sub.5, CONHR.sub.5, CON(R.sub.5).sub.2 or R.sub.5 groups;
- R.sub.5 is alkyl of 1 to 6 carbons,
- m is an integer between 1 to 10, and
- n is an integer between 1 to 10.
8 more elements
Dependencies are inferred from the claim text.