Oligonucleotide Analogues Incorporating 5-Aza-Cytosine Therein
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Abstract
Oligonucleotide analogues are provided that incorporate 5-aza-cytosine in the oligonucleotide sequence, e.g., in the form of 5-aza-2′-deoxycytidine (decitabine) or 5-aza-cytidine. In particular, oligonucleotide analogues rich in decitabine-deoxyguanosine islets (DpG and GpD) are provided to target the CpG islets in the human genome, especially in the promoter regions of genes susceptible to aberrant hypermethylation. Such analogues can be used for modulation of DNA methylation, such as effective inhibition of methylation of cytosine at the C-5 position. Methods for synthesizing these oligonucleotide analogues and for modulating nucleic acid methylation are provided. Also provided are phosphoramidite building blocks for synthesizing the oligonucleotide analogues, methods for synthesizing, formulating and administering these compounds or compositions to treat conditions, such as cancer and hematological disorders.
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Citations
231 Claims
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1-114. -114. (canceled)
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115. A pharmaceutical combination comprising:
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1) a first therapeutic agent that is an isolated or synthetic dinucleotide analogue, or its salt or ester, comprising one 5-aza-cytosine as a base residue in the sequence of the dinucleotide analogue, wherein the dinucleotide analogue has a general formula of;
5′
-DpG-3′
or 5′
GpD-3′
, wherein D is decitabine;
p is a phospholinker wherein the number of phosphorus atoms in the phospholinker is one; and
G is deoxyguanosine; and2) a second therapeutic agent. - View Dependent Claims (116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150)
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151. A method for treating a disease in a patient in need of relief thereof, the method comprising administering to the patient:
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1) a therapeutically-effective amount of a first therapeutic agent that is an isolated or synthetic dinucleotide analogue, or its salt or ester, comprising one 5-aza-cytosine as a base residue in the sequence of the dinucleotide analogue, wherein the dinucleotide analogue has a general formula of;
5′
-DpG-3′
or 5′
GpD-3′
, wherein D is decitabine;
p is a phospholinker wherein the number of phosphorus atoms in the phospholinker is one; and
G is deoxyguanosine; and2) a therapeutically-effective amount of a second therapeutic agent. - View Dependent Claims (152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197)
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198. A kit comprising:
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1) a first vessel containing a first therapeutic agent that is an isolated or synthetic dinucleotide analogue, or its salt or ester, comprising one 5-aza-cytosine as a base residue in the sequence of the dinucleotide analogue, wherein the dinucleotide analogue has a general formula of;
5′
-DpG-3′
or 5′
GpD-3′
, wherein D is decitabine;
p is a phospholinker wherein the number of phosphorus atoms in the phospholinker is one; and
G is deoxyguanosine;2) a second vessel containing a second therapeutic agent; and 3) a third vessel containing a pharmaceutically-acceptable carrier. - View Dependent Claims (199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231)
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Specification