Gilead Sciences, Inc.

Isis Pharmaceuticals, Inc.

Chris A Buhr

Mark D Matteucci

Brian C Froehler

Norbert W Bischofberger

Kuei-Ying Lin

Rick Wagner

Ken Kent

Oligomers which have substituents on the 2' position are resistant to oligonucleases and furthermore can be derivatized to deliver reagents or drugs, to carry label, or to provide other properties.

2' Modified oligonucleotides

Novel hydrogen-phosphonodithioate compositions are provided which are particularly useful for forming internucleotide and internucleoside linkages in oligonucleosides or oligonucleotides. The oligonucleotides and analogs thereof made by using the hydrogen-phosphonodithioate compositions may be therapeutically useful as antiviral and anticancer agents and may have other therapeutic or diagnostic uses. A method for making the hydrogen-phosphonodithioates is provided as well as a method for converting same to an activated intermediate for substitution on the phosphorus atom.

Nucleoside hydrogen phosphonodithioate diesters and activated phosphonodithioate analogues

Oligomers which have substituents on the 2&prime; position are resistant to oligonucleases and furthermore can be derivatized to deliver reagents or drugs, to carry label, or to provide other properties.

2&prime; Modified oligonucleotides

2' Modified Oligonucleotides

Oligonucleotides that are capable of passive diffusion across cell membranes are disclosed. These oligonucleotides contain at least two nucleotide residues and show a log distribution coefficient in octanol:water of about 0.0-2.5 and a solubility in water of at least 0.001 .mu.g/mL. In preferred embodiments, either at least 80% of the internucleotide linkages are non-ionic, or at least 80% of the bases contain lipophilic hydrocarbyl substitutions, or a combination of these sums to 80%. These oligonucleotides may be conjugated to label and used to visualize cells.

Oligonucleotides and their analogs capable of passive cell membrane

Novel oligonucleotides analogs and nucleoside analogs as well as methods for their synthesis are described. The oligonucleotides are useful in diagnostic and therapeutic applications. The oligonucleotides are stable to nuclease degradation.

Nucleoside 5'-methylene phosphonates

Oligonucleotide analogs capable of passive cell membrane permeation

Novel hydrogen-phosphonodithioate compositions are provided which are particularly useful for forming internucleotide and internucleoside linkages in oligonucleosides or oligonucleotides, The oligonucleotides and analogs thereof made by using the hydrogen-phosphonodithioate compositions may be therapeutically useful as antiviral and anticancer agents and may have other therapeutic or diagnostic uses, A method for making the hydrogen-phosphonodithioates is provided as well as a method for converting same to an activated intermediate for substitution on the phosphorus atom.

Nucleoside hydrogen phosphonodithioate diesters and activated

The present invention relates to an oligonucleotide or analog thereof conjugated to a molecule comprising a structure, which structure (a) is of substantially fixed conformation; (b) contains, is directly attached to, or is attached to a carbon atom that is directly attached to, an first amine; and (c) contains, is directly attached to, or is attached to an atom that is directly attached to a phosphate, a second amine, or a cationic sulfur. In a preferred embodiment, the structure consists of at least a nonaromatic cyclic portion or substituted derivative thereof. In a specific embodiment, the structure is a nonaromatic cyclic compound. In another embodiment, the molecule is a steroid. In yet another particular aspect, the structure is an aromatic compound. In another embodiment, the structure can bind to a nucleic acid sequence in a nonintercalative manner. The invention also relates to a conjugate comprising a steroid or substituted derivative thereof containing, or attached directly or through a carbon atom to, an amine, which steroid or substituted derivative is conjugated to at least one hydrogen-phosphonate and a cation; such a conjugate may be used as an intermediate in synthesis. The oligonucleotide conjugates of the invention can have a number of uses. For example, the conjugates may be used for diagnostic purposes by detecting a nucleic acid sequence.

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Daly City, CA, United States of America

Chris A Buhr