Johns Hopkins University

Other

Genta Incorporated

Paul S Miller

Paul O Ts'o

Paul O T'so

Lionel N Simon

Purshotam Bhan

Michael J Rossi

Acid resistant Oligomers suitable for oral administration, orally acceptable formulations of such Oligomers and preparation of pharmaceutical formations of such Oligomers are provided.

Oligonucleotide analogues having improved stability at acid pH

A composition for inactivating a target nucleic acid which comprises an oligonucleoside alkyl or arylphosphonate analogue which is complementary to the sequence of the target nucleic acid and includes a functional group which reacts with the target nucleic acid to render the target nucleic acid inactive or nonfunctional.

Oligonucleoside alkyl or arylphosphonate derivatives capable of

A specific segment of double stranded DNA may be detected or recognized by formation of a triple helix structure using an Oligomer comprising an 8-modified purine base such as 8-oxo-adenine or 8-oxo-guanine to form a detectable triple helix complex. Function or expression of double stranded DNA segments may be prevented by triple helix formation. Novel Oligomers comprising an 8-modified purine base are useful in triple helix formation, and may be optionally derivatized with DNA modifying groups.

Formation of triple helix complexes for the detection of double stranded

An oligonucleotide or analog thereof including a single cytidine residue at a selected position and having one or more cytidine residues which are 5-methyl substituted. The cytidine nucleus can be selectively transaminated to include an aminoalkyl or carboxyalkyl group as a linker for other functional groups which can be used to form DNA duplexes and triplexes.

Formation of oligonucleotide triplexes with selectively modified

A process for selectively controlling or interfering with the effect or function of foreign nucleic acid in the presence of otherwise normal living cells which comprises determining the base sequence for said nucleic acid and binding the said nucleic acid with an appropriately prepared nonionic oligonucleoside alkyl or arylphosphonate analogue which is complementary to the indicated sequence of the foreign nucleic acid.

Method for selectively controlling unwanted expression or function of

Oligonucleoside-3'-alkyl or aryl phosphonates are prepared by condensing (i) a 5'-protected nucleoside 3'-alkyl or aryl phosphonic imidazolide with (ii) a nucleoside or oligomer which is attached through its 3'-position to a polymer support. The process is advantageously carried out in the presence of tetrazole.

Preparation of oligodeoxyribonucleoside alkyl or arylphosphonates

A nucleic acid-protein conjugate which is specific with respect to a selected living cell is prepared by linking said nucleic acid to a protein specific to said living cell.

Linkage of proteins to nucleic acids

A process for selectively controlling or interfering with the effect or function of foreign nucleic acid in the presence of otherwise normal living cells which comprises determining the base sequence for the nucleic acid and binding the nucleic acid with an appropriately prepared nonionic oligonucleoside alkyl or arylphosphonate analogue which is complementary to the indicated sequence of the foreign nucleic acid.

Process for selectively controlling unwanted expression or function of

Process for synthesizing deoxyribonucleoside methylphosphonates on polystyrene polymer supports which involves condensing 5'-dimethoxytrityldeoxynucleoside 3'-methylphosphonates. The oligomers are removed from the support and the base protecting groups hydrolyzed by treatment with ethylenediamene in ethanol, which avoids hydrolysis of the methylphosphonate linkages. Two types of oligomers are synthesized: those containing only methylphosphonate linkages, d-Np(Np).sub.n N, and those which terminate with a 5' nucleotide residue, dNp(Np).sub.n N. The latter oligomers can be phosphorylated by polynucleotide kinase, and are separated by polyacrylamide gel electrophoresis according to their chain length. Piperidine randomly cleaves the oligomer methylphosphonate linkages and generates a series of shorter oligomers whose number corresponds to the length of the original oligomer. Apurinic sites introduced by acid treatment spontaneously hydrolyze to give oligomers which terminate with free 3' and 5'-OH groups. These reactions may be used to characterize the oligomers.

Oligonucleoside alkyl-- or aryl phosphonates are nonionic analogues of nucleic acid which possess unique physical and biological properties. These properties enable the analogues to enter living cells intact and to bind with specifically selected nucleic acids within the cell. As a result, the analogues can specifically inhibit the function or expression of a preselected nucleic acid sequence. Thus the analogues could be used to specifically inhibit the growth of tumor cells or replication of viruses in infected cells. Four methods are provided for preparing oligonucleoside methylphosphonates: (1) Coupling a protected nucleoside 3'-alkyl or aryl phosphonate with the 5'-hydroxyl group of a protected nucleoside using a condensing agent; (2) Coupling protected nucleoside 3'-alkyl or aryl phosphonic acid derivative with the 5'-hydroxy group of a protected nucleoside with the activated alkyl or aryl phosphonic acid derivative possessing functionalities which are good leaving groups; (3) Coupling a protected nucleoside 3'-alkyl or aryl phosphinate derivative with the 5'-hydroxyl group of a protected nucleoside with the resulting phosphinate derivative being then oxidized to the phosphonate; and (4) Converting a oligonucleoside methoxyphosphite derivative to the alkyl or aryl phosphonate derivative by reaction with an alkyl or aryl iodide. It has been demonstrated that procedures (1) and (2) can be used to prepare oligonucleoside methylphosphonates. Others have shown that procedure (4) can be used to prepare a diribonucleoside methylphosphonate.

Nonionic nucleic acid alkyl and aryl phosphonates and processes for

Portions of the confining frame of a water bed are made so they can be tilted away from the water-filled mattress of that water bed to facilitate the positioning, and the smoothing, of a cover for that water-filled mattress adjacent the sides and end of that water-filled mattress.

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Baltimore, MD, United States of America

Paul S Miller