Synthesis of Oligodeoxyribo‐ and Oligoribonucleotides According to the H‐Phosphonate Method

Oligonucleotides can be synthesized by condensing a protected nucleoside H‐phosphonate monoester with a second nucleoside in the presence of a coupling agent to produce a dinucleoside H‐phosphonate diester. This can then be converted to a dinucleoside phosphate or to a backbone‐modified analog such as a phosphorothioate or phosphoramidite. This unit discusses four alternative methods for synthesizing nucleoside H‐phosphonate monoesters. The methods are efficient and experimentally simple, and use readily available reagents. The unit describes the activation of the monoesters, as well as competing acylation and other potential side reactions.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143594/1/cpnc0304.pd

Protection of 2′‐Hydroxy Functions of Ribonucleosides

The main purpose of this article is to discuss 2′‐protection in the context of effective oligoribonucleotide synthesis. Emphasis is placed on the 2′‐protecting groups of choice in the synthesis of oligo‐and polyribonucleotides, and the requirements that a protective group must satisfy to become the 2′‐hydroxyl‐protecting group of choice. Finally, the unit discusses the issue of 2′‐O‐acyl and 2′‐O‐silyl group migration to the 3′‐hydroxy function of ribonucleosides during protection, along with the consequences of the conditions used for their removal on the stability of internucleotide linkages.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143728/1/cpnc0202.pd

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5′-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5′-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5′-monophosphate, which is further transformed to the active 5′-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan’s research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents

Studies on Intrachain Conjugation, Hybridization and Invasion of Oligonucleotides

Siirretty Doriast

Phosphoramidite derivatives of macrocycles

The invention is directed to phosphoramidite derivatives of macrocycles, such as porphyrins and expanded porphyrins, including sapphyrins and texaphyrins. The phosphoramidite derivatives are useful as intermediates in the preparation of macrocycle-oligonucleotide conjugates.Board of Regents, University of Texas Syste

Probing the HIV reverse-transcriptase enzyme with novel bifunctional HIV-1 RT inhibitors of the general formula (NRTI)-spacer-(NNRTI)

Includes abstract.Includes bibliographical references (leaves 224-233).The high levels of resistance elicited by both nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors have prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance as well as searching for synergism between the two drug target sites on HIV reverse transcriptase (RT). The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of developing a mixed-site inhibitor combining the inhibitory actions of each drug. This thesis describes the rational drug-design and synthesis of nine bifunctional drugs combining a nucleos(t)ide and a non-nucleoside reverse transcriptase inhibitor linked via different non-cleavable spacers. The C-5 position of the nucleos(t)ide portion of the bifunctional was used for attachment of the spacer throughout. However, the site of attachment on the nonnucleoside drug varies according to the inhibitor type