Search

Integrating lipid conjugation strategies into the design of nucleoside monophosphate and monophosphonate prodrugs is a well-established approach for discovering potential therapeutics. The unique prodrug design endows nucleoside analogues with strong lipophilicity and structures resembling lysoglycerophospholipids, which improve cellular uptake, oral bioavailability and pharmacological activity. In addition, the metabolic stability, pharmacological activity, pharmacokinetic profiles and biodistribution of lipid prodrugs can be finely optimized by adding biostable caps, incorporating transporter-targeted groups, inserting stimulus-responsive bonds, adjusting chain lengths, and applying proper isosteric replacements. This review summarizes recent advances in the structural features and application fields of lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs. This collection provides deep insights into the increasing repertoire of lipid prodrug development strategies and offers design inspirations for medicinal chemists for the development of novel chemotherapeutic agents. [Display omitted] • Characterized by structures resembling lysoglycerophospholipids, lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs exhibit enhanced cellular uptake, increased oral bioavailability and improved pharmacological activity. • Extensive preclinical studies indicate that the metabolic stability, pharmacological activities, pharmacokinetic profiles and biodistribution of lipid prodrugs can be optimized with the addition of ω-functionalized caps, incorporation of transporter-targeted groups, insertion of stimulus-responsive bonds, adjustment of chain lengths, and application of proper isosteric replacements, etc. • Emerging novel lipid prodrugs have promising applications for intracellular drug delivery, topical drug administration, long-acting antiretroviral therapies, stimulus-responsive drug release, anti -SARS-CoV-2, fighting drug resistance, etc. [ABSTRACT FROM AUTHOR]

The synthesis and the antiviral evaluation of 3'-halo (iodo and fluoro) 5'-norcarbocyclic nucleoside phosphonates is described. No antiviral activity was observed against Zika virus, Dengue virus 2, HSV-1, HSV-2 and Chikungunya virus. In contrast, some of the synthesized compounds are potent inhibitors of the replication of HIV-1, comparatively to ( R )-PMPA, with no concomitant cytotoxicity. [ABSTRACT FROM AUTHOR]

New aromatic and aliphatic 3′- O -acyl-5-fluoro-2′-deoxyuridine derivatives were synthesized and evaluated as candidates for prodrugs against various cancer cell lines. As the most promising candidate for antimalignant therapeutics was found a dual-acting acyl derivative 7h , which apparently released not only the known anticancer nucleoside, 5-fluoro-2′-deoxyuridine (FdU), but also an additional active metabolite, acetylsalicylic acid, reinforcing thus therapeutic effect of FdU. Promising therapeutic indices showed also some aromatic dicarboxylic acids derivatives decorated with FdU esters ( 11 and 12 ). [ABSTRACT FROM AUTHOR]

The 2′-deoxynucleoside 5′-phosphate N -hydrolase 1 (DNPH1) has been proposed as a new molecular target for cancer treatment. Here, we describe the synthesis of a series of novel 6-aryl- and 6-heteroarylpurine riboside 5′-monophosphates via Suzuki–Miyaura cross-coupling reactions, and their ability to inhibit recombinant rat and human DNPH1. Enzymatic inhibition studies revealed competitive inhibitors in the low micromolar range. Crystal structures of human and rat DNPH1 in complex with one nucleotide from this series, the 6-naphthylpurine derivative, provided detailed structural information, in particular regarding the possible conformations of a long and flexible loop wrapping around the large hydrophobic substituent. Taking advantage of these high-resolution structures, we performed virtual docking studies in order to evaluate enzyme–inhibitor interactions for the whole compound series. Among the synthesized compounds, several molecules exhibited significant in vitro cytotoxicity against human colon cancer (HCT15, HCT116) and human promyelocytic leukemia (HL60) cell lines with IC 50 values in the low micromolar range, which correlated with in vitro DNPH1 inhibitory potency. [ABSTRACT FROM AUTHOR]

Abstract: Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone. 1 [1] 2-ONN: 2-oxonicotinonitrile. Herein, we describe the synthesis of 2-ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a Ac showed good anti SARS-CoV and anti influenza A (H5N1) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis. [Copyright &y& Elsevier]