S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) as the STING agonist for antitumor immunotherapy

Xie, Zhiqiang; Lu, Liqing; Wang, Zhenghua; Luo, Qinhong; Yang, Yuchen; Fang, Tian; Chen, Ziyi; Ma, Dejun; Quan, Jing; Xi, Zhen

doi:10.1016/j.ejmech.2022.114796

Cited by 13 publications

(14 citation statements)

References 52 publications

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“…We successfully applied the new methodology to the synthesis of SATE-protected sugar phosphates and phospho-amino acid derivatives and demonstrated it to be compatible with a range of commonly used protecting groups. In addition to its potential impact on the development of SATE-protected prodrugs, 14,15 the approach offers a valuable extension to the available toolkit for the synthesis of phosphorylated saccharides. 28 By tuning the ester groups on the phosphotriester precursor, different types of mixed phosphates should also be within reach.…”

Section: Discussionmentioning

confidence: 99%

“…First described for the intracellular delivery of nucleoside 5′-monophosphate derivatives of an anti-HIV drug, 13 SATE protection is still commonly used as a prodrug strategy for nucleoside monophosphates and phosphonates. 14,15 The biological instability of SATE groups is attributed to hydrolysis of the thioesters by carboxy- or thioesterase activity naturally present in mammalian cells. 13,16 The resulting mercaptoethyl groups are presumed to spontaneously decompose by an intramolecular nucleophilic displacement mechanism that generates ethylene disulfide and releases the desired phosphate monoester (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

et al. 2023

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“…320,321 Among those being investigated extensively for preclinical characterization are summarized in Table 4, including bacterial vectors (such as SYNB1891 and STACT-TREX-1), ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) inhibitors, s-acylthioalkyl ester (SATE)-based STING-activation prodrugs selenium-containing chemicals based on the structure of benzothiophene oxobutanoic acid (MSA-2), newly developed 7-(het)aryl 7-deazapurine CDNs, small-molecule STING agonist include SR-001, SR-012, SR-717, SR-301 and SR-717, as well as novel compound named HB3089, and so on. [322][323][324][325][326] These preclinical small molecular STING agonists have been recently extensively reviewed by Garland et al, 327 and will therefore not be discussed in detail in this review.…”

Section: Targeting the Cgas-sting Signaling Pathway In Cancer Preclin...mentioning

confidence: 99%

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Yang

Zhou

et al. 2023

MedComm

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Immune checkpoint inhibitors (ICIs) have shown remarkable success in cancer treatment. However, in cancer patients without sufficient antitumor immunity, numerous data indicate that blocking the negative signals elicited by immune checkpoints is ineffective. Drugs that stimulate immune activation‐related pathways are emerging as another route for improving immunotherapy. In addition, the development of nanotechnology presents a promising platform for tissue and cell type‐specific delivery and improved uptake of immunomodulatory agents, ultimately leading to enhanced cancer immunotherapy and reduced side effects. In this review, we summarize and discuss the latest developments in nanoparticles (NPs) for cancer immuno‐oncology therapy with a focus on lipid‐based NPs (lipid‐NPs), including the characteristics and advantages of various types. Using the agonists targeting stimulation of the interferon genes (STING) transmembrane protein as an exemplar, we review the potential of various lipid‐NPs to augment STING agonist therapy. Furthermore, we present recent findings and underlying mechanisms on how STING pathway activation fosters antitumor immunity and regulates the tumor microenvironment and provide a summary of the distinct STING agonists in preclinical studies and clinical trials. Ultimately, we conduct a critical assessment of the obstacles and future directions in the utilization of lipid‐NPs to enhance cancer immunotherapy.

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“…Extending the scope of the bis-SATE-protected phosphate synthesis methodology. The two-step reaction procedure was applied to various GlcNAc derivatives (10)(11)(12)(13)(14)(15) and amino acid analogues (16)(17)(18)(19)(20)(21). Yields are shown following either the optimised procedure (A) or the adapted protocol with the addition of triethylamine (B) and represent overall yields over both steps of the reaction unless indicated otherwise.…”

Section: Substratementioning

confidence: 99%

“…First described for the intracellular delivery of nucleoside 5'-monophosphate derivatives of an anti-HIV drug, 13 SATE protection is still commonly used as a prodrug strategy for nucleoside monophosphates and phosphonates. 14,15 The biological instability of SATE groups is attributed to hydrolysis of the thioesters by esterases naturally present in mammalian cells. 13 The resulting mercaptoethyl groups then spontaneously decompose by an intramolecular nucleophilic displacement mechanism that generates ethylene disulfide and releases the desired phosphate monoester (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

Murphy

Huxley

Wilding

et al. 2023

Preprint

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Phosphates are regularly incorporated into bioactive small molecules, for example in sugar-1-phosphate derivatives that are used for metabolic oligosaccharide engineering. To enable efficient cellular uptake, the phosphate groups are commonly masked with biolabile S-acyl-2-thioethyl (SATE) protecting groups that are removed once the molecule is inside the cell. Typically, SATE-protected monophosphates are synthesised through phosphoramidite chemistry, which suffers from issues with hazardous and unstable reagents and can give unreliable yields. Here, we report the development of an alternative approach that makes use of an easy to synthesise tri(2-bromoethyl)phosphotriester precursor, providing access to bis-SATE-protected mixed phosphotriesters in two steps. We demonstrate the viability of our strategy on tetrabenzylated glucose as a model monosaccharide, onto which a bis-SATE-protected phosphate is introduced at either the anomeric position or at C6. We also show compability with various protecting groups and further explore the scope and limitations of the approach on different substrates, including N-acetylhexosamines and amino acid derivatives.

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S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) as the STING agonist for antitumor immunotherapy

Cited by 13 publications

References 52 publications

Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

Synthesis of biolabile thioalkyl-protected phosphates from an easily accessible phosphotriester precursor

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