Synthesis of Amide‐Linked Cyclic Dinucleotide Analogues with Pyrimidine Bases

Pal, Chandan; Chakraborty, Tushar Kanti

doi:10.1002/ajoc.201700260

Cited by 11 publications

(7 citation statements)

References 46 publications

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“…Carell’s group made 2′,3′-cGAMP mimetics by replacing the linkage with amide and triazole bridges . Chakraborty and others developed a linkage with amide bonds and obtained C2-symmetrical CDNs containing all pyrimidine bases . Lioux and others substituted the guanosine in cGAMP with inosine and obtained cyclic adenosine-inosine monophosphate (cAIMP) analogues with changed linkage positions and sulfur or fluorine substitution of phosphate (Figure b).…”

Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

121

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Personalized cancer vaccines (PCVs) are reinvigorating vaccine strategies in cancer immunotherapy. In contrast to adoptive T-cell therapy and checkpoint blockade, the PCV strategy modulates the innate and adaptive immune systems with broader activation to redeploy antitumor immunity with individualized tumor-specific antigens (neoantigens). Following a sequential scheme of tumor biopsy, mutation analysis, and epitope prediction, the administration of neoantigens with synthetic long peptide (SLP) or mRNA formulations dramatically improves the population and activity of antigen-specific CD4+ and CD8+ T cells. Despite the promising prospect of PCVs, there is still great potential for optimizing prevaccination procedures and vaccine potency. In particular, the arduous development of tumor-associated antigen (TAA)-based vaccines provides valuable experience and rational principles for augmenting vaccine potency which is expected to advance PCV through the design of adjuvants, delivery systems, and immunosuppressive tumor microenvironment (TME) reversion since current personalized vaccination simply admixes antigens with adjuvants. Considering the broader application of TAA-based vaccine design, these two strategies complement each other and can lead to both personalized and universal therapeutic methods. Chemical strategies provide vast opportunities for (1) exploring novel adjuvants, including synthetic molecules and materials with optimizable activity, (2) constructing efficient and precise delivery systems to avoid systemic diffusion, improve biosafety, target secondary lymphoid organs, and enhance antigen presentation, and (3) combining bioengineering methods to innovate improvements in conventional vaccination, "smartly" re-educate the TME, and modulate antitumor immunity. As chemical strategies have proven versatility, reliability, and universality in the design of T cell-and B cell-based antitumor vaccines, the union of such numerous chemical methods in vaccine construction is expected to provide new vigor and vitality in cancer treatment.

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Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

121

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“…To this end, many 3',3'-CDNs with thiourea, urea, carbodiimide, guanidinium, amide and trizole linkages have been synthesized (Scheme 10A). [153][154][155] Recently, Carell reported the synthesis of 2',3'-cGAMP analogues with one amide and one trizole linkage (Scheme 10B). [127] The trizole linkage between the C3' of adenosine and C5' of guanosine is first constructed based on Cu(I)-catalysed click chemistry.…”

Section: Synthesis Of Neutral 2'3'-cgamp Analoguesmentioning

confidence: 99%

2′,3′‐Cyclic GMP‐AMP Dinucleotides for STING‐Mediated Immune Modulation: Principles, Immunotherapeutic Potential, and Synthesis

Shang

Guan

et al. 2021

ChemMedChem

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The cGAS-STING pathway discovered ten years ago is an important component of the innate immune system. Activation of cGAS-STING triggers downstream signalling, such as TBK1-IRF3, NF-kB and autophagy, which in turn leads to antipathogen responses, durable antitumour immunity or autoimmune diseases. 2',3'-Cyclic GMP-AMP dinucleotides (2',3'-cGAMP), the key second messengers produced by cGAS, play a pivotal role in cGAS-STING signalling by binding and activating STING. Thus, 2',3'-cGAMP has immunotherapeutic potential, which in turn has stimulated research on the design and synthesis of 2',3'-cGAMP analogues for clinical applications over the past ten years. This review presents the discovery, metabolism, and function of 2',3'-cGAMP in the cGAS-STING innate immune signalling axis. The enzymatic and chemical syntheses of 2',3'-cGAMP analogues as STING-targeting therapeutics are also summarized.

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“…One advantage of using triazole is that it is metabolically more stable than the phosphodiester linkage, because of its resistance to degradation by nuclease. The second modification was to replace the adenine base of anthraniloyl-AMP with pyrimidine bases, such as thymidine, 2′-deoxyuridine and 2′-deoxycytidine [ 29 ]. Finally, the ribose sugar of the natural ligand was replaced with 2′-deoxyribose ( Figure 4 ).…”

Section: Design and Synthesis Of Novel Pqsa Inhibitorsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance

et al. 2020

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The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production.

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Synthesis of Amide‐Linked Cyclic Dinucleotide Analogues with Pyrimidine Bases

Cited by 11 publications

References 46 publications

Chemical Strategies to Boost Cancer Vaccines

Chemical Strategies to Boost Cancer Vaccines

2′,3′‐Cyclic GMP‐AMP Dinucleotides for STING‐Mediated Immune Modulation: Principles, Immunotherapeutic Potential, and Synthesis

Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance

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