127212-34-4

Upstream product

• 18162-48-6 tert-butyldimethylsilyl chloride 
• 119898-59-8 9-[(2R,3R,4S,5R)-5-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-3,4-dihydroxytetrahydrofuran-2-yl]-1,9-dihydro-6H-purin-6-one 
• 40615-36-9 4,4'-dimethoxytrityl chloride 
• 58-63-9 Inosine 
• 896131-05-8 9-[2,2-di-tert-butyl-7-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furo[3,2-d][1,3,2]dioxasilin-6-yl]-1,9-dihydro-purin-6-one 
• 58479-61-1 tert-butylchlorodiphenylsilane 

Downstream Products

• 138473-94-6 2'-O-(tert-butyldimethylsilyl)-5'-O (p,p'-dimethoxytrityl)inosine 3'-[(2-cyanoethyl)N,N-diisopropylaminophosphoramidite] 
• 911128-69-3 Diisopropyl-phosphoramidous acid (2R,3R,4R,5R)-2-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-5-(6-oxo-1,6-dihydro-purin-9-yl)-tetrahydro-furan-3-yl ester methyl ester 

Relevant academic research and scientific papers

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Synthesis and biological evaluation of all possible inosine-mixed cyclic dinucleotides that activate different hSTING variants

Cyclic dinucleotides (CDNs) could activate stimulator of interferon genes (STING) protein to produce type I interferon and other pro-inflammation cytokines in mammalian cells. To explore new types of potentially efficient STING activators targeting all five major hSTING variants (WT, R232H, HAQ, AQ and R293Q), we here reported the synthesis of a total of 19 inosine-containing CDNs based on the combinations of hypoxanthine with four natural bases (A, G, C and U) and three phosphodiester linkage backbones (3′-3′, 2′-3′, 2′-2′). The IFN-β induction results showed that all of the 2′-3′ and 2′-2′ CDNs linked by inosine and purine nucleosides favored the stacking interaction with Y167 and R238 residues of hSTING protein, and several CDNs constructed by hypoxanthine and pyrimidine like c[I(2′,5′)U(2′,5′)] could also activate all five hSTING variants. The molecular dynamic simulation and the isothermal titration calorimetric (ITC) assay further demonstrated the potential of cAIMP isomers with 2′-5′ phosphate to form the hydrogen binding with R232 and R238 residues of hSTING in an entropically driven manner compared to cGAMP isomers. It would be promising to exploit novel inosine-mixed CDNs as activators of hSTING variants in immune therapy.

Enzymatic Preparation of 2′-5′,3′-5′-Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations

Cyclic dinucleotides are second messengers in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which plays an important role in recognizing tumor cells and viral or bacterial infections. They bind to the STING adaptor protein and trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB (IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling cascades. In this work, we describe an enzymatic preparation of 2′-5′,3′-5′-cyclic dinucleotides (2′3′CDNs) with use of cyclic GMP-AMP synthases (cGAS) from human, mouse, and chicken. We profile substrate specificity of these enzymes by employing a small library of nucleotide-5′-triphosphate (NTP) analogues and use them to prepare 33 2′3′CDNs. We also determine affinity of these CDNs to five different STING haplotypes in cell-based and biochemical assays and describe properties needed for their optimal activity toward all STING haplotypes. Next, we study their effect on cytokine and chemokine induction by human peripheral blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect on monocytes. Additionally, we report X-ray crystal structures of two new CDNs bound to STING protein and discuss structure-activity relationship by using quantum and molecular mechanical (QM/MM) computational modeling.

CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTS

The present invention is directed to compounds of the formulae I, II and III as shown below wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

STING MODULATOR COMPOUNDS, AND METHODS OF MAKING AND USING

The present disclosure provides STING modulators/agonists, and methods of synthesis and methods for using for the prophylaxis or treatment of cancer and other STING-related diseases. The present disclosure relates to a compound represented by the Formula (I): wherein each symbol is as defined in the description, or a pharmaceutically acceptable salt thereof.

Synthesis of cyclic di-nucleotidic acids as potential inhibitors targeting diguanylate cyclase

Five analogs of cyclic di-nucleotidic acid including c-di-GMP were synthesized and evaluated for their biological activities on Slr1143, a diguanylate cyclase of Synechocystis sp. Slr1143 was overexpressed from the recombinant plasmid which contained the gene of interest and subsequently purified by affinity chromatography. A new HPLC method capable of separating the compound and product peaks with good resolution was optimized and applied to the analysis of the compounds. Results obtained show that cyclic di-inosinylic acid 1b demonstrates a stronger inhibition on Slr1143 than c-di-GMP and is a potential inhibitor for biofilm formation.

Polymorphism of the signaling molecule c-di-GMP

Using UV, CD, and NMR, we demonstrate that the important bacterial signaling molecule involved in biofilm formation, cyclic diguanosine monophosphate (c-di-GMP), exists as a mixture of five different but related structures in an equilibrium that is sensit

An improved synthesis of inosine 3'-phosphoramidite

A protocol for the efficient conversion of inosine into its 3'-phosphoramidite synthon for solid phase oligonucleotide synthesis has been developed.