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Patent

Cyclic dinucleotides for cytokine induction

TL;DR: In this article, a cyclic dinucleotide compound of Formula (I) was described, where X 1 is H or F; X 2 is H and X 3 is F; at least one among X 1 and X 2 was a fluorine atom; Z is OH, OR 1, SH or SR 1, wherein: R 1 is Na or NH 4, or R 2 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B 1 and B 2 are bases chosen from Adenine, Hypox
Abstract: The invention concerns a cyclic dinucleotide compound of Formula (I) wherein X 1 is H or F; X 2 is H or F; at least one among X 1 and X 2 is a fluorine atom; Z is OH, OR 1 , SH or SR 1 , wherein: R 1 is Na or NH 4 , or R 1 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B 1 and B 2 are bases chosen from Adenine, Hypoxanthine or Guanine, and B 1 is a different base than B 2 and a pharmaceutically acceptable salt thereof. The invention also concerns pharmaceutical compositions comprising said cyclic dinucleotide, as well as their use in the treatment of a bacterial infection, a viral infection or a cancer.
Citations
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Patent
18 May 2014
TL;DR: In this article, a cyclic-di-nucleotide (CDN) immune stimulator that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes).
Abstract: The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2', 5', 2', 5' and 2', 5 ',3 ',5' CDNs, and prefereably Rp,Rp stereosiomers thereof.

161 citations

Patent
11 Aug 2016
TL;DR: In this article, a class of polycyclic compounds of general formula (II), of general form (II'), or of general condition (II) was defined, which may be useful as inductors of type I interferon production, specifically as STING active agents.
Abstract: A class of polycyclic compounds of general formula (II), of general formula (II'), or of general formula (II"), wherein Base 1 , Base 2 , Y, Y a , X a , X a1 , X b , X b1 , X c , X c1 , X d , X d1 , R 1 , R 1a , R 2 , R 2a , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.

109 citations

Patent
02 Jun 2015
TL;DR: A compound of formula (I) or a pharmaceutically acceptable salt and tautomers thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation is defined in this article.
Abstract: A compound of formula (I) or a pharmaceutically acceptable salt and tautomers thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, in the treatment of diseases and conditions in which modulation of STING (Stimulator of Interferon Genes) is beneficial, for example inflammation, allergic and autoimmune diseases, infectious diseases, cancer and as vaccine adjuvants

75 citations

Patent
29 Apr 2014
TL;DR: In this article, the authors describe compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.
Abstract: The invention relates to compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.

66 citations

Patent
17 Mar 2017
TL;DR: In this article, cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy are discussed.
Abstract: Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

57 citations

References
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Book
30 Oct 2006
TL;DR: The role of protection groups in organic synthesis is discussed in this paper, where the authors present several general methods for phosphate Ester formation. But none of these methods are suitable for practical applications.
Abstract: Preface to the Fourth Edition. Preface to the Third Edition. Preface to the Second Edition. Preface to the First Edition. Abbreviations. 1. The Role of Protective Groups in Organic Synthesis. 2. Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. Ethers. Esters. Protection for 1,2- and 1,3-Diols. 3. Protection for Phenols and Catechols. Protection for Phenols. Ethers. Silyl Ethers. Esters. Carbonates. Aryl Carbamates. Phosphinates. Sulfonates. Protection for Catechols. Cyclic Acetals and Ketals. Cyclic Esters. Protection for 2-Hydroxybenzenethiols. 4. Protection for the Carbonyl Group. Acetals and Ketals. Miscellaneous Derivatives. Monoprotection of Dicarbonyl Compounds. 5. Protection for the Carboxyl Group. Esters. Amides and Hydrazides. Protection of Boronic Acids. Protection of Sulfonic Acids. 6. Protection for the Thiol Group. Thioethers. Thioesters. Miscellaneous Derivatives. 7. Protection for the Amino Group. Carbamates. Amides. Special -NH Protective Groups. Protection for Imidazoles, Pyrroles, Indoles, and other Aromatic Heterocycles. Protection for the Amide -NH. Protection for the Sulfonamide -NH. 8. Protection for the Alkyne -CH. 9. Protection for the Phosphate Group. Some General Methods for Phosphate Ester Formation. Removal of Protective Groups from Phosphorus. Alkyl Phosphates. Phosphates Cleaved by Cyclodeesterifi cation. Benzyl Phosphates. Phenyl Phosphates. Photochemically Cleaved Phosphate Protective Groups. Amidates. Miscellaneous Derivatives. 10. Reactivities, Reagents, and Reactivity Charts. Reactivities. Reagents. Reactivity Charts. 1 Protection for the Hydroxyl Group: Ethers. 2 Protection for the Hydroxyl Group: Esters. 3 Protection for 1,2- and 1,3-Diols. 4 Protection for Phenols and Catechols. 5 Protection for the Carbonyl Group. 6 Protection for the Carboxyl Group. 7 Protection for the Thiol Group. 8 Protection for the Amino Group: Carbamates. 9 Protection for the Amino Group: Amides. 10 Protection for the Amino Group: Special -NH Protective Groups. 11 Selective Deprotection of Silyl Ethers. Index.

1,989 citations

Journal ArticleDOI
TL;DR: The most common functional groups that are amenable to prodrug design are described, and examples of prodrugs that are either launched or are undergoing human trials are highlighted.
Abstract: Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

1,412 citations

Journal ArticleDOI
Roger Simm1, Michael Morr, Abdul Kader1, Manfred Nimtz, Ute Römling1 
TL;DR: The data suggest that c‐di‐GMP is a novel global second messenger in bacteria the metabolism of which is controlled by GGDEF and EAL domain proteins.
Abstract: Cyclic nucleotides represent second messenger molecules in all kingdoms of life. In bacteria, mass sequencing of genomes detected the highly abundant protein domains GGDEF and EAL. We show here that the GGDEF and EAL domains are involved in the turnover of cyclic-di-GMP (c-di-GMP) in vivo whereby the GGDEF domain stimulates c-di-GMP production and the EAL domain c-di-GMP degradation. Thus, most probably, GGDEF domains function as c-di-GMP cyclase and EAL domains as phosphdiesterase. We further show that, in the pathogenic organism Salmonella enterica serovar Typhimurium, the nosocomial pathogen Pseudomonas aeruginosa and the commensal species Escherichia coli, GGDEF and EAL domains mediate similar phenotypic changes related to the transition between sessility and motility. Thus, the data suggest that c-di-GMP is a novel global second messenger in bacteria the metabolism of which is controlled by GGDEF and EAL domain proteins.

896 citations

Journal ArticleDOI
TL;DR: The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation, and showed that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages.

782 citations

Journal ArticleDOI
23 May 2013-Cell
TL;DR: Structural, chemical, biochemical, and cellular assays are combined to demonstrate that this second messenger contains G(2',5')pA and A(3',5']pG phosphodiester linkages, designated c[G(2,5')sDNA binding, cGAS] as a founding member of a family of metazoan 2',5'-containing cyclic heterodinucleotide second messengers distinct from bacterial 3',5' cyclic dinucleotides

763 citations