Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.


:Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.


Bioorg Med Chem Lett


Prakash TP,Kinberger GA,Murray HM,Chappell A,Riney S,Graham MJ,Lima WF,Swayze EE,Seth PP




Has Abstract


2016-06-15 00:00:00














  • Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis.

    abstract::RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited VEGF-induced angiogenesis. Tested in a H460a xenograft tumor model this agent effected significant tumor growth inhibition at doses as low a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: McDermott LA,Higgins B,Simcox M,Luk KC,Nevins T,Kolinsky K,Smith M,Yang H,Li JK,Chen Y,Ke J,Mallalieu N,Egan T,Kolis S,Railkar A,Gerber L,Liu JJ,Konzelmann F,Zhang Z,Flynn T,Morales O,Chen Y

    更新日期:2006-04-01 00:00:00

  • Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors.

    abstract::A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patel HK,Grotzfeld RM,Lai AG,Mehta SA,Milanov ZV,Chao Q,Sprankle KG,Carter TA,Velasco AM,Fabian MA,James J,Treiber DK,Lockhart DJ,Zarrinkar PP,Bhagwat SS

    更新日期:2009-09-01 00:00:00

  • Development of an efficient method for phosphorodiamidate bond formation by using inorganic salts.

    abstract::Phosphorodiamidate morpholino oligonucleotides (PMOs) have been extensively applied in antisense strategies for gene regulation because of their high stability in serum and low toxicity. However, chain elongation of PMOs requires long reaction time because few efficient methods have been developed for the formation of...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Harakawa T,Tsunoda H,Ohkubo A,Seio K,Sekine M

    更新日期:2012-02-01 00:00:00

  • Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase.

    abstract::The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Chapron C,Glen R,La Colla M,Mayes BA,McCarville JF,Moore S,Moussa A,Sarkar R,Seifer M,Serra I,Stewart A

    更新日期:2014-06-15 00:00:00

  • Novel dual inhibitors of calpain and lipid peroxidation.

    abstract::A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidatio...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Auvin S,Pignol B,Navet E,Pons D,Marin JG,Bigg D,Chabrier PE

    更新日期:2004-07-16 00:00:00

  • Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones.

    abstract::A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure-activity relationships. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Meza-Aviña ME,Lingerfelt MA,Console-Bram LM,Gamage TF,Sharir H,Gettys KE,Hurst DP,Kotsikorou E,Shore DM,Caron MG,Rao N,Barak LS,Abood ME,Reggio PH,Croatt MP

    更新日期:2016-04-01 00:00:00

  • In vitro characterization of the Gd complex of [2,6-pyridinediylbis(methylene nitrilo)] tetraacetic acid (PMN-tetraacetic acid) and of its Eu analogue, suitable bimodal contrast agents for MRI and optical imaging.

    abstract::Gd and Eu complexes of PMN-tetraacetic acid show interesting properties either for MRI or for optical imaging; that is, for the Gd-complex, a high proton relaxivity with favorable water residence time; for the Eu-complex, a luminescence lifetime of 400 micros at room temperature compatible with the use of time-resolve...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Laurent S,Vander Elst L,Wautier M,Galaup C,Muller RN,Picard C

    更新日期:2007-11-15 00:00:00

  • Progress in discovery of small-molecule modulators of protein-protein interactions via fragment screening.

    abstract::Protein-protein interactions (PPIs) present a formidable challenge to medicinal chemistry. The extended and open nature of many binding sites at protein interfaces has made it difficult to find useful chemical matter by traditional screening methods using standard screening libraries. This Digest focuses on the progre...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章,评审


    authors: Magee TV

    更新日期:2015-06-15 00:00:00

  • TR-FRET binding assay targeting unactivated form of Bruton's tyrosine kinase.

    abstract::Bruton's Tyrosine Kinase (BTK) is one of the crucial kinases for the B cell maturation and mast cell activation, and specific inhibitors of BTK are considered to be attractive targets in drug discovery research. In this Letter, we have designed and synthesized a new fluorescent probe for TR-FRET-based high-throughput ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Asami T,Kawahata W,Sawa M

    更新日期:2015-01-01 00:00:00

  • Discovery of 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide activators of the M2 isoform of pyruvate kinase (PKM2).

    abstract::Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic 'Warburg effect' characteristic of aberrant metabolism. In this Letter, we describe the opti...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xu Y,Liu XH,Saunders M,Pearce S,Foulks JM,Parnell KM,Clifford A,Nix RN,Bullough J,Hendrickson TF,Wright K,McCullar MV,Kanner SB,Ho KK

    更新日期:2014-01-15 00:00:00

  • Identification and functional analysis of brassicicene C biosynthetic gene cluster in Alternaria brassicicola.

    abstract::The biosynthetic gene cluster of brassicicene C was identified in Alternaria brassicicola strain ATCC 96836 from genome database search. In vivo and in vitro study clearly revealed the function of Orf8 and Orf6 as a fusicoccadiene synthase and methyltransferase, respectively. The understanding toward the biosynthetic ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Minami A,Tajima N,Higuchi Y,Toyomasu T,Sassa T,Kato N,Dairi T

    更新日期:2009-02-01 00:00:00

  • Dopamine/serotonin receptor ligands. Part 15: Oxygenation of the benz-indolo-azecine LE 300 leads to novel subnanomolar dopamine D1/D5 antagonists.

    abstract::Relying on the high affinities of the benz-indolo-azecine LE 300 (1) and the hydroxylated dibenz-azecine LE 404 (2b) for the D1/D5 receptor subtypes, we synthesized methoxylated, hydroxylated and an indole-N methylated derivatives of 1 (Fig. 1). Hydroxylation of azecine derivatives is beneficial with regard to the aff...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Enzensperger C,Kilian S,Ackermann M,Koch A,Kelch K,Lehmann J

    更新日期:2007-03-01 00:00:00

  • Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.

    abstract::A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, resp...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Palmer WS,Alam M,Arzeno HB,Chang KC,Dunn JP,Goldstein DM,Gong L,Goyal B,Hermann JC,Hogg JH,Hsieh G,Jahangir A,Janson C,Jin S,Ursula Kammlott R,Kuglstatter A,Lukacs C,Michoud C,Niu L,Reuter DC,Shao A,Silva T,Tr

    更新日期:2013-03-01 00:00:00

  • Chemical constituents from the fruit of Gardenia jasminoides and their inhibitory effects on nitric oxide production.

    abstract::Three new iridoid glycosides, 6"-O-trans-caffeoylgenipin gentiobioside (1), genipin 1-O-β-D-apiofuranosyl (1→6)-β-D-glucopyranoside (2), genipin 1-O-α-D-xylopyranosyl (1→6)-β-D-glucopyranoside (3), three new monocyclic monoterpenoids, jasminoside R (4), jasminoside S (5), jasminoside T (6), together with nine known ir...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Peng K,Yang L,Zhao S,Chen L,Zhao F,Qiu F

    更新日期:2013-02-15 00:00:00

  • The search for novel TRPV1-antagonists: from carboxamides to benzimidazoles and indazolones.

    abstract::Based on a series of diaryl amides the corresponding inverse amides have been found to be potent TRPV1 receptor antagonists. Benzimidazole and indazolone derivatives prepared retained good potency in vitro and indazolone 4a was identified as a novel TRPV1 receptor antagonist suitable for evaluating orally in animal mo...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fletcher SR,McIver E,Lewis S,Burkamp F,Leech C,Mason G,Boyce S,Morrison D,Richards G,Sutton K,Jones AB

    更新日期:2006-06-01 00:00:00

  • Quantitative screening of EGF receptor-binding peptides by using a peptide library with multiple fluorescent amino acids as fluorescent tags.

    abstract::EGF receptor-binding peptides could be found by a peptide screening method using fifteen fluorescent amino acids as fluorescent tags. Of 225 peptides, we found an 8-mer peptide containing a dipeptide unit, Y-F, which was the strongest binding peptide to the EGF receptor. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kitamatsu M,Yamamoto T,Futami M,Sisido M

    更新日期:2010-10-15 00:00:00

  • Synthesis of new conjugated coumarin-benzimidazole hybrids and their anticancer activity.

    abstract::A series of novel coumarin-benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A sign...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 信件


    authors: Paul K,Bindal S,Luxami V

    更新日期:2013-06-15 00:00:00

  • Identification of novel 7-amino-5-methyl-1,6-naphthyridin-2(1H)-one derivatives as potent PI3K/mTOR dual inhibitors.

    abstract::Inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is one of the most intensively studied approaches to cancer therapy. Rational design led to the identification of novel 7-amino-5-methyl-1,6-naphthyridin-2(1H)-one derivatives as potent PI3K/mTOR dual inhibito...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lin S,Han F,Liu P,Tao J,Zhong X,Liu X,Yi C,Xu H

    更新日期:2014-02-01 00:00:00

  • Combined treatment with zingerone and its novel derivative synergistically inhibits TGF-β1 induced epithelial-mesenchymal transition, migration and invasion of human hepatocellular carcinoma cells.

    abstract::The epithelial-mesenchymal transition (EMT) is an important cellular process during which polarized epithelial cells become motile mesenchymal cells, which promote cancer metastasis. Ginger, the rhizome of Zingiber officinale, is extensively used in cooking worldwide and also as a traditional medicinal herb with antio...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Kim YJ,Jeon Y,Kim T,Lim WC,Ham J,Park YN,Kim TJ,Ko H

    更新日期:2017-02-15 00:00:00

  • The synthesis and selective IL-2 inhibitory activity of bis piperazine-phenol Mannich adducts.

    abstract::Novel phenol bis-Mannich adducts were identified as IL-2 expression inhibitors in a T cell proliferation screening assay. Analogues of the lead compound were prepared through parallel synthesis and a highly selective IL-2 inhibitor was discovered that provided a suitable compound for further optimization. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Geng B,Fleming PR,Umlauf S,Lin A,Pallai PV

    更新日期:2002-03-11 00:00:00

  • Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids.

    abstract::Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physico...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Rakesh,Bruhn DF,Scherman MS,Singh AP,Yang L,Liu J,Lenaerts AJ,Lee RE

    更新日期:2016-01-15 00:00:00

  • Inhibitors of the Yersinia protein tyrosine phosphatase through high throughput and virtual screening approaches.

    abstract::The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target. Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches. The identified inhibitors represent a di...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu X,Vujanac M,Southall N,Stebbins CE

    更新日期:2013-02-15 00:00:00

  • The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

    abstract::A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain pe...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Johnson DJ,Forbes IT,Watson SP,Garzya V,Stevenson GI,Walker GR,Mudhar HS,Flynn ST,Wyman PA,Smith PW,Murkitt GS,Lucas AJ,Mookherjee CR,Watson JM,Gartlon JE,Bradford AM,Brown F

    更新日期:2010-09-15 00:00:00

  • 2-Aryl-3-(6-trifluoromethoxy)benzo[d]thiazole-based thiazolidinone hybrids as potential anti-infective agents: Synthesis, biological evaluation and molecular docking studies.

    abstract::The search for new antimicrobial agents is greater than ever due to the perpetual threat of multidrug resistance in known pathogens and the relentless emergence of new infections. In this manuscript, ten thiazole-based thiazolidinone hybrids bearing a 6-trifluoromethoxy substituent on the benzothiazole core were synth...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Haroun M,Tratrat C,Petrou A,Geronikaki A,Ivanov M,Ciric A,Sokovic M

    更新日期:2021-01-15 00:00:00

  • Rational design, synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole hybrids.

    abstract::Molecular hybridization is an emerging structural modification tool to design molecules with better pharmacophoric properties. A series of novel 2-(trifluoromethyl)phenothiazine-1,2,3-triazoles 5a-v designed by hybridizing two antitubercular drugs trifluoperazine and I-A09 in a single molecular architecture, were synt...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Addla D,Jallapally A,Gurram D,Yogeeswari P,Sriram D,Kantevari S

    更新日期:2014-01-01 00:00:00

  • Novel 3-aminochromans as potential pharmacological tools for the serotonin 5-HT(7) receptor.

    abstract::The synthesis of novel C6-aryl substituted derivatives of 3-(dimethylamino)chroman is described. The novel derivatives display 5-HT(7) receptor affinities that varies from nM to muM, indicating that this small set of derivatives constitute a novel and interesting starting point for further structure-serotonin 5-HT(7) ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Holmberg P,Tedenborg L,Rosqvist S,Johansson AM

    更新日期:2005-02-01 00:00:00

  • Structure activity relationship study of burkholdine analogues toward simple antifungal agents.

    abstract::Cyclic and linear lipopeptides, burkholdine analogues, were synthesized by conventional Fmoc-SPPS and cyclisation with DIPC/HOBt in the solution phase. Synthesized peptides were evaluated for antifungal activities with MIC values against Saccharomyces cerevisiae and Aspergillus oryzae. As a result, the stereochemistry...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Konno H,Abumi K,Sasaki Y,Yano S,Nosaka K

    更新日期:2015-08-15 00:00:00

  • An endogenous sleep-inducing compound is a novel competitive inhibitor of fatty acid amide hydrolase.

    abstract::2-Octyl gamma-bromoacetoacetate (O gamma Br), an endogenous compound originally isolated from human cerebrospinal fluid (CSF), has previously been demonstrated to increase REM sleep duration in cats. Based on the chemical structure of O gamma Br and its reported sleep-inducing effects, we synthesized O gamma Br along ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Patricelli MP,Patterson JE,Boger DL,Cravatt BF

    更新日期:1998-03-17 00:00:00

  • In silico multi-filter screening approaches for developing novel beta-secretase inhibitors.

    abstract::A large database of chemical structures was screened for potential inhibitors of beta-secretase was carried out using in silico multi-filter techniques. Substructure screening, computer-aided ligand docking, binding free energy calculations, and partial interaction energy analyses were performed successively to identi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Fujimoto T,Matsushita Y,Gouda H,Yamaotsu N,Hirono S

    更新日期:2008-05-01 00:00:00

  • Folic acid conjugates of a bleomycin mimic for selective targeting of folate receptor positive cancer cells.

    abstract::A major challenge in the application of cytotoxic anti-cancer drugs is their general lack of selectivity, which often leads to systematic toxicity due to their inability to discriminate between malignant and healthy cells. A particularly promising target for selective targeting are the folate receptors (FR) that are o...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Geersing A,de Vries RH,Jansen G,Rots MG,Roelfes G

    更新日期:2019-08-01 00:00:00