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61.
Thazha P. Prakash Jinghua Yu Garth A. Kinberger Audrey Low Michaela Jackson Frank Rigo Eric E. Swayze Punit P. Seth 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3774-3779
The potency of antisense oligonucleotide (ASO) drugs has significantly improved in the clinic after exploiting asialoglycoprotein receptor (ASGR) mediated delivery to hepatocytes. To further this technology, we evaluated the structure–activity relationships of oligonucleotide chemistry on in vivo potency of GalNAc-conjugated Gapmer ASOs. GalNAc conjugation improved potency of ASOs containing 2′-O-methyl (2′-O-Me), 3′-fluoro hexitol nucleic acid (FHNA), locked nucleic acid (LNA), and constrained ethyl bicyclo nucleic acid (cEt BNA) 10–20-fold compared to unconjugated ASOs. We further demonstrate that GalNAc conjugation improves activity of 2′-O-(2-methoxyethyl) (2′-O-MOE) and Morpholino ASOs designed to correct splicing of survival motor neuron (SMN2) pre-mRNA in liver after subcutaneous administration. GalNAc modification thus represents a viable strategy for enhancing potency of ASO with diverse nucleic acid modifications and mechanisms of action for targets expressed in hepatocytes. 相似文献
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Eric E. Swayze William M. Shannon Robert W. Buckheit Linda L. Wotring John C. Drach Leroy B. Townsend 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1507-1527
Abstract A number of 6-substituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine and 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of 2-amino-5-bromo-3,4-dicyanopyrrole (2) with triethylorthoformate, followed by alkylation via the sodium salt method with either 2-(acetoxyethoxy)methyl bromide or (1,3-diacetoxy-2-propoxy)methyl bromide, furnished the corresponding N-substituted pyrroles 3a and 3b. These compounds were then smoothly converted to the requisite deprotected 4-amino-6-bromopyrrolo[2,3-d]-pyrimidine-5-carbonitriles 5a and 5b (toyocamycin analogs) by methanolic ammonia. The 6-amino-derivatives were obtained by a displacement of the bromo group with liquid ammonia. Conventional functional group transformations involving the 5-cyano group furnished the 5-carboxamide (sangivamycin) and 5-thioamide analogs. Compounds substituted at the 7-position with a ribosyl moiety were active against human cytomegalovirus (HCMV) at micromolar concentrations, but the apparent activity was not selective. The 7-ribosyl compounds also had no activity against human immunodeficiency virus (HIV), though they were all cytotoxic. The new compounds were also evaluated against HCMV, herpes simplex virus type I (HSV-1), HIV, and also for their ability to inhibit the growth of L1210 murine leukemic cells in vitro. None of these compounds with (2-hydroxyethoxy)methyl substituents or 7-(1,3-dihydroxy-2-propoxy)methyl substituent at N-7 showed significant cytotoxicity toward L1210, or toward uninfected human foreskin fibroblasts (HFF cells), and KB cells. Nor were they cytotoxic in human lines CEM or MT2. Only compound 4a was found to be active against HCMV, having an IC50 of 32 μM. 相似文献
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Peter W. Davis Stephen A. Osgood Normand Hbert Kelly G. Sprankle Eric E. Swayze 《Biotechnology and bioengineering》1999,61(3):143-154
A combinatorial library motif has been developed based on orthogonally protected aminodiol scaffolds. Amine functionality was derivatized by commercially available electrophiles including carboxylic acids, sulfonyl chlorides, isocyanates, and aldehydes. A hydroxyl moiety was converted to a carbamate linkage, allowing a variety of amines to be incorporated. The scaffold was anchored to TentaGel at the second hydroxyl via a succinyl linker, which was hydrolyzed by mild aqueous basic conditions. The method was used to make a library of about 17,000 different members in mixtures of 5 per sample. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 61:143–154, 1998/1999. 相似文献
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Murray S Ittig D Koller E Berdeja A Chappell A Prakash TP Norrbom M Swayze EE Leumann CJ Seth PP 《Nucleic acids research》2012,40(13):6135-6143
We report the evaluation of 20-, 18-, 16- and 14-mer phosphorothioate (PS)-modified tricycloDNA (tcDNA) gapmer antisense oligonucleotides (ASOs) in T(m), cell culture and animal experiments and compare them to their gap-matched 20-mer 2'-O-methoxyethyl (MOE) and 14-mer 2',4'-constrained ethyl (cEt) counterparts. The sequence-matched 20-mer tcDNA and MOE ASOs showed similar T(m) and activity in cell culture under free-uptake and cationic lipid-mediated transfection conditions, while the 18-, 16- and 14-mer tcDNA ASOs were moderate to significantly less active. These observations were recapitulated in the animal experiments where the 20-mer tcDNA ASO formulated in saline showed excellent activity (ED(50) 3.9 mg/kg) for reducing SR-B1 mRNA in liver. The tcDNA 20-mer ASO also showed better activity than the MOE 20-mer in several extra-hepatic tissues such as kidney, heart, diaphragm, lung, fat, gastrocnemius and quadriceps. Interestingly, the 14-mer cEt ASO showed the best activity in the animal experiments despite significantly lower T(m) and 5-fold reduced activity in cell culture relative to the 20-mer tcDNA and MOE-modified ASOs. Our experiments establish tcDNA as a useful modification for antisense therapeutics and highlight the role of chemical modifications in influencing ASO pharmacology and pharmacokinetic properties in animals. 相似文献
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Hanessian S Pachamuthu K Szychowski J Giguère A Swayze EE Migawa MT François B Kondo J Westhof E 《Bioorganic & medicinal chemistry letters》2010,20(23):7097-7101
Incorporation of an hydrophobic (phenethylamino)ethyl ether at C2″ of N1-(HABA)-3',4'-dideoxyparomomycin led to a novel analog with an excellent antibacterial profile against a host of resistant bacteria. 相似文献
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A. Al-Shamma S.D. Drake L.E. Guagliardi L.A. Mitscher J.K. Swayze 《Phytochemistry》1982,21(2):485-487
Investigation of extracts of Boehmeria cylindrica resulted in identification of cryptopleurine and 3,4-dimethoxy-ω-(2′-piperidyl)acetophenone, known alkaloids, as agents responsible for intense activity against Candida albicans. Julandine, the secophenanthroquinolizidine alkaloid related to cryptopleurine, was also active but not definitely identified in the extracts examined. 相似文献