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Solid-Phase Synthesis of Phosphorothioate/ Phosphonothioate and Phosphoramidate/ Phosphonamidate Oligonucleotides

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Solid-Phase Synthesis of Phosphorothioate/ Phosphonothioate and Phosphoramidate/ Phosphonamidate Oligonucleotides molecules Article Solid-Phase Synthesis of Phosphorothioate/ Phosphonothioate and Phosphoramidate/ Phosphonamidate Oligonucleotides OndˇrejKostov *, Radek Liboska, OndˇrejPáv *, Pavel Novák and Ivan Rosenberg * Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; [email protected] (R.L.); [email protected] (P.N.) * Correspondence: [email protected] (O.K.); [email protected] (O.P.); [email protected] (I.R.); Tel.: +420-220-183-381 (I.R.) Received: 1 May 2019; Accepted: 14 May 2019; Published: 15 May 2019 Abstract: We have developed a robust solid-phase protocol which allowed the synthesis of chimeric oligonucleotides modified with phosphodiester and O-methylphosphonate linkages as well as their P-S and P-N variants. The novel O-methylphosphonate-derived modifications were obtained by oxidation, sulfurization, and amidation of the O-methyl-(H)-phosphinate internucleotide linkage introduced into the oligonucleotide chain by H-phosphonate chemistry using nucleoside-O-methyl-(H)-phosphinates as monomers. The H-phosphonate coupling followed by oxidation after each cycle enabled us to successfully combine H-phosphonate and phosphoramidite chemistries to synthesize diversely modified oligonucleotide strands. Keywords: H-phosphinate; H-phosphonate; phosphoramidite; oligonucleotide; phosphonate; phosphorothioate; phosphonothioate; phosphoramidate; phosphonamidate 1. Introduction Recently,we published a detailed study on the influence of the incorporation of 20-deoxy-nucleoside 30-O- and 50-O-methylphosphonate units on the hybridization properties of modified DNA strands and on their ability to elicit E. coli RNase H activity in heteroduplexes [1]. Although the insertion of the bridging –CH2– group into the phosphodiester linkage should increase the total entropy of the system due to an additional degree of freedom, leading to duplex destabilization, only the incorporation of 30-O-methylphosphonate units into the DNA strand decreased the stability of the appropriate heteroduplexes. In contrast, the presence of 50-O-methylphosphonate units slightly stabilized the modifDNA*RNA heteroduplexes. These oligonucleotides, known as MethylPhosphonate Nucleic Acids (MePNA), when they contained various ratios of nucleoside-50-phosphate and 50-O-methyl-phosphonate units in an alternating mode exhibited superior enhancement of the RNase H cleavage rate. To improve the synthesis of MePNA, we developed the straightforward synthesis of nucleoside-O-methyl-(H)-phosphinates and 50-deoxynucleoside-50-S-methyl-(H)-phosphinates [2,3] that were closely related to the well-known nucleoside H-phosphonates, [4,5] and demonstrated their compatibility with the H-phosphonate chemistry of the oligonucleotide synthesis. Recently, Herdewijn [6] has exploited this methodology to introduce various nucleoside phosphonates into oligonucleotides. In this study, we present the extension of our methodology on the synthesis of modified oligonucleotides by a combination of phosphoramidite and H-phosphonate chemistries using nucleoside phosphoramidite, and H-phosphonate 1, nucleoside-O-methyl-(H)-phosphinate, and Molecules 2019, 24, 1872; doi:10.3390/molecules24101872 www.mdpi.com/journal/molecules Molecules 2019, 24, 1872 2 of 12 Molecules 2019, 24, x FOR PEER REVIEW 2 of 11 50-deoxynucleoside-50-S-methyl-(H)-phosphinate monomers 2 as building blocks (Figure1), respectively.respectively. Standard Standard p phosphoramiditehosphoramidite chemistry chemistry allows allows the the synthesis synthesis of phosphatephosphate 3,, andand phosphorothioatephosphorothioate4 internucleotide4 internucleotide linkages. linkageH-phosphonates. H-phosphonate chemistry chemistry affords evenaffords wider even possibilities wider sincepossibilities the H-phosphonate since the H- internucleotidephosphonate internucleotide linkage in 5 can linkage be oxidized, in 5 can sulfurized, be oxidized, or amidated sulfurized, to form or appropriateamidated to phosphateform appropriate3 [7,8], phosphate phosphorothioate 3 [7,8], phosphorothioate4 [9] or phosphoramidate 4 [9] or phosphor6 [10] internucleotideamidate 6 [10] linkagesinternucleotide (Figure linkages1). To be(Figure able to1). synthesize To be able oligonucleotides to synthesize modifiedoligonucleotides with phosphodiester, modified with phosphodiester, O-methylphosphonate, and 5′-deoxy-5′-S-methylphosphonate linkages, we O-methylphosphonate, and 50-deoxy-50-S-methylphosphonate linkages, we developed procedures whichdeveloped allowed procedures the synthesis which of Hallowed-phosphinate the synthesis internucleotide of H-phosphinate linkage 7 (Figure internucleotide1). This linkage linkage could 7 be(Figure oxidized, 1). This sulfurized, linkage orcou amidatedld be oxidized, to form sulfurized, the O-methylphosphonate or amidated to form8a, O the-methylphosphonothioate O-methylphosphonate 9a8a,, O--methylphosphonamidatemethylphosphonothioate 9a10, ,OS--methylphosphonatemethylphosphonamidate8b and10, SS-methylphosphonate-methylphosphonothioate 8b and9b S- internucleotidemethylphosphonothioate linkages, respectively.9b internucleotide The insertion linkages, of therespectively. oxidation stepThe afterinsertion each ofH -phosphonatethe oxidation couplingstep after step each [11 H,12-phosphonate] allowed us tocoupling combine step easily [11 phosphonate-derived,12] allowed us to combine units with easily the phosphodiester phosphonate- onesderived and units to prepare with the unique phosphodiester set of modified ones oligonucleotides. and to prepare unique set of modified oligonucleotides. FigureFigure 1. 1Overview. Overview of of possible possible combinations combinations of of the the phosphodiester phosphodiester3, 34,, 46, 6and and phosphonate phosphonate8a 8a, 8b, 8b, 9a, , 9b and 10 linkages. 9a, 9b and 10 linkages. 2. Results and Discussion 2. Results and Discussion 2.1. Study on Model Dimers 2.1. Study on Model Dimers Our results on novel nucleoside-O-methyl-(H)-phosphinates [2,3] as monomers for H-phosphonate chemistryOur results prompted on usnovel to develop nucleoside robust-O-methyl synthetic-(H protocols)-phosphinates that would[2,3] allowas monomers the synthesis for H of- oligonucleotidesphosphonate chemistry bearing anyprompted combination us to ofdevelop phosphodiester robust synthetic3, phosphorothioate protocols that4, phosphoramidatewould allow the 6synthesis, O-methylphosphonate of oligonucleotides8a ,bearingO-methylphosphonothioate any combination of phosphodiester9a, O-methyl-phosphonamidate 3, phosphorothioate10 4, Sphosphoramidate-methylphosphonate 6, 8bO-andmethylphosphonateS-methylphosphonothioate 8a, O-methylphosphonothioate9b internucleotide linkages 9a, (FigureO-methyl1). - Thephosphonamidate optimization of10, the S-methylphosphonate oxidative couplings 8b affording and S-methylphosphonothioate the abovementioned modified 9b internucleotide bonds was performedlinkages (Fig onure a model1). The dimer. optimiza Thus,tion of TentaGel the oxidative modified coupling with 4-s Naffording-benzoyl-2 the0-deoxy-3 abovementioned0-O-DMTr- cytidine-5modified 0bonds-hemisuccinate was performed11 was extendedon a model with dimer. thymidine- Thus,O T-methyl-(entaGelH modified)-phosphinate with or4-N thymidine-5-benzoyl-2′0- deoxy-5deoxy-3′0 -SO-methyl-(-DMTr-cytidineH)-phosphinate-5′-hemisuccinate monomer 112 towas provide extended TentaGel-attached with thymidine (dCT)-O- dimermethyl with-(H)- Hphosphinate-phosphinate or internucleotidethymidine-5′-deoxy linkage-5′-S12b-methyl. This-(H) linkage-phosphinate was subjected monomer to 2 oxidativeto provide procedures TentaGel- (oxidationattached (dCT)/sulfurization dimer with/amidation) H-phosphinate under internucleotide various conditions linkage (Scheme 12b. This1). linka All experimentsge was subjected with to Hoxidative-phosphinate procedures monomers (oxidation/sulfurization/amidation)2 were always compared to the under standard various thymidine conditionsH-phosphonate (Scheme 1).1 Allas aexperiments control of the with efficacy H-phosphinate of the reaction monomers conditions 2 were (For morealways details compared see Supporting to the standard Information). thymidine H- phosphonate 1 as a control of the efficacy of the reaction conditions (For more details see Supporting Information). Molecules 2019, 24, 1872 3 of 12 Molecules 2019, 24, x FOR PEER REVIEW 3 of 11 Scheme 1 1.. Model dimer for the optimization of H--phosphonatephosphonate chemistry chemistry.. 2.1.1. H--PhosphonatePhosphonate Coupling The optimization of of coupli couplingng reaction reaction of of HH-phosphinate-phosphinate monomers monomers 2 [2,32 [2] ,was3] was performed performed at 0.1 at 0.1M concentration M concentration in inacetonitrile acetonitrile-pyridine-pyridine mixture mixture (1:1 (1:1)) with with a aseries series of of activating activating agents agents [[13]13] commonly usedused in inH -phosphonateH-phosphonate chemistry chemistry such such as pivaloyl as pivaloyl chloride, chloride, adamantanecarbonyl adamantanecarbonyl chloride, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinanechloride, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane 2-oxide (DMOCP),2-oxide (DMOCP), diphenyl chloro-phosphatediphenyl chloro- (DPCP),phosphate and (DPCP) bis(2-oxo-3-oxazolidinyl)phosphinic, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride chloride (OXP) (OXP) at 0.3 at M 0.3 concentration M concentration in acetonitrile-pyridinein acetonitrile-pyridine mixtures mixture (95:5).s (95:5). Of Of all all tested tested coupling coupling
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