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New aspects of organochalcogen ChemistrySchultz, Erwin. January 1999 (has links)
The potential of chalcogen containing reagents in organic synthesis was investigated. More specifically, the efficiency of bis(triphenylstannyl) selenide (105) and telluride (95) in the reductive dehalogenation of alpha-halocarbonyl compounds was illustrated. The mechanism of the dehalogenation process was also examined. The intermediacy of a transitional enolate species was established by the successful isolation of the chalcone condensation product, resulting from reaction with benzaldehyde. A difference in the reactivity of bis(triphenylstannyl) selenide (105) and bis(tert-butyldimethylsilyl) telluride (95) in the dehalogenation process was discerned. / An investigation directed at the elaboration of a system capable of generating a diatomic selenium unit was carried out. The thermal decomposition of titanocene pentaselenide (177), in the presence of diene trap 2,3-diphenyl-1,3-butadiene (153), was demonstrated to generate the monoselenide adduct 2,5-dihydro-2,3-diphenylselenophene (207). In the process, 1H NMR evidence was obtained for the formation of diselenide 180, indicative of the generation of a diatomic selenium species. Extensive refluxing of a reaction mixture composed of titanocene pentaselenide (177) and 2,3-diphenyl-1,3-butadiene (153) was shown to ultimately result in the formation of 3,4-diphenylselenophene (181). Mechanisms were proposed to account for these processes.
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Predictive rules for the enantioselectivity of hydrolases towards alcohols and aminesWeissfloch, Alexandra N. E. January 1999 (has links)
To help organic chemists use enzymes as synthetic reagents, guidelines are needed to help them choose an appropriate enzyme. / We proposed reliable empirical substrate rules that predict the stereochemical outcome of reactions catalyzed by hydrolases. These rules, developed through a combination of substrate screening and literature surveys, are based on the difference in size of the substituents at the stereocenter of substrates. One proposed rule predicts the enantiopreference of cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosa towards secondary alcohols and their esters. / A similar rule is proposed to predict the enantiopreference of subtilisins towards isosteric primary amines of the type NH2CHRR' . The enantiopreference of lipases towards primary amines and of subtilisins toward secondary alcohols is reviewed. Lipases and subtilisins have opposing enantiopreferences towards both secondary alcohols and primary amines. We also observed that the regioselectivity of subtilisin is opposite to that of lipases. We offer a rationalization to explain these opposing selectivities, based on known crystal structures of lipases and subtilisin. / A similar rule is also found to predict the enantiopreference of lipase from Pseudomonas cepacia towards primary alcohols; this rule excludes substrates having an oxygen atom directly attached to the stereocenter. The favored enantiomer of primary alcohols is opposite to the favored enantiomer of secondary alcohols. Experiments conducted on substrates with two stereocenters and molecular modeling studies suggest that both classes of alcohols bind in the same regions of the active site. / We proposed a method to enhance enantioselectivity of lipases and esterases towards secondary alcohols. This technique, based on increasing the difference in size of the substituents at the stereocenter, was successfully applied to the preparation of two useful chiral synthons: (S)-(-)-4-acetoxy-2-cyclohexen-1-one and esters of (R)-lactic acid. / Using a similar approach, we designed a synthetic scheme for the preparation of both enantiomers of a useful C2-symmetric synthon. The key step is an acylation reaction catalyzed by lipase from Candida rugosa. (1R,4R)- and (1S,2 S)-bicyclo[2.2.1]heptan-2,5-diones were obtained with high optical purity.
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Organometallic reactions in aqueous media : reactivity, selectivity and synthetic applicationsLu, Wenshuo, 1971- January 2001 (has links)
Because of the concern for the environment and the search for the synthetic efficiency, the metal-mediated aqueous carbon-carbon bond formation reactions were studied. By employing sulfonimines, the scope of the metal-mediated aqueous Barbier-type allylation reactions was expanded to C=N electrophiles and the regio- and stereoselectivities of these reactions were examined. / The stereochemical factors in the indium-mediated aqueous Barbier-type allylation reactions of sulfonimines were investigated, and chelation control was observed and applied in the stereoselective crotylation reactions. By using chiral-modified sulfonimines or sulfinimines, the asymmetric aqueous Barbier-type allylation reaction of C=N electrophiles was also studied. / Highly regioselective propargylation reactions of sulfonimines mediated by zinc were discovered through the coupling of propargylic bromides with sulfonimines in aqueous media. Beyond the allylation transformations, zinc was also found as the metal of choice for the mediation of the Barbier-type benzylation reaction of sulfonimines and the coupling reaction of aldehydes with alpha-bromoacetonitriles in aqueous media. / The indium-mediated aqueous coupling reaction of 1,4-dibromobut-2-yne with aldehydes was demonstrated to be a concise way for the synthesis of 1,3-dien-ol compounds. Further synthetic applications of this reaction including the intro-molecular Diels-Alder reactions were preliminarily studied.
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A dinuclear approach to phosphate diester hydrolysisWahnon, Daphne C. January 1995 (has links)
The catalysis of the transesterification reaction of 2-hydroxypropyl p-nitrophenyl phosphate HPNP by a series of copper(II) complexes is investigated. Dichloro- ((bis(benzimidazol-2-ylmethyl)amine)copper(II)$ rm rbrack{ cdot}CH sb3OH (Cu(N3))$ and chloro- ((bis(benzimidazol-2ylmethyl)hydroxyethylamine)copper(II)$ rm rbrack chloride{ cdot}3(H sb2O)$ (Cu(N3OH)) are the most reactive mononuclear catalysts for promoting HPNP cleavage. A second order dependence on catalyst and a second order hydroxide dependence is observed for the transesterification reaction of HPNP promoted by Cu(N3). A mechanism is proposed in which a dimerized complex provides double Lewis acid activation followed by nucleophilic attack of the internal alkoxide of HPNP. / A dinuclear copper(II) complex dichloro- ((N,N,N$ sp prime$,N$ sp prime$-tetrakis(2-benzimidazolyl)-2-hydroxy-$1, 3$-di-aminopropane)dicopper(II)) chloride LCu$ sb2$ is also shown to be extremely reactive in promoting the cleavage of HPNP. LCu$ sb2$ (2 mM) cleaves HPNP with an observed psuedo first order rate constant of $ rm 3.9 times 10 sp{-3} s sp{-1}$ at pH 7 and 25$ sp circ$C. The half-life for this reaction is 3 mins. LCu$ sb2$ is as effective as Cu(N3) and Cu(N3OH) for promoting the transesterification reaction of HPNP. A mechanism is proposed which involves double Lewis acid activation and facilitation of nucleophilic attack by the internal alkoxide of HPNP. A value for the rate enhancement expected by a double Lewis acid mechanism $6 times 10 sp6$ in the cleavage reaction of phosphate diesters is reported. The novel compound LCu$ sb2$DMP is synthesized and characterized. The structure of LCu$ sb2$DMP provides supporting evidence for the mechanism proposed. / Two novel and structurally interesting dinuclear cobalt(III) complexes, $ mu$-dimethylphosphato-di-$ mu$-hydroxy-bis ((1,4,7-triazacylononane)cobalt(III)) triperchlorate tacn$ sb2$Co$ sb2$(OH)$ sb2$DMP and $ mu$-(methyl-p-nitro-phenylphosphato)-di-$ mu $-hydroxy-bis ((1,4,7-triazacylononane)cobalt(III)) triperchlorate tacn$ sb2$Co$ sb2$(OH)$ sb2$MPNP are synthesized and characterized. The second order rate constant for the hydroxide caltalyzed hydrolysis of the doubly coordinated methyl (p-nitrophenyl) phosphate MPNP is $ rm 1.1 times 10 sp6 M sp{-1}s sp{-1}$ at 45$ sp circ$C. The proposed mechanism involves double Lewis activation of the phosphate diester and nucleophilic attack by a bridging oxy nucleophile. The breakdown of the species formed by this nucleophilic attack involves Co-O bond cleavage. Oxygen labeling experiments, pH-rate data and the identified reaction products are consistent with the proposed mechanism. A rate acceleration of $6 times 10 sp{11}$ fold is observed for the hydrolysis of the P-O bond in tacn$ sb2$Co$ sb2$OH$ sb2$MPNP over the background hydrolysis rate of MPNP.
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Synthesis of (plus or minus)-oxetanocin and related compoundsHambalek, Robert J. (Robert Josef) January 1992 (has links)
Photo-adducts of aldehydes and furan were transformed to substituted monocyclic oxetanes, using a modification of the Fraser-Reid-Mootoo glycosidation procedure, and the chemistry of these oxetanes was studied. The photo-adduct of 2-methylfuran and propionyloxyacetaldehyde was transformed in a one-pot reaction to oxetane 75a, which gave oxetanocin and its epimer as described. The coupling of various oxetanes of the type 75 to nitrogenous bases was also investigated. / During the course of this work, it was found that epoxides of the type 23 could be transformed into bicyclic nucleosides 91 and furanosides 93. Bicyclic nucleosides 99 were also prepared, again using a modified Fraser-Reid-Mootoo coupling procedure. / An investigation into the resolution of photo-adducts of aldehydes and furans was initiated.
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Studies toward the synthesis of hydroxylated indolizidine alkaloidsSt-Denis, Yves January 1991 (has links)
The formation of the indolizidine ring system was studied. First, the intramolecular electrophilic cyclisation of substituted allylsilanes, vinylsilanes and enol ethers was attempted. Reactions with the allylsilane moiety indeed gave the desired ring system, whereas the vinylsilanes failed to give any cyclisation product. In order to easily introduce oxygen functionalities in the rings, enol ether cyclisations were also attempted but did not produce the expected bicyclic systems. / Secondly, the intramolecular nucleophilic cyclisation of free amines bearing suitable leaving groups was attempted, providing an easy method for the formation of the indolizidine system, with an interesting entry into the synthesis of biologically active polyhydroxylated alkaloids Swainsonine and Castanospermine. The synthesis of these two natural compounds, as well as some of their analogues, using the successful nucleophilic methodology was attempted. / Finally, the regioselective and stereoselective introduction of hydroxyl groups into the pyrrolidine ring system was studied in order to prepare mono- and di-hydroxylated pyrrolidines for the synthesis of the aforementioned natural products.
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Synthesis of a non-hydrolyzable dinucleoside analogueKawai, Stephen H. January 1990 (has links)
The synthesis of 95, a non-hydrolyzable dinucleotide analogue bearing an internucleoside thioether linkage, is described. The 3$ sp prime$-deoxy-3$ sp prime$-C-(2$ sp{ prime prime}$-substituted-ethyl) branched-chain sugar and nucleoside precursors were efficiently prepared from 1,2-O-isopropylidene-$ alpha$- scD-xylofuranose. / In the course of this work, it was found that intramolecular 5,2$ sp prime$-sulfide formation occurs very rapidly, in spite of the trans-fusion of the bicyclic ring system. This enabled the straightforward preparation of the novel perhydro-oxathiahydrindane nucleosides 41 and 43 as well as the cAMP analogue 51. Detailed NMR analysis of the bicyclic compounds was performed. / The acetolytic deacetalation of branched-chain thiosugars 11 and 68 was found to give a variety of non-furanose products, including the novel thiolanes 71 and 74, whose formation was dependent on the reaction temperature. The competing acetolysis mechanisms and the implications on related phenomena are discussed.
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Design, synthesis and physicochemical properties of aromatic peptide nucleic acidsFader, Lee David, 1974- January 2002 (has links)
Synthetic methods were developed for the preparation of several structurally diverse aromatic peptide nucleic acid (APNA) monomers containing all four natural DNA bases. This set of building blocks was useful for the preparation of oligomers designed to evaluate the hybridization properties of novel peptide nucleic acid (PNA) analogues, which incorporate aromatic rings into their backbone. Protocols for the solid-phase synthesis of APNA-PNA chimeras and APNA homopolymers were also developed. / Thermal denaturation experiments involving APNA-PNA chimeras demonstrated that APNA backbones comprised of N-(2-aminomethylphenyl) glycine and N-(2-aminobenzyl) glycine as the backbone moiety exhibited good binding affinity for DNA and RNA. Further studies with PNA oligomers composed partly of repeating N-(2-aminobenzyl) glycine APNAs showed that these analogues displayed good sequence recognition for DNA and RNA. Furthermore, continuous tracts of APNA units were well tolerated in both the triplex and duplex binding modes. The binding of APNA modified oligomers was investigated using UV, circular dichroism spectropolarimetry (CD) and complex formation with the cyanine dye 3-ethyl-2-[5-(3-ethyl-3H-benzothiazol-2-ylidene)-penta-1,3-dienyl]-benzothiazol-3-ium iodide (DiSC2(5)). In the latter experiments, binding of the dye to complexes formed between APNA modified oligomers and DNA or RNA suggested that the minor grooves of these complexes were not drastically different from those formed in the corresponding PNA:DNA or PNA:RNA complexes. / Finally, fully modified APNA homopolymers were prepared in order to investigate their physicochemical properties. These oligomers were found to be essentially insoluble in aqueous buffers, which prohibited study of their binding affinity to nucleic acids. However, a short homothymine oligomer was synthesized which was modified at the C- and N-terminals so that it can be dissolved in water in sufficient quantities to allow for evaluation of its recognition and binding to DNA and RNA. Complex formation was confirmed by CD and DiSC 2(5) binding experiments. These studies indicated that the APNA homopolymer bound to DNA and RNA, apparently through Watson-Crick base pairing, and formed a complex that was more stable than those formed by the corresponding homothymine DNA oligomer with complementary DNA under similar conditions.
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Design and structure of new classes of phosphorus-based 1,3-dipolar cycloaddition reagentsSt Cyr, Daniel Jean January 2010 (has links)
This thesis describes the design of unique classes of 1,3-dipolar cycloaddition reagents. The purpose of this study was to develop general and practical methods for the modular syntheses of heterocycles via 1,3-dipolar cycloaddition. It was found that several 1,3-dipolar reagents can be generated from imines, acid chlorides, and isocyanides or trivalent phosphorus derivatives, and can be exploited in cycloadditions for pyrrole synthesis. / In Chapter 2, a direct synthesis of pyrroles from imines, acid chlorides, and alkynes mediated by isocyanides is reported. This reaction proceeds with a range of each of these substrates, providing a method to generate families of pyrroles in high yield. This discovery evolved out of the palladium-catalyzed synthesis of Münchnones, a reaction reported by our research group. Munchnones are a known class of 1,3-dipole with practical applications in the synthesis of pyrroles. Mechanistic studies suggest that the isocyanide-mediated reaction involves the generation of imino analogues of Munchnones, which liberate isocyanate rather than carbon dioxide upon pyrrole formation. / Chapter 3 demonstrates that, in addition to isocyanides, phosphites and phosphonites may also mediate the one-pot reaction of imines, acid chlorides, and alkynes to synthesize pyrroles. The most rapid cycloadditions and optimal pyrrole yields are obtained with PPh(catechyl) (catechyl = o-O2C6H4). This third generation protocol is proposed to involve amido-substituted Wittig-type intermediates. Upon cycloaddition with alkynes, these intermediates abstract oxygen from the former acid chloride unit generating phosphonate as the reaction byproduct. This oxidation of the phosphorus(III) mediator during pyrrole synthesis is analogous to the oxidation of carbon monoxide to carbon dioxide during the palladium-catalyzed pyrrole synthesis. / In Chapter 4, a closer inspection of the cycloaddition intermediate reported in Chapter 3 reveals these are a new class of phosphorus-based 1,3-dipolar cycloaddition reagent. These substrates undergo cycloaddition with alkynes to form pyrroles in a fashion directly analogous to Munchnones. Their ability to participate in cycloaddition is dependent upon the PR3 employed, and 1H, 13C and 31P NMR analysis suggest this PR3-dependence arises from a varying structure of the phosphorus-containing intermediate, with electron poor phosphonites and phosphites favoring the cyclic 1,3-dipolar structure, while more electron rich phosphines adopt a classic acyclic Wittig-type valence tautomer. This has been confirmed by X-ray crystallographic studies. In addition to representing a new class of dipole, the presence of the phosphorus unit creates a large steric and electronic bias across the 1,3-dipole, allowing for the regiospecific cycloaddition of unsymmetrical alkynes to form pyrroles. / Chapter 5 discloses an alternative route for the generation of phosphorus-based 1,3-dipoles, via Wadsworth-Emmons reagents rather than Wittig-type reagents. These substrates also participate in (3+2) cycloaddition with alkynes to afford pyrroles with elimination of phosphate. The amido-substituted phosphonate precursors of the Wadsworth-Emmons reagents may be generated in situ via a TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites of the form (RO)2POTMS. This was exploited in an overall three-component synthesis of pyrroles with complete and independent control of all five pyrrole substituents. / Cette thèse décrit la conception de classes uniques de réactifs de cycloaddition 1,3-dipôlaires. Le but de cette étude était d'élaborer des méthodes de synthèse générales, pratiques et modulaires d'hétérocycles via une stratégie de cycloaddition 1,3-dipôlaires. Il a été constaté que plusieurs réactifs 1,3-dipôlaires peuvent être facilement générés à partir des imines, chlorures d'acid et isocyanides ou des dérivés du phosphore trivalent et peuvent être exploités dans des réactions de cycloaddition pour la synthèse des pyrroles. / Au chapitre 2, une synthèse directe de pyrroles à partir d'imines, de chlorures d'acids et d'alkynes est reportée dont les isocyanides servent comme réactif en lieu et place du monoxyde de carbone. Cette réaction se produit avec une gamme de chacun de ces substrats, fournissant une méthode pour générer des familles de pyrroles à haut rendement. Les études mécanistiques suggèrent que l'utilisation des isocyanides dans cette réaction implique la génération d'analogues imino des Munchnones qui libèrent de l'isocyanate plutôt que du dioxyde de carbone lors de la formation de pyrroles. / Le chapitre 3 nous montre que les phosphites et les phosphonites peuvent également permettre la réaction «one-pot» des imines, chlorures d'acids et d'alcynes afin de synthétiser des pyrroles. Les cycloadditions les plus rapides et les meilleurs rendements de pyrrole ont été obtenus avec PPh(catechyl) (catechyl = o-O2C6H4). Nous proposons que cette réaction, de troisième génération, passe par des intermédiaires de type Wittig à substitution amido. Lors de cycloaddition avec les alcynes, un biproduit de phosphonate est généré qui contient l'oxygène provenant du réactif de chlorure d'acid. L'oxydation du réactif phosphore(III), lors de la synthèse du pyrrole, est analogue à l'oxydation du monoxyde de carbone en dioxyde de carbone au cours de la réaction analogue catalysée par le palladium. / Au chapitre 4, une inspection plus poussée de l'intermédiaire, qui participe dans la réaction de cycloaddition, signalé dans le chapitre 3 révèle ces derniers comme étant une nouvelle classe de réactifs 1,3-cycloadditions dipôlaires contenant le phosphore. Ces substrats subissent une cycloaddition avec les alcynes pour former des pyrroles d'une façon analogue aux Munchnones. Leur capacité à participer à la cycloaddition dépend du substrat PR3 employé, et l'analyse de RMN 1H, 13C et 31P suggère que cette dépendance sur le groupement PR3 repose sur une structure variable des intermédiaires contenant du phosphore, avec des phosphites et phosphonites plutôt électrons pauvres favorisant la structure cyclique 1,3-dipôlaire, tandis que les phosphines plus riches en électrons mènent à une structure tautomèrique de valence linéaire plus classique de Wittig. Celles-ci ont été confirmées par l'analyse aux rayons-X cristallographiques. En plus de représenter une nouvelle classe de dipôles, la présence de l'unité de phosphore crée un biais stérique et électronique à travers le 1,3-dipôle d'envergure, permettant la cycloaddition d'alcynes dissymétriques pour former un des deux régioisomères pyrroliques de façon séléctive. / Le chapitre 5 révèle une voie alternative pour la génération de 1,3-dipôle contenant le phosphore, empruntant des réactifs de Wadsworth-Emmons plutôt que des réactifs de Wittig comme intermédiares. Ces réactifs alternatifs peuvent également participer à la cycloaddition (3 +2) avec alcynes pour fournir des pyrroles avec l'élimination de phosphate. Les précurseurs de phosphonates amido-substitués des réactifs Wadsworth-Emmons peuvent également être générés in situ par une réaction d'Arbuzov d'imines, chlorures d'acids et phosphites de la forme (RO)2POTMS, catalysée par le TMSOTf. Ceci a été exploité dans une réaction globale qui permet la synthèse de pyrroles avec un contrôle complet et indépendant de tous les cinq substituants du pyrrole.
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New methods for the synthesis of RNA, novel RNA pro-drugs and RNA microarraysLackey, Jeremy January 2010 (has links)
The demand for synthetic oligonucleotides has grown exponentially over the past decades as genome sequencing, functional genomics, polymerase chain reaction (PCR)-based detection methods, and gene silencing via RNA interference (RNAi) consume enormous numbers of DNA and RNA oligonucleotides. Although various RNA synthesis chemistries now allow oligoribonucleotides to be produced routinely, the higher complexity and cost of RNA (over DNA) has somewhat limited its availability. / A major goal of this thesis work was aimed at finding ribonucleoside synthons that potentially benefit two critical aspects of RNA manufacturing: yield and ease of post-synthesis processing. Towards these goals, we developed methods for the synthesis of RNA using 2'-O-Lv and 2'-O-acetal Lv (ALE) ribonucleoside derivatives. Deprotection of the RNA chains consisted of a three-step deprotection scheme, which eliminated the need for any harsh basic hydrolytic steps, generally composed of: (1) treatment with anhydrous NEt3 (r.t., 1 h) to deblock the phosphate's cyanoethyl groups; (2) hydrazinolysis (r.t., 30 min 4 h) to simultaneously deprotect the nucleobases and 2'-OH positions, and (3) fluoride treatment (r.t., 30 min) to effect cleavage from the controlled pore glass solid support. Significantly, the rather mild conditions to remove 2'-O-Lv or 2'-O-ALE protecting groups did not lead to RNA strand scission. Furthermore, in the case of 2'-O-ALE protection, higher step-wise monomer coupling yields (~98.7%) was possible, since the ALE protection is less bulky than conventional silyl protection, i.e. TBDMS. Furthermore, both 2'-O-Lv or 2'O-ALE chemistries are completely compatible with the synthesis cycles used by all automated gene synthesizers. / With adjustments in protecting group strategies for the 5'-OH, exocyclic amino nucleobase groups and the development of a light-labile solid support, two other major goals were achieved: (1) the first in situ synthesis of RNA on microarrays, and (2) synthesis of chemically modified RNA strands with 2'-O-acetal ester and 2'-O-acetal ester pyrrolidines in order to increase lipophilicity and cellular permeability over native RNA. When RNA synthesis was carried out with 5'-O-NPPOC 2'-O-ALE monomers on a microarray ("chip"), deprotection typically involved (1) cleavage of the photolabile 5'-protecting group; (2) treatment with anhydrous NEt3 (r.t., 1 h) to deblock the phosphate's cyanoethyl groups; (3) hydrazinolysis (r.t., 30 min 4 h) to simultaneously deprotect bases and 2'-OH positions. The latter step could also be accomplished with ethylenediamine at room temperature. An RNase A assay was performed as "proof-of-principle" to demonstrate the value of a DNA-RNA microarray for studying enzyme kinetics and specificity on oligonucleotide based libraries. We showed that RNase A acts effectively on a DNA-RNA substrate with measurable kinetics analogous to those of the reference substrates. / The novel 2'-O-modified RNA were tested as short interfering RNA pro-drugs ("pro-siRNA") that would cross the cell membrane and be hydrolyzed (at the 2'-O-ester groups) by ubiquitous esterases to release the active (siRNA) molecules. Indeed, both siRNA and pro-siRNA prepared via 2'-O-ALE chemistry were shown to be active in an RNAi luciferase gene knockdown assay, confirming the integrity of the synthesized RNA strands and the promise of the pro-siRNA approach.
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