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Nucleoside and nucleotide analogues have proven to be transformative in the treatment of viral infections and cancer. One branch of structural modification to deliver new nucleoside analogue classes explores replacement of canonical ribose oxygen with a sulfur atom. Whilst biological activity of such analogues has been shown in some cases, widespread exploration of this compound class is hitherto hampered by the lack of a straightforward and universal nucleobase diversification strategy. Herein, we present a synergistic platform enabling both biocatalytic nucleobase diversification from 4'-thiouridine in a one-pot process, and chemical functionalization to access new entities. This methodology delivers entry across pyrimidine and purine 4'-thionucleosides, paving a way for wider synthetic and biological exploration. We exemplify our approach by enzymatic synthesis of 5-iodo-4'-thiouridine on multi-milligram scale and from here switch to complete chemical synthesis of a novel nucleoside analogue probe, 5-ethynyl-4'-thiouridine. Finally, we demonstrate the utility of this probe to monitor RNA synthesis in proliferating HeLa cells, validating its capability as a new metabolic RNA labelling tool.
Assuntos
RNA , Tionucleosídeos , Tiouridina , Tiouridina/análogos & derivados , Tiouridina/química , Tiouridina/metabolismo , Humanos , Tionucleosídeos/química , Tionucleosídeos/metabolismo , Tionucleosídeos/síntese química , RNA/metabolismo , RNA/química , Células HeLa , Biocatálise , Estrutura MolecularRESUMO
With the aim to identify new antiviral agents with antibacterial properties, a series of 2-quinolone-1,2,3-triazole derivatives bearing α-aminophosphonates was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, single crystal XRD and HRMS analyses. These compounds were examined against five RNA viruses (YFV, ZIKV, CHIKV, EV71 and HRV) from three distinct families (Picornaviridae, Togaviridae and Flaviviridae) and four bacterial strains (S. aureus, E. feacalis, E. coli and P. aeruginosa). The α-aminophosphonates 4f, 4i, 4j, 4k, 4p and 4q recorded low IC50 values of 6.8-10.91 µM, along with elevated selectivity indices ranging from 2 to more than 3, particularly against YFV, CHIKV and HRV-B14. Besides, the synthesized compounds were generally more sensitive toward Gram-positive bacteria, with the majority of them displaying significant potency against E. feacalis. Specifically, an excellent anti-enterococcus activity was obtained by compound 4q with MIC and MBC values of 0.03 µmol/mL, which were 8.7 and 10 times greater than those of the reference drugs ampicillin and rifampicin, respectively. Also, compounds 4f, 4p and 4q showed potent anti-staphylococcal activity with MIC values varying between 0.11 and 0.13 µmol/mL, compared to 0.27 µmol/mL for ampicillin. The results from DFT and molecular docking simulations were in agreement with the biological assays, proving the binding capability of hybrids 4f, 4i, 4j, 4k, 4p and 4q with viral and bacterial target enzymes through hydrogen bonds and other non-covalent interactions. The in silico ADME/Tox prediction revealed that these molecules possess moderate to good drug-likeness and pharmacokinetic properties, with a minimal chance of causing liver toxicity or carcinogenic effects.
Assuntos
Hidroxiquinolinas , Quinolonas , Infecção por Zika virus , Zika virus , Humanos , Antibacterianos/química , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacologia , Staphylococcus aureus , Simulação de Acoplamento Molecular , Escherichia coli , Ampicilina/farmacologia , Antivirais/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
The development of biomolecule-derived biocompatible scaffolds for drug delivery applications is an emerging research area. Herein, we have synthesized a series of nucleobase guanine (G) functionalized amino acid conjugates having different chain lengths to study their molecular self-assembly in the hydrogel state. The gelation properties have been induced by the correct choice of chain lengths of fatty acids present in nucleobase functionalized molecules. The effect of alkali metal cations, pH, and the concentration of nucleobase functionalized amino acid conjugates in the molecular self-assembly process has been explored. The presence of Hoogsteen hydrogen bonding interaction drives the formation of a G-quadruplex functionalized hydrogel. The DOSY nuclear magnetic resonance is also performed to evaluate the self-assembling behavior of the newly formed nucleobase functionalized hydrogel. The nanofibrillar morphology is responsible for the formation of a hydrogel, which has been confirmed by various microscopic experiments. The mechanical behaviors of the hydrogel were evaluated by rheological experiments. The in vitro biostability of the synthesized nucleobase amino acid conjugate is also investigated in the presence of hydrolytic enzymes proteinase K and chymotrypsin. Finally, the nucleobase functionalized hydrogel has been used as a drug delivery platform for the control and sustained pH-responsive release of vitamins B2 and B12. This synthesized nucleobase functionalized hydrogel also exhibits noncytotoxic behavior, which has been evaluated by their in vitro cell viability experiment using HEK 293 and MCF-7 cell lines.
Assuntos
Hidrogéis , Vitaminas , Humanos , Hidrogéis/farmacologia , Hidrogéis/química , Preparações de Ação Retardada/farmacologia , Células HEK293 , Aminoácidos/químicaRESUMO
Nucleosides modification via conventional cross-coupling has been performed using different catalytic systems and found to take place via long reaction times. However, since the pandemic, nucleoside-based antivirals and vaccines have received widespread attention and the requirement for rapid modification and synthesis of these moieties has become a major objective for researchers. To address this challenge, we describe the development of a rapid flow-based cross-coupling synthesis protocol for a variety of C5-pyrimidine substituted nucleosides. The protocol allows for facile access to multiple nucleoside analogues in very good yields in a few minutes compared to conventional batch chemistry. To highlight the utility of our approach, the synthesis of an anti-HSV drug, BVDU was also achieved in an efficient manner using our new protocol. Supplementary Information: The online version contains supplementary material available at 10.1007/s41981-023-00265-1.
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Analogs of pyrimidine and 1,3,4-oxadiazole are two well established class of molecules proven as potent antiviral and anticancer agents in the pharmaceutical industry. We envisioned designing new molecules where these two heterocycles were conjugated with the goal of enhancing biological activity. In this vein, we synthesized a series of novel pyrimidine-1,3,4-oxadiazole conjugated hybrid molecules as potential anticancer and antiviral agents. Herein, we present a new design for 5-fluorocytosine-1,3,4-oxadiazole hybrids (5a-h) connected via a methylene bridge. An efficient synthesis of new derivatives was established, and all compounds were fully characterized by NMR and MS. Eight compounds were evaluated for their cytotoxic activity against fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), lung carcinoma (A-549), and for their antiviral activity against SARS-CoV-2. Among all compounds tested, the compound 5e showed marked growth inhibition against all cell lines tested, particularly in HT-1080, with IC50 values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC50 >100 µM. The mechanism of cell death was investigated using Annexin V staining, caspase-3/7 activity, and analysis of cell cycle progression. The compound 5e induced apoptosis by the activation of caspase-3/7 and cell-cycle arrest in HT-1080 and A-549 cells at the G2M phase. The molecular docking suggested that the compound 5e activated caspase-3 via the formation of a stable complex protein-ligand.
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Modification of nucleosides via cross-coupling processes has been carried out extensively on unprotected halonucleosides to produce functionalized nucleosides that are often developed for incorporation into oligonucleotides or used as fluorescent probes. This approach requires protection of the 5'-OH with the 4,4'-dimethoxytrityl (DMTr) group, which is complicated and a common cause of reaction failure. Here we report a method for direct functionalization of 5'-O-DMTr-5-iodo-2'-deoxyuridine via Suzuki-Miyaura cross-coupling, Heck alkenylation, and carboamidation. This approach facilitates rapid synthesis of a variety of C5-substituted 5'-O-DMTr-2'-deoxyuridine derivatives. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of the SerrKap palladacycle complex Basic Protocol 2: Suzuki-Miyaura coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 3: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 4: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine with Ruth linker using Pd(OAc)2 /PTABS Basic Protocol 5: Carbonylative amidation of 5'-O-DMTr-5-iodo-2'-deoxyuridine using Pd(OAc)2 /PTABS.
Assuntos
Idoxuridina , Paládio , Catálise , Nucleosídeos , OligonucleotídeosRESUMO
An improved protocol for the transformation of ribonucleosides into 2',3'-dideoxynucleoside and 2',3'-didehydro-2',3'-dideoxynucleoside derivatives, including the anti-HIV drugs stavudine (d4T), zalcitabine (ddC) and didanosine (ddI), was established. The process involves radical deoxygenation of xanthate using environmentally friendly and low-cost reagents. Bromoethane or 3-bromopropanenitrile was the alkylating agent of choice to prepare the ribonucleoside 2',3'-bisxanthates. In the subsequent radical deoxygenation reaction, tris(trimethylsilyl)silane and 1,1'-azobis(cyclohexanecarbonitrile) were used to replace hazardous Bu3SnH and AIBN, respectively. In addition, TBAF was substituted for camphorsulfonic acid in the deprotection step of the 5'-O-silyl ether group, and an enzyme (adenosine deaminase) was used to transform 2',3'-dideoxyadenosine into 2',3'-dideoxyinosine (ddI) in excellent yield.
Assuntos
Fármacos Anti-HIV , Zidovudina , Didanosina , Didesoxinucleosídeos , Estavudina , ZalcitabinaRESUMO
Trifluoromethylated nucleosides, such as trifluridine, have widespread applications in pharmaceuticals as anticancer and antiviral agents. However, site-selective addition of a trifluoromethyl group onto a nucleobase typically requires either inconvenient multi-step synthesis or expensive trifluoromethylation reagents, or results in low yield. This article describes a simple, scalable, and high-yielding protocol for late-stage direct trifluoromethylation of pyrimidine nucleosides via a microwave-irradiated pathway. First, 5-iodo pyrimidine nucleosides undergo complete benzoylation to obtain N3 -benzoyl-3',5'-di-O-benzoyl-5-iodo-pyrimidine nucleosides as key precursors. Next, trifluoromethylation is carried out under both conventional and microwave heating using an inexpensive and commercially accessible Chen's reagent, i.e., methyl fluorosulfonyldifluoroacetate, to produce N3 -benzoyl-3',5'-di-Obenzoyl-5-trifluoromethyl-pyrimidine nucleosides. The microwave-assisted transformation accentuates its simplicity, mild reaction conditions, and dominance, providing a facile route to access trifluoromethylation. Finally, the envisioned 5-trifluoromethyl pyrimidine nucleosides are obtained by a routine debenzoylation procedure. This concludes a convenient three-step synthesis to obtain trifluridine and its 2'-modified analogs on a gram scale with consistently high yields, starting from their respective iodo-precursors, and requires only one chromatographic purification at the trifluoromethylation step. Furthermore, this operationally simple protocol can be utilized as a definitive methodology to produce various other trifluoromethylated therapeutics. © 2021 Wiley Periodicals LLC. Basic Protocol: Synthesis of 5-trifluoromethyl pyrimidine nucleosides 4a-c Alternate Protocol: Conventional trifluoromethylation: Synthesis of N3-benzoyl-3',5'-di-O-benzoyl-5-trifluoromethyl pyrimidine nucleosides (3a-c).
Assuntos
Nucleosídeos de Pirimidina , Antivirais , Micro-Ondas , NucleosídeosRESUMO
Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or ß-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First, the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.
Assuntos
Antineoplásicos/química , Nucleosídeos/análogos & derivados , Oxidiazóis/química , Tetrazóis/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética/economia , Técnicas de Química Sintética/métodos , Humanos , Neoplasias/tratamento farmacológico , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Estereoisomerismo , Tetrazóis/síntese química , Tetrazóis/farmacologiaRESUMO
Synthesis of novel homoazanucleosides and their peptidyl analogs as hybrid molecules comprised of amino acids, an iminosugar and natural nucleobases is reported for the first time. A pluripotent amino-substituted chiral polyhydroxypyrrolidine, possessing orthogonally different functional groups on either arm of the pyrrolidine ring, served as an ideal substrate for the synthesis of the proposed peptidyl homoazanucleosides. The acid sensitive primary benzyloxy group, on one arm of the pyrrolidine ring, after selective deprotection, was utilized for the introduction of nucleobases to obtain the homoazanucleosides. The amino group on the other side offered the opportunity to be coupled with amino acids to deliver the desired peptidyl homoazanucleosides. Glycosidase inhibition studies revealed that the acetamido derivatives of homoazanucleosides were found to be sub-millimolar inhibitors of ß-N-acetyl-glucosaminidase.
Assuntos
Acetilglucosaminidase/antagonistas & inibidores , Compostos Aza/farmacologia , Inibidores Enzimáticos/farmacologia , Nucleosídeos/farmacologia , Peptídeos/farmacologia , Acetilglucosaminidase/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fabaceae/enzimologia , Modelos Moleculares , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Peptídeos/síntese química , Peptídeos/químicaRESUMO
Nucleic acid derivatives are imperative biomolecules and are involved in life governing processes. The chemical modification of nucleic acid is a fascinating area for researchers due to the potential activity exhibited as antiviral and antitumor agents. In addition, these molecules are also of interest toward conducting useful biochemical, pharmaceutical, and mutagenic study. For accessing such synthetically useful structures and features, transition-metal catalyzed processes have been proven over the years to be an excellent tool for carrying out the various transformations with ease and under mild reaction conditions. Amidst various transition-metal catalyzed processes available for nucleoside modification, Pd-catalyzed cross-coupling reactions have proven to be perhaps the most efficient, successful, and broadly applicable reactions in both academia and industry. Pd-catalyzed C-C and C-heteroatom bond forming reactions have been widely used for the modification of the heterocyclic moiety in the nucleosides, although a single catalyst system that could address all the different requirements for nucleoside modifications isvery rare or non-existent. With this in mind, we present herein a review showcasing the recent developments and improvements from our research groups toward the development of Pd-catalyzed strategies including drug synthesis using a single efficient catalyst system for the modification of nucleosides and other heterocycles. The review also highlights the improvement in conditions or the yield of various bio-active nucleosides or commercial drugs possessing the nucleoside structural core. Scale ups wherever performed (up to 100 g) of molecules of commercial importance have also been disclosed.
Assuntos
Compostos Heterocíclicos/química , Nucleosídeos/química , Paládio/química , Catálise , Estrutura Molecular , SolubilidadeRESUMO
For the first time, a series of novel 1'-homo-N-2'-deoxy-α-nucleosides containing natural nucleobases as well as 5-fluoro and 5-iodopyrimidine analogs have been synthesized in an efficient manner. Additionally, a high yield protocol for the assembly of a dimeric scaffold containing two sugar moieties linked to the N-1 and N-3 positions of a single pyrimidine base has been accomplished. The structures of the novel homonucleosides were established by a single crystal X-ray structure of 1'-homo-N-2'-deoxy-α-adenosine and NMR studies. The biological activity of these 1'-homo-N-2'-deoxy-α-nucleosides as antiviral (HIV-1 and HBV) and cytotoxic studies was measured in multiple cell systems. The unique structure and easy accessibility of these compounds may allow their use in the design of new nucleoside analogs with potential biological activity and as a scaffold for combinatorial chemistry.
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The synthesis and catalytic applications of the highly water-soluble ligand 7-phospha-1,3,5-triaza-admantane butane sultonate (PTABS) has been described. The synthesized PTABS ligand along with palladium acetate exhibits excellent reactivity towards the amination reaction of 6-chloro-9-(ß-D-ribofuranosyl)-9H-purine at ambient temperature. This protocol offers an advantage over the previously published procedures for the amination of 6-chloropurine nucleoside furnishing 6-N-substituted adenosine analogues. The validation of the present strategy has been demonstrated via synthesis of a uracil-based, anti-diabetic drug alogliptin. © 2018 by John Wiley & Sons, Inc.
Assuntos
Hipoglicemiantes/síntese química , Paládio/química , Piperidinas/síntese química , Uracila/análogos & derivados , Aminação , Catálise , Hipoglicemiantes/química , Espectroscopia de Ressonância Magnética/métodos , Piperidinas/química , Solubilidade , Uracila/síntese química , Uracila/química , ÁguaRESUMO
In the asymmetric unit, equalling the unit cell (triclinic, P1, Z = 1), two mol-ecules of the title compound, 8-(4-methyl-phen-yl)-d-2'-de-oxy-adenosine, C17H19N5O3, are present, with distinct conformations of the two sugar moieties, together with one solvent water mol-ecule. All three ribose O atoms are involved in hydrogen bonding and the crystal packing is largely determined by hydrogen-bonding or hydrogen-heteroatom inter-actions (O-Hâ¯O, O-Hâ¯N, N-Hâ¯O, C-Hâ¯O and C-Hâ¯N) with one independent mol-ecule directly linked to four neighbouring mol-ecules and the other mol-ecule directly linked to six neighbouring mol-ecules. The two independent mol-ecules of the asymmetric unit display three weak intra-molecular C-H-to-heteroatom contacts, two of which are very similar despite the different conformations of the deoxyribosyl moieties. The aromatic ring systems of both mol-ecules are in proximity to each other and somehow aligned, though not coplanar. The absolute structures of the two mol-ecules were assumed with reference to the reactant 8-bromo-d-2'-de-oxy-adenosine as they could not be determined crystallographically.
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This unit presents an update of recent developments and clinical progress in chemically modified oliogonucleotides useful for therapeutic applications. During the last decade, the number of therapeutic oligonucleotides in clinical trials has nearly tripled. This is primarily due to advances in the synthesis protocols, better understanding of the biology, improved delivery, and better formulation technologies. Currently, over 100 clinical trials with oligonucleotide-based drugs are ongoing in the United States for potential treatment of a variety of life-threatening diseases. Among various oligonucleotides, antisense technology has been at the forefront, with one product on the market. Antisense technologies represent about half of the active clinical trials. Similarly, siRNA, aptamers, spiegelmers microRNA, shRNA, IMO, and CpG have been other active classes of oligonucleotides that are also undergoing clinical trials. This review attempts to summarize the current status of synthesis, chemical modifications, purification, and analysis in light of the rapid progress with multitude of oligonucleotides pursued as therapeutic modality.
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Oligonucleotídeos/síntese química , Oligonucleotídeos/uso terapêutico , Antineoplásicos/uso terapêutico , Ilhas de CpG , Desenho de Fármacos , Indústria Farmacêutica , Oligonucleotídeos/isolamento & purificação , Oligonucleotídeos Antissenso/uso terapêutico , RNA Interferente Pequeno/uso terapêuticoRESUMO
An optimized process to synthesize DMT protected 2 '-O-methoxyethylguanosine is described. A key step involves the enzymatic deamination of a mixture of alkylated products to selectively afford the desired material without resorting to chromatography for purification. This approach was scaled up to kilogram quantities for use in oligonucleotide therapeutics. [Formula: see text].
Assuntos
Regulação da Expressão Gênica/genética , Guanosina/análogos & derivados , Oligonucleotídeos/síntese química , Adenosina Desaminase/química , Cromatografia Líquida de Alta Pressão , Guanosina/síntese química , Espectrometria de Massas , Estrutura Molecular , Oligonucleotídeos/genéticaRESUMO
A short and convenient synthesis of 3'- and 5'-O-levulinyl-2'-deoxynucleosides has been developed from the corresponding 3',5'-di-O-levulinyl derivatives by regioselective enzymatic hydrolysis, avoiding several tedious chemical protection/deprotection steps. Thus, Candida antartica lipase B (CAL-B) was found to selectively hydrolyze the 5'-levulinate esters, furnishing 3'-O-levulinyl-2'-deoxynucleosides 3 in >80% isolated yields. On the other hand, immobilized Pseudomonas cepacia lipase (PSL-C) and Candida antarctica lipase A (CAL-A) exhibit the opposite selectivity toward the hydrolysis at the 3'-position, affording 5'-O-levulinyl derivatives 4 in >70% yields. A similar hydrolysis procedure was successfully extended to the synthesis of 3'- and 5'-O-levulinyl-protected 2'-O-alkylribonucleosides 7 and 8. This work demonstrates for the first time application of commercial CAL-B and PSL-C toward regioselective hydrolysis of levulinyl esters with excellent selectivity and yields. It is noteworthy that protected cytidine and adenosine base derivatives were not adequate substrates for the enzymatic hydrolysis with CAL-B, whereas PSL-C was able to accommodate protected bases during selective hydrolysis. In addition, we report an improved synthesis of dilevulinyl esters using a polymer-bound carbodiimide as a replacement for dicyclohexylcarbodiimide (DCC), thus considerably simplifying the workup for esterification reactions.
Assuntos
Lipase/metabolismo , Oligonucleotídeos/síntese química , Burkholderia cepacia/enzimologia , Candida/enzimologia , Catálise , Química Orgânica/métodos , Cromatografia Líquida de Alta Pressão , Chromobacterium/enzimologia , Esterificação , Proteínas Fúngicas , Hidrólise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utilized to prepare a series of dimeric nucleosides as mimics of natural nucleic acids. The systematic optimization of the reaction conditions allowed for the single-step conversion of the appropriate iodides and oximes into the 2'-deoxy dimers 9 in moderate to excellent yields. For example, the reaction of 3'-deoxy-3'-iodo-5'-(triphenylmethyl)thymidine (6a) with 3'-O-(tert-butyldiphenylsilyl)-5'-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81% yield of 3'-de(oxyphosphinico)-3'-(methyleneimino)-5'-O-(triphenylmethyl)thymidylyl-(3'-->5')-3'-O-(tert-butyldiphenylsilyl)thymidine (9a). Similarly prepared were dimers containing both pyrimidine (thymine, 5-methylcytosine) and purine (adenine, guanine) bases. The reaction was highly stereoselective, giving only a single dimeric species having the ribo-configuration of the newly introduced C-3'-branched methylene moiety. Also prepared were dimers 16, incorporating 2'-O-methyl ribonucleosides in both halves of the dimer. This required the synthesis of 3'-deoxy-3'-iodo-2'-O-methyl nucleosides 12 as well as 2'-O-methyl-5'-O-methyleneimino nucleosides 15. For example, 5'-O-(tert-butyldiphenylsilyl)-3'-deoxy-3'-iodo-2'-O-methyl-5-methyluridine (12e) was prepared in 80% yield by displacement of the corresponding triflate with Bu(4)NI. Also prepared were the suitably protected 3'-deoxy-3'-iodo adenosine and guanosine derivatives. Compounds 15 were prepared in high yield by a regioselective Mitsunobu reaction to give the corresponding 5'-O-phthalimido nucleosides 13, which were subsequently converted to the requisite oximes 15. In the 2'-O-methyl series, the pinacolate coupling reaction proceeded with efficiency equal to that observed for the 2'-deoxy series 9, but with slightly less stereoselectivity, giving predominantly the C-3'ribo products 16, contaminated with 5-25% of the epimeric material. Mixed base dimers containing both pyrimidine and purine bases at all possible positions, including purine-purine dimers were prepared. The hydroxylamine or methyleneimino (MI) backbone of several representative dimers so prepared was converted via methylation to give the corresponding methylenemethylimino (MMI)-linked compounds, which are novel phosphate surrogates for use in antisense oligonucleotides.