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Martinez-Montero S.,University of Oviedo | Fernandez S.,University of Oviedo | Sanghvi Y.S.,Rasayan Inc. | Gotor V.,University of Oviedo | Ferrero M.,University of Oviedo
European Journal of Organic Chemistry | Year: 2012

We demonstrate that the sugar ring conformation of nucleosides plays a critical role during Candida antarctica lipase B (CAL-B) catalyzed acylation. Specifically, the North (N), but not the South (S) nucleoside sugar ring conformation is preferred for efficient binding at the catalytic site. In this study, we used nuclear magnetic resonance (NMR) spectroscopy experiments to establish the sugar ring conformation of nucleosides and performed molecular modeling studies to support the observations. The ribo-and 2'-substituted (OMe, F) nucleosides displaying the N-conformation undergo rapid and facile acylation compared to the 2'-deoxynucleosides with the S-conformation. This study improves our understanding of the critical role that sugar conformation plays in enzyme-substrate recognition during biotransformations using CAL-B. To the best of our knowledge, this is the first experimental report offering a rationale for the observed selectivity during acylation of nucleosides containing the N-sugar conformation. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Rodriguez-Perez T.,University of Oviedo | Fernandez S.,University of Oviedo | Sanghvi Y.S.,Rasayan Inc. | Detorio M.,Emory University | And 3 more authors.
Bioconjugate Chemistry | Year: 2010

Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A, and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5′-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose conjugates improve the water solubility of the nucleoside analogues, for example, up to 31-fold for the ara-A conjugate compared to that of ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility of improving the physicochemical properties and therapeutic activity of nucleoside analogues. © 2010 American Chemical Society. Source

Sanghvi Y.S.,Rasayan Inc.
Current protocols in nucleic acid chemistry / edited by Serge L. Beaucage ... [et al.] | Year: 2011

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. © 2011 by John Wiley & Sons, Inc. Source

Kapdi A.R.,Institute of Chemical Technology | Ardhapure A.,Institute of Chemical Technology | Sanghvi Y.S.,Rasayan Inc.
Synthesis (Germany) | Year: 2015

Subtle modulation of the electronic properties of the dibenzylideneacetone (dba) ligand allows the development of an efficient protocol for the Heck alkenylation of 5-iodo-2′-deoxyuridine. This protocol enables the large-scale synthesis of commercially important nucleoside building blocks. The isolation of one key molecule was accomplished under column-free conditions on a 10-gram scale. © Georg Thieme Verlag Stuttgart · New York. Source

Martinez-Montero S.,University of Oviedo | Fernandez S.,University of Oviedo | Sanghvi Y.S.,Rasayan Inc. | Gotor V.,University of Oviedo | Ferrero M.,University of Oviedo
Organic and Biomolecular Chemistry | Year: 2011

Preparation of abasic site precursors through a divergent chemoenzymatic synthesis has been accomplished. Several biocatalysts and acylating agents were studied furnishing a practical and scalable green method useful for industrial applications. Highly regioselective acylation and deacylation reactions with 1,2-dideoxy-d-ribose are described resulting in excellent yield. A fast, atom-efficient and convenient synthesis of 3-, and 5-O-DMTr-1,2-dideoxyribose 17 and 19 has been achieved. These compounds are useful precursors for the preparation of phosphoramidites required for the assembly of oligonucleotides containing the tetrahydrofuran abasic lesions. © 2011 The Royal Society of Chemistry. Source

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