Yogesh S. Sanghvi
Isis Pharmaceuticals
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Featured researches published by Yogesh S. Sanghvi.
Bioorganic & Medicinal Chemistry Letters | 1994
Alain De Mesmaeker; Adrian Waldner; Yogesh S. Sanghvi; Jacques Lebreton
Abstract Stepwise restriction of free rotation, as well as introduction of positive changes in the internucleosidic linkage are factors which can positively influence the thermal melting behaviour of the corresponding duplexes formed between modified DNA and their RNA complement. By correct positioning of the rigidity within backbone, it is possible to achieve even higher binding affinity (Tms) than with natural oligodeoxyribonucleotides (ODNs).
Journal of Chromatography A | 2000
Ranjit R. Deshmukh; Timothy N. Warner; Fred Hutchison; Michael Murphy; William E. Leitch; Patricia De Leon; G.Susan Srivatsa; Douglas L. Cole; Yogesh S. Sanghvi
Very high flux ion-exchange membranes were utilized for a novel purification of antisense oligonucleotides (20-mer). Strong anion-exchange membranes were produced by attaching polymeric ligands onto a microporous cellulosic matrix. The oligonucleotides purified were therapeutic single-stranded phosphorothioates deoxyribonucleotides. Although small-scale membrane devices (15 cm2) had similar resolution to traditional chromatographic columns; their throughputs were superior. Greater than a 1300-fold scale-up produced very similar purity and yields of the phosphorothionate product. Scale-up experiments were conducted with a 2 m2 surface area membrane module. These modules were easily capable of very high throughputs of 0.5 to 2 l/min. High purity and yields were achieved by both step and linear gradient elution.
Current protocols in human genetics | 2011
Yogesh S. Sanghvi
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. Curr. Protoc. Nucleic Acid Chem. 46:4.1.1‐4.1.22.
Green Chemistry | 2003
Matthew C. Uzagare; Yogesh S. Sanghvi; Manikrao M. Salunkhe
The ionic liquid 1-methoxyethyl-3-methyl imidazolium methanesulfonate (MOEMIM.OMs) is employed as a ‘green’ alternative to the conventional organic solvents used as a reaction medium in nucleoside chemistry.
Journal of The Chemical Society-perkin Transactions 1 | 1990
K. J. Divakar; Alexander Mottoh; Colin B. Reese; Yogesh S. Sanghvi
2′-Deoxy-2′-mercaptouridine (1) was obtained in 75% isolated yield by heating 2′-deoxy-2′-(4-methoxybenzylthio)uridine (4a) with phenol in trifluoroacetic acid solution. When triphenylmethanol or 9-phenylxanthen-9-ol (5) was added to the products before work-up, compound (4c) or (4d) was obtained. Compound (4d) was also obtained in satisfactory overall yield from crude (1), prepared in two steps from 2′-deoxy-2′-(t-butylthio)uridine (4b). Treatment of compound (4d) first with acetic anhydride in pyridine and then with phosphoryl trichloride, triethylamine, and 1,2,4-triazole in acetonitrile gave the triazolo compound (10) in 73% overall yield. Reaction between compound (10) and ammonia in dichloromethane [or dimethylamine in dioxane] followed by methanolic ammonia gave the cytidine derivative (11a)[or (11b)] in good yield. When compounds (11a) and (11b) were allowed to react with hydrochloric acid in 2-mercaptoethanol solution at room temperature, the hydrochloride salts of 2′-deoxy-2′-mercaptocytidine (2a) and its 4,4-di-N-methyl derivative (2b) were obtained in high isolated yields. The latter compounds readily underwent aerial oxidation in the presence of triethylamine in methanol solution to give the corresponding dimeric disulphides (12a) and (12b). The NMR spectra of the synthetic products are discussed.
Journal of Chromatography A | 2001
Nihal Tugcu; Ranjit R. Deshmukh; Yogesh S. Sanghvi; James A. Moore; Steven M. Cramer
The development of efficient techniques for large-scale oligonucleotide purification is of great interest due to the increased demand for antisense oligonucleotides as therapeutics as well as their use for target validation and gene functionalization. This paper describes the use of anion-exchange displacement chromatography for the purification of 20-mer phosphorothioate oligonucleotide from its closely related impurities using low-molecular-mass amaranth as the displacer. Experiments were carried out to examine the effect of the feed load on the performance of the displacement chromatography. In contrast to prior work, displacement chromatography was successfully scaled-up to high column loadings while maintaining high purity and yields. Experiments carried out on a Source 15Q column indicated that crude oligonucleotide loading as high as 39.2 mg/ml of column were readily processed, resulting in product recovery of 86% and purity of 92%. These results demonstrate that anion-exchange displacement chromatography can indeed be employed for large-scale oligonucleotide separations at high column loading.
Nucleosides, Nucleotides & Nucleic Acids | 1997
Yogesh S. Sanghvi; Eric E. Swayze; Didier Peoc'h; Balkrishen Bhat; Stuart Dimock
Abstract Methylene(methylimino) or MMI linkage is a novel backbone modification that has enormous potential in the oligonucleotide-based antisense therapeutics as a replacement for the natural phosphodiester linkage. This presentation synopsis covers the rationale, detailed SAR on the optimization process of this linkage vs. others, various synthetic strategies to construct MMI linkage and a brief discussion on the biological properties of the modified oligonucleotides.
Reactive & Functional Polymers | 2003
Nihal Tugcu; Ranjit R. Deshmukh; Yogesh S. Sanghvi; Steven M. Cramer
In performing displacement chromatography for the purification of biomolecules, one of the biggest challenges has been the selection of the proper high affinity displacer. The displacer not only has to have sufficient dynamic affinity to carry out the displacement but must also have suitable operational properties which will enable a cost effective and simple process. One of these requirements is the non-toxic nature of the displacer, which if satisfied will make displacement chromatography a more attractive tool for biopharmaceutical applications. In this study, a new non-toxic low molecular weight displacer, saccharin, was introduced and characterized for the purification of an oligonucleotide and proteins by anion exchange displacement chromatography. It was demonstrated that saccharin, with only one charge, can indeed displace and purify very highly retained oligonucleotides and proteins. The operating conditions for the displacement experiments were predicted using operating regime plots. The results indicate that saccharin is not only effective as a displacer for isotachic displacements but for selective displacements as well.
Tetrahedron Letters | 1997
Balkrishen Bhat; Yogesh S. Sanghvi
Abstract N -Benzoyltetrazole has been developed as a mild and selective reagent for monobenzoylation of the exocyclic amino group in nucleic acid bases. Its usefulness is demonstrated by protection of adenine and cytosine bases, an important procedure in the nucleic acid chemistry field.
Organic and Biomolecular Chemistry | 2009
Alba Díaz-Rodríguez; Yogesh S. Sanghvi; Susana Fernández; Raymond F. Schinazi; Emmanuel A. Theodorakis; Miguel Ferrero; Vicente Gotor
A chiral synthesis of a series of hexahydroisobenzofuran (HIBF) nucleosides has been accomplished via glycosylation of a stereo-defined (syn-isomer) sugar motif 16 with the appropriate silylated bases. All nucleoside analogs were obtained in 52-71% yield as a mixture of alpha- and beta-anomeric products increasing the breadth of the novel nucleosides available for screening. The structure of the novel bicyclic HIBF nucleosides was established by a single crystal X-ray structure of the beta-HIBF thymine analog 22b. Furthermore, the sugar conformation for these nucleosides was established as N-type. Among the novel HIBF nucleosides synthesized, twenty-five compounds were tested as inhibitor of HIV-1 in human peripheral blood mononuclear (PBM) cells and seven were found to be active (EC(50) = 12.3-36.2 microM). Six of these compounds were purine analogs with beta-HIBF inosine analog 22o being the most potent (EC(50) = 12.3 microM) among all compounds tested. The striking resemblance between didanosine (ddI) and 22o may explain the potent anti-HIV activity.