Comparison of D-G3139 and Its Enantiomer L-G3139 in Melanoma Cells Demonstrates Minimal In Vitro but Dramatic In Vivo Chiral Dependency

Lai, Johnathan C.; Brown, Bob D.; Voskresenskiy, Anatoliy M.; Vonhoff, Stefan; Klussman, Sven; Tan, Wenzhi; Colombini, Marco; Weeratna, Risini D.; Miller, Paul S.; Benimetskaya, Luba; Stein, C. A.

doi:10.1038/sj.mt.6300037

“…It is well known that protein binding drives many important pharmaceutical parameters, such as toxicity, plasma half-life, tissue accumulation, cellular uptake, and activity of antisense oligonucleotides. 67 , 73 , 74 , 75 , 76 , 77 …”

Section: Discussionmentioning

confidence: 99%

Electronic Structures of LNA Phosphorothioate Oligonucleotides

Bohr

¹

,

Shim

²

,

Stein

³

et al. 2017

Molecular Therapy - Nucleic Acids

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Important oligonucleotides in anti-sense research have been investigated in silico and experimentally. This involves quantum mechanical (QM) calculations and chromatography experiments on locked nucleic acid (LNA) phosphorothioate (PS) oligonucleotides. iso-potential electrostatic surfaces are essential in this study and have been calculated from the wave functions derived from the QM calculations that provide binding information and other properties of these molecules. The QM calculations give details of the electronic structures in terms of e.g., energy and bonding, which make them distinguish or differentiate between the individual PS diastereoisomers determined by the position of sulfur atoms. Rules are derived from the electronic calculations of these molecules and include the effects of the phosphorothioate chirality and formation of electrostatic potential surfaces. Physical and electrochemical descriptors of the PS oligonucleotides are compared to the experiments in which chiral states on these molecules can be distinguished. The calculations demonstrate that electronic structure, electrostatic potential, and topology are highly sensitive to single PS configuration changes and can give a lead to understanding the activity of the molecules.

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“…This enantioselective cytotoxicity indicates that the enantiomers of some chiral drugs may differ both quantitatively and qualitatively in their biological activity (Liu et al, 2009;Shelley et al, 1999). Moreover, enantiomers demonstrate minimal in vitro but a dramatic in vivo chiral dependency in their anti-tumour activities (Lai et al, 2007;Brown et al, 2010). Table 3.…”

Section: Resolution Of (Rs)-1 Into Its Eantiomers: Biological Activitiesmentioning

confidence: 99%

Enantiomerically Pure Substituted Benzo-Fused Heterocycles — A New Class of Anti-Breast Cancer Agents

Campos¹,

García-Rubiño²,

Mahfoudh³

et al. 2015

A Concise Review of Molecular Pathology of Breast Cancer

1

0

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“…This enantioselective cytotoxicity indicates that the enantiomers of some chiral drugs may differ both quantitatively and qualitatively in their biological activity (Liu et al, 2009;Shelley et al, 1999). Moreover, enantiomers demonstrate minimal in vitro but a dramatic in vivo chiral dependency in their anti-tumour activities (Lai et al, 2007;Brown et al, 2010). Once the anti-tumour activity of compounds was determined against the different breast cell lines, we carried out a selection between those that showed a great cytotoxic effect against MCF-7, including (R)-1 and (S)-1, in order to determine their influence on the several cell cycle phases.…”

Section: Discussionmentioning

confidence: 95%