New coupling reagents for the preparation of disulfide cross-linked conjugates with increased stability

Bioconjugate Chemistry
S ArpiccoL Cattel

Abstract

To improve the in vivo stability of disulfide-linked immunotoxins (ITs), a series of sterically hindered cross-linking reagents were designed and synthesized. These ligands are characterized by a thioimidate group linked to an S-acetyl thiol or a substituted aryldithio group. To select the reagent of choice, several aryldithio thioimidates, substituted with a methyl or a phenyl group adjacent to the disulfide, were analyzed in thiol-disulfide exchange reactions. Also analyzed were the following: (i) the stability and solubility of the linkers in aqueous solution, (ii) the rate of protein derivatization, and (iii) the steric hindrance due to methyl or phenyl group substituents toward cleavage of the disulfide bond by glutathione. Ethyl S-acetyl 3-mercaptobutyrothioimidate (M-AMPT) was chosen as reagent to prepare two types of stable disulfide-containing AR-3-gelonin conjugates (IT2 and IT3). IT2 was prepared by a 3-(4-carboxamidophenyldithio)propionthioimidate (CDPT)-derivatized antibody coupled to the M-AMPT-derivatized gelonin to afford a conjugate characterized by the presence of a methyl group adjacent to the sulfide bond. In the IT3 conjugate, an M-AMPT-derivatized toxin was coupled to the antibody thiolated with M-AMPT and...Continue Reading

References

Aug 2, 1985·Journal of Immunological Methods·O GrosH Vidal
Jun 1, 1995·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·M G RosenblumL Cheung

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Citations

Aug 26, 2011·Bioconjugate Chemistry·Aaron D Baldwin, Kristi L Kiick
Jul 10, 2010·BioTechniques·Xiaoying ChenWei-Chiang Shen
Jun 22, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Lorine BrülisauerJean-Christophe Leroux
Aug 28, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·M Rachèl ElzesJos M J Paulusse
Apr 23, 2013·Bioconjugate Chemistry·Menči KunsteljSimona Jevševar
May 23, 2013·Nature Communications·Jesús MosqueraJosé L Mascareñas
Aug 2, 2012·Angewandte Chemie·Adrián Jiménez-BalsaM Eugenio Vázquez
Mar 31, 2005·Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine·Yuda ZongZheng-Rong Lu
Oct 1, 2010·Advanced Materials·Sonja BauhuberAchim Göpferich
Jul 21, 2005·Technology in Cancer Research & Treatment·Serengulam V GovindanDavid M Goldenberg
Oct 30, 2014·Chemistry : a European Journal·Linxiang ZhaiChuanliu Wu
Jul 23, 2011·Chemistry : a European Journal·Chuanliu WuMarc A Gauthier

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