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Selective Release of Potent N-Alkylisatin Based Cytotoxins via Hydrolysis of pH Sensitive Imine Linkers

Conference Paper


Abstract


  • Ligand-targeted drug delivery is currently one of the most challenging areas in pharmaceutical research involving the judicious choice of the targeting ligand, drug and linker [1]. A promising new strategy involves conjugating a cytotoxin with a tumour targeting protein through an acid-labile linker that is stable at physiological pH. Internalisation at the target tumour site via receptor mediated processes exposes the conjugate to endosomal and lysosomal pH (4.5 6.0), resulting in selective release of the original cytotoxin inside the tumour cell. Herein, we report the design, synthesis and utility of a series of novel acid-labile, imine-based linkers, which have been conjugated to potent N-alkylisatin-based cytotoxins, derived from metabolites isolated from the Australian mollusc Dicathius orbita (e.g. 3a-c) [2-4]. Furthermore, in order to model the conjugation of these acid-labile linkers to the lysine residues of tumour-targeting proteins, the aryl imines (e.g. 3a-c) were coupled via their free carboxylic acids to a protected lysine amino acid residue to produce a novel series of imine-lysine conjugates (e.g. 4a-c). Both the aryl imines (e.g. 3a-c) and the imine-lysine conjugates (e.g. 4a-c) were stable for an extended period at pH 7.4 but readily cleaved in aqueous acidic solutions at physiological temperature, with half-lives ranging from 17.0 to 85.2 min [5]. Furthermore, the rate of hydrolysis could be fine-tuned through the use of differing chain lengths and aromatic substitution patterns. Our work to-date on the development of new tumour targeting imine-linked cytotoxin protein conjugates will also be presented.

Publication Date


  • 2011

Citation


  • Matesic, L., Locke, J. M., Vine, K. L., Ranson, M., Bremner, J. B. & Skropeta, D. (2011). Selective Release of Potent N-Alkylisatin Based Cytotoxins via Hydrolysis of pH Sensitive Imine Linkers. 27th International Symposium on the Chemistry of Natural Products and the 7th International Conference on Biodiversity (ISCNP-27 & ICOB-7) (pp. CT-19-CT-19). Brisbane: IUPAC.

Start Page


  • CT-19

End Page


  • CT-19

Place Of Publication


  • http://www.icob7.org/

Abstract


  • Ligand-targeted drug delivery is currently one of the most challenging areas in pharmaceutical research involving the judicious choice of the targeting ligand, drug and linker [1]. A promising new strategy involves conjugating a cytotoxin with a tumour targeting protein through an acid-labile linker that is stable at physiological pH. Internalisation at the target tumour site via receptor mediated processes exposes the conjugate to endosomal and lysosomal pH (4.5 6.0), resulting in selective release of the original cytotoxin inside the tumour cell. Herein, we report the design, synthesis and utility of a series of novel acid-labile, imine-based linkers, which have been conjugated to potent N-alkylisatin-based cytotoxins, derived from metabolites isolated from the Australian mollusc Dicathius orbita (e.g. 3a-c) [2-4]. Furthermore, in order to model the conjugation of these acid-labile linkers to the lysine residues of tumour-targeting proteins, the aryl imines (e.g. 3a-c) were coupled via their free carboxylic acids to a protected lysine amino acid residue to produce a novel series of imine-lysine conjugates (e.g. 4a-c). Both the aryl imines (e.g. 3a-c) and the imine-lysine conjugates (e.g. 4a-c) were stable for an extended period at pH 7.4 but readily cleaved in aqueous acidic solutions at physiological temperature, with half-lives ranging from 17.0 to 85.2 min [5]. Furthermore, the rate of hydrolysis could be fine-tuned through the use of differing chain lengths and aromatic substitution patterns. Our work to-date on the development of new tumour targeting imine-linked cytotoxin protein conjugates will also be presented.

Publication Date


  • 2011

Citation


  • Matesic, L., Locke, J. M., Vine, K. L., Ranson, M., Bremner, J. B. & Skropeta, D. (2011). Selective Release of Potent N-Alkylisatin Based Cytotoxins via Hydrolysis of pH Sensitive Imine Linkers. 27th International Symposium on the Chemistry of Natural Products and the 7th International Conference on Biodiversity (ISCNP-27 & ICOB-7) (pp. CT-19-CT-19). Brisbane: IUPAC.

Start Page


  • CT-19

End Page


  • CT-19

Place Of Publication


  • http://www.icob7.org/