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Issue 33, 2016
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Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents

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Abstract

A versatile and efficient modular synthetic platform was developed for assembling multifunctional conjugates and targeted forms of platinum–(benz)acridines, a class of highly cytotoxic DNA-targeted hybrid agents. The synthetic strategy involved amide coupling between succinyl ester-modified platinum compounds (P1, P2) and a set of 11 biologically relevant primary and secondary amines (N1–N11). To demonstrate the feasibility and versatility of the approach, a structurally and functionally diverse range of amines was introduced. These include biologically active molecules, such as rucaparib (a PARP inhibitor), E/Z-endoxifen (an estrogen receptor antagonist), and a quinazoline-based tyrosine kinase inhibitor. Micro-scale reactions in Eppendorf tubes or on 96-well plates were used to screen for optimal coupling conditions in DMF solution with carbodiimide-, uronium-, and phosphonium-based compounds, as well as other common coupling reagents. Reactions with the phosphonium-based coupling reagent PyBOP produced the highest yields and gave the cleanest conversions. Furthermore, it was demonstrated that the chemistry can also be performed in aqueous media and is amenable to parallel synthesis based on multiple consecutive reactions in DMF in a “one-tube” format. In-line LC-MS was used to assess the stability of the conjugates in physiologically relevant buffers. Hydrolysis of the conjugates occurs at the ester moiety and is facilitated by the aquated metal moiety under low-chloride ion conditions. The rate of ester cleavage greatly depends on the nature of the amine component. Potential applications of the linker technology are discussed.

Graphical abstract: Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents

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Supplementary files

Article information


Submitted
11 Apr 2016
Accepted
24 May 2016
First published
26 May 2016

Dalton Trans., 2016,45, 13104-13113
Article type
Paper

Linker design for the modular assembly of multifunctional and targeted platinum(II)-containing anticancer agents

S. Ding and U. Bierbach, Dalton Trans., 2016, 45, 13104
DOI: 10.1039/C6DT01399F

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