Exploiting azide-alkyne click chemistry in the synthesis, tracking and targeting of platinum anticancer complexes

Abstract

Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop novel Pt-based anticancer drugs and to better understand the biological effects of Pt-based anticancer drugs at a cellular level. Innovative azide-alkyne cycloaddition-based approaches are being used to functionalise Pt-based complexes with biomolecules to enhance tumour targeting. Valuable information in relation to the mechanisms of action and resistance of Pt-based drugs is also being revealed through click-based detection, isolation and tracking of Pt drug surrogates in biological and cellular environments. Although less well-explored, inorganic Pt-click reactions enable synthesis of novel (potentially multimetallic) Pt complexes and provide plausible routes to introduce functional groups and monitoring Pt-azido drug localisation.

Keywords: Alkyne; Analyse; Anticancer; Azide; CuAAC; Cycloaddition; Functionalise; Platinum; SPAAC; Synthesis; Target; Track; Triazole; iClick.

Graphical abstract

Figure 1

Pt drugs, azide-alkyne cycloadditions and article focus.(a) Structures of three clinically approved Pt(II)-based anticancer drugs. (b) General schemes for azide–alkyne click reactions and representative cycloalkynes used for SPAAC, where DIBO is dibenzocyclooctyne, DIFO is difluorocyclooctyne and BCN is bicyclononyne, N.B. SPAAC with fuctionalised cycloalkynes can lead to the formation of regioisomers (e.g. DIBO derivatives and nonchiral azide), enantiomers (e.g. BCN and nonchiral azide) or diastereoisomers (e.g. BCN and chiral azide) (c) Outline of article focus. SPAAC, strain-promoted [3 + 2] azide–alkyne cycloaddition.

Figure 2

Pt ligand-based click platforms and conjugates. (a) Representative Pt ligand-based click platform for the functionalisation of Pt complexes. (b) Structures of Pt ligand-based click templates; azide modified Pt(II) acridine complex 1 [21,22], cis-[Pt(2-azidopropane-1,3-diamine)Cl₂] 2 [23,24], picazoplatin 3 [25], [Pt(2-azidopropane-1,3-diamine)(CBDCA_-2H)] 4 [20∗,23] azidoplatin 5 and (f) cis-[Pt(2-(5-hexynyl)amido-1,3-propanediamine)Cl₂] 6 [26] cis,cis,trans-[Pt(DACH)(Ox)(OAc)(OAc-N₃)] 7 [27] and Platin-Az 8 [28]. Figure 2 (c) Structures of Pt(II) human serum albumin (HSA) conjugate,[18∗] Pt(II) estrogendiol (EDiol) conjugate [19] and Pt(II) fluorophore (Flu, NIR-AZA) conjugate [20∗].

Figure 3

Post-treatment labelling of Pt-bound biomolecules and real-time tracking of Pt drug surrogates. (a) Reports to date concerning click chemistry enabled post-treatment labelling of Pt-bound biomolecules. (b) Workflow for labelling of cellular Pt-bound proteins; treatment of S. cerevisiae with Pt azide complex 5 and protein extraction, followed by CuAAC-enabled labeling of Pt-bound proteins with a fluorescent tag or biotin. Diagram adapted from the previously reported Figure 1 (b) ACS Chem. Biol. 2017, 12 (11), 2737–2745. (c) Strategy for click-enabled real-time tracking of Pt drug surrogates. CuAAC, Cu(I)-catalysed [3 + 2] azide–alkyne cycloaddition.

Figure 4

Pt-azido-based and Pt-alkyne based azide-alkyne cycloadditions. (a) Cu-catalysed or Au-promoted reactions. General Cu(I)-catalysed synthesis involving (i) Pt-azide and acetylene and (ii) Pt-acetylene and azide; (iii) example synthesis of metallopolytriazolates; (iv) general Au(I)-promoted synthesis of 4,5 trisubstituted 1,2,3-triazolate bridged dimetallic complexes and (v) Pt–Au cycloaddition products, which show some similarity to auranofin [44]. (b) Use of electron-deficient acetylenes and strain (SPAAC) to produce Pt(II) and Pt(IV) inorganic click products. Possible different synthetic strategies to access Pt(IV)–N1-coordinated and Pt(IV)–N2-coordinated triazoles. SPAAC, strain-promoted [3 + 2] azide–alkyne cycloaddition.