Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages

Roan A S Vasdev; Lachlan F Gaudin; Dan Preston; Jackmil P Jogy; Gregory I Giles; James D Crowley

doi:10.3389/fchem.2018.00563

Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd₂L₄]⁴⁺ Metallosupramolecular Cages

Front Chem. 2018 Nov 22:6:563. doi: 10.3389/fchem.2018.00563. eCollection 2018.

Authors

Roan A S Vasdev^{1

2

3}, Lachlan F Gaudin¹, Dan Preston¹, Jackmil P Jogy³, Gregory I Giles³, James D Crowley^{1

2}

Affiliations

¹ Department of Chemistry, University of Otago, Dunedin, New Zealand.
² MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand.
³ Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.

Abstract

New bis-quinoline (L _q) and bis-isoquinoline-based (L _iq) ligands have been synthesized, along with their respective homoleptic [Pd₂(L _q or L _iq)₄]⁴⁺ cages (C _q and C _iq). The ligands and cages were characterized by ¹H, ¹³C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the bis-quinoline cage, X-ray crystallography. The crystal structure of the C _q architecture showed that the [Pd₂(L _q)₄]⁴⁺ cage formed a twisted meso isomer where the [Pd(quinoline)₄]²⁺ units at either end of the cage architecture adopt the opposite twists (left and right handed). Conversely, Density Functional Theory (DFT) calculations on the C _iq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd₂(L _tripy)₄]⁴⁺ systems (where L _tripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The C _iq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the C _q architecture shows no interaction with the guest under the same conditions. The kinetic robustness of the two cages in the presence of Cl^- nucleophiles was also different. The C _iq cage was completely decomposed into free L _iq and [Pd(Cl)₄]^2- within 1 h. However, the C _q cage was more long lived and was only fully decomposed after 7 h. The new ligands (L _iq and L _q) and the Pd(II) cage architectures (C _iq and C _q) were assessed for their cytotoxic properties against two cancerous cell lines (A549 lung cancer and MDA-MB-231 breast cancer) and one non-cancerous cell line (HDFa skin cells). It was found that L _q and C _q were both reasonably cytotoxic (IC_50S ≈ 0.5 μM) against A549, while C _iq was slightly less active (IC₅₀ = 7.4 μM). L _iq was not soluble enough to allow the IC₅₀ to be determined against either of the two cancerous cell lines. However, none of the molecules showed any selectivity for the cancer cells, as they were all found to have similar cytotoxicities against HDFa skin cells (IC₅₀ values ranged from 2.6 to 3.0 μM).

Keywords: anticancer; metallosupramolecular; palladium(II); quinoline; self-assembly.