Abstract
New bis-quinoline (Lq) and bis-isoquinoline-based (Liq) ligands have been synthesized, along with their respective homoleptic [Pd2(Lq or Liq)4]4+ cages (Cq and Ciq). 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 Cq architecture showed that the [Pd2(Lq)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 Ciq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd2(Ltripy)4]4+ systems (where Ltripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The Ciq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the Cq 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 Ciq cage was completely decomposed into free Liq and [Pd(Cl)4]2− within 1 h. However, the Cq cage was more long lived and was only fully decomposed after 7 h. The new ligands (Liq and Lq) and the Pd(II) cage architectures (Ciq and Cq) 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 Lq and Cq were both reasonably cytotoxic (IC50S ≈ 0.5 μM) against A549, while Ciq was slightly less active (IC50 = 7.4 μM). Liq 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).
Highlights
Metallosupramolecular architectures (MSAs) (Cook and Stang, 2015) have been attracting increasing attention over the past two decades due to their many potential applications including catalysis (Yoshizawa et al, 2009; Yoshizawa and Fujita, 2010; Martí-Centelles et al, 2018), storage (Mal et al, 2009), and sensing (Wang et al, 2011)
Some time ago we reported that a [Pd2(Ltripy)4]4+ cage (where Ltripy = 2,6-bis(pyridin-3ylethynyl)pyridine) could host two molecules of the anticancer drug cisplatin within the cavity of the cage (Lewis et al, 2012), and had potential as a drug delivery vector
While is well-known that isoquinoline and quinoline ligands can bind with palladium(II) and platinum(II) (Bondy et al, 2004) their use as donor systems in ligands for the generation MSAs has not been extensively explored (Bloch et al, 2016, 2017). These quinoline derived systems feature different electronic and steric properties compared to the parent pyridyl systems we examine the effect these changes have on the host-guest chemistry with cisplatin, the stability of the cages in the presence of nucleophiles and the antiproliferative properties of the cages
Summary
Metallosupramolecular architectures (MSAs) (Cook and Stang, 2015) have been attracting increasing attention over the past two decades due to their many potential applications including catalysis (Yoshizawa et al, 2009; Yoshizawa and Fujita, 2010; Martí-Centelles et al, 2018), storage (Mal et al, 2009), and sensing (Wang et al, 2011). We showed that the parent [Pd2(Ltripy)4]4+ was modestly cytotoxic (IC50 values range from 40 to 70 μM) against a range of cancer cell lines but was less active than related bis-1,2,3-triazole [Pd2(L)4]4+ helicates (McNeill et al, 2015).
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