Daniel Yuan Qiang Wong

Discovery and Investigation of Anticancer Ruthenium–Arene Schiff-Base Complexes via Water-Promoted Combinatorial Three-Component Assembly

The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal-based, three-component assembly reaction for the synthesis of a library of 442 Ru-arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one-pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(η6-1,3,5-triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayed low micromolar IC50 values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC50 value between p53+/+ and p53-/- cells suggests that 4 and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer.

Anticancer Platinum (IV) Prodrugs with Novel Modes of Activity

Over the past four decades, the search for improved platinum drugs based on the classical platinum (II)-diam(m)ine pharmacophore has yielded only a handful of successful candidates. New methodologies centred on platinum (IV) complexes, with better stability and expanded coordination spheres, offer the possibility of overcoming limitations inherent to platinum (II) drugs. In this review, novel strategies of targeting and killing cancer cells using platinum (IV) constructs are discussed. These approaches exploit the unique electrochemical characteristics and structural attributes of platinum (IV) complexes as a means of developing anticancer prodrugs that can target and selectively destroy cancer cells. Anticancer platinum (IV) prodrugs represent promising new strategies as targeted chemotherapeutic agents in the ongoing battle against cancer.

Immuno‐Chemotherapeutic Platinum(IV) Prodrugs of Cisplatin as Multimodal Anticancer Agents

There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off-target immune-modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt-based chemotherapeutic agents to exploit their immune-activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal Pt(IV) prodrug containing a FPR1/2-targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach.

Structural Determinants of p53-Independence in Anticancer Ruthenium-Arene Schiff-base Complexes

p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity.

Platinum(IV) Carboxylate Prodrug Complexes as Versatile Platforms for Targeted Chemotherapy.

Kinetically-inert Pt(IV) carboxylate complexes have emerged in recent years as candidates for the development of next-generation platinum anticancer drugs. Being native prodrugs of clinically-important Pt(II) chemotherapeutic agents, the Pt(IV) scaffold can be exploited to incorporate additional functionalities while keeping the Pt(II) pharmacophore intact. This mini-review examines recent work performed to illuminate the mechanism of Pt(IV) prodrug activation and their use as versatile platforms for targeted chemotherapy.

DEVELOPMENT OF PLATINUM(IV) COMPLEXES AS ANTICANCER PRODRUGS: THE STORY SO FAR

The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinicians arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

Probing the Platinum(IV) Prodrug Hypothesis. Are Platinum(IV) Complexes Really Prodrugs of Cisplatin

Amongst the metallopharmaceuticals in development, platinum(IV) complexes are unique because they are native prodrugs of clinically-relevant platinum(II) pharmacophores such as cisplatin and oxaliplatin (Fig. 3.1) These platinum(II) drugs are some of the most effective anticancer agents in clinical use and the first line treatment for many malignancies today (Fig. 3.1) (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). The general consensus is that these platinum(IV) prodrug complexes are themselves pharmacologically inactive and must undergo reductive elimination by endogenous reductants to release the active square-planar platinum(II) core with concomitant dissociation of the axial ligands (Fig. 3.2) (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). As such, the axial ligands confers unique possibilities of tuning the pharmacokinetic parameters such as lipophilicity and solubility as well as the attaching any targeting groups or synergistic co-drugs without altering the cellular mechanism of action of the innate platinum(II) pharmacophore (Hall et al. J Med Chem 50:3403–3411, 2007 [1]; Hall et al. Coord Chem Rev 232:49–67, 2002 [2]; Chin et al. J Med Chem 55:7571–7582, 2012 [3]). Open image in new window Fig. 3.1 Top: cisplatin and oxaliplatin are two platinum(II) agents in clinical use today. Bottom: Satraplatin is a promising platinum(IV) anticancer prodrug under clinical trials. Complexes 1 and 2 are newly synthesized asymmetrical platinum(IV) complexes bearing a benzaldehyde moiety for facile imine ligation to any therapeutically-relevant substrate Open image in new window Fig. 3.2 The platinum(IV) prodrug hypothesis: reductive elimination of platinum(IV) prodrugs occurs with the release the active platinum(II) core as well as both axial carboxylate ligands