ABSTRACT
BACKGROUND: Photodynamic therapy (PDT) is an increasingly prominent field in anticancer research. PDT agents are typically nontoxic in the absence of light and can be stimulated with nonionising irradiation to "activate" their cytotoxic effect. Photosensitzers are not classified as chemotherapy drugs although it is advantageous to control the toxicity of a drug through localised irradiation allowing for selective treatment. Transition metals are an extremely versatile class of compounds with various unique properties such as oxidation state, coordination number, redox potential and molecular geometry that can be tailored for specific uses. This makes them excellent PDT candidates as their properties can be manipulated to absorb a specific range of light wavelengths, cross cellular membranes or target specific sites in vitro. This article reviews recent advances in transition metal PDT agents, with a focus on structural scaffolds from which several metal complexes in a series are synthesised, as well as their in vitro cytotoxicity in the presence or absence of irradiation. CONCLUSION: The success of clinical photoactive agents such as Photofrin® has inspired the development of thousands of potential PDT agents. Transition metal complexes in particular have demonstrated excellent versatility and diversity when it comes to PDT for treatment of invasive cancers. This review has highlighted some of the many recent advances of transition metal PDT agents with high in vitro and in vivo phototoxic activity. Photoactive transition metal complexes have proven their potential due to their inherent physicochemical variety, allowing them to fill a niche in the PDT world.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Metals/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Humans , Metals/chemistry , Neoplasms/therapy , PhotochemotherapyABSTRACT
Azeotropic distillation is typically required to achieve fluorine-18 radiolabeling during the production of positron emission tomography (PET) imaging agents. However, this time-consuming process also limits fluorine-18 incorporation, due to radioactive decay of the isotope and its adsorption to the drying vessel. In addressing these limitations, the fluorine-18 radiolabeling of one model rhenium(I) complex is reported here, which is significantly improved under conditions that do not require azeotropic drying. This work could open a route towards the investigation of a simplified metal-mediated late-stage radiofluorination method, which would expand upon the accessibility of new PET and PET-optical probes.
ABSTRACT
A series of 28 norcantharidin (NorC)-inspired analogues were accessed via a robust two-step Ugi intramolecular Diels-Alder (IMDA) sequence. Four analogues displayed whole-cell cytotoxicity equipotent to that of NorC and cisplatin against a number of cancer cell lines and a normal breast cell line (MCF10A). Notably, (3S,3aS,6R)-2-benzyl-7-methyl-N-(naphthalen-2-yl)-1-oxo-1,2,3,6-tetrahydro-3a,6-epoxyisoindole-3-carboxamide (trans-27) displayed superior whole-cell activity against breast (MCF-7, GI50 =2.9â µm) and colon (HT29, GI50 =6.4â µm) cancer cell lines relative to the control (cisplatin), which elicited respective GI50 values of 6.5 and 11.3â µm against the aforementioned cell lines. This analogue also displayed improved activity relative to NorC across the breast (MCF-7, GI50 =2.9â µm; NorC GI50 =7.5â µm), ovarian (A2780, GI50 =2.2â µm; NorC GI50 =4.4â µm), and neuroblastoma (BE2-C, GI50 =2.2â µm; NorC GI50 =3.7â µm) cancer cell lines. Structure-activity relationship (SAR) investigations demonstrated that retention of sp2 hybridized connections within the tetrahydroepoxyisoindole carboxamide scaffold is crucial, as aromatization to a phenolic functionality decreased activity, whereas removal of a single olefin bond abolished cytotoxicity. Nonetheless, with respect to the latter, use of crotonic acid as opposed 2-butynoic acid in the Ugi-IMDA sequence imparted a significant improvement to diastereoselectivity, with the cis/trans isomer ratio shifting from ≈1:1.2 to ≈0.5:9.5.
Subject(s)
Amides/chemistry , Antineoplastic Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/toxicity , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Isoindoles/chemistry , Isomerism , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Eight platinum(II) complexes with anticancer potential have been synthesised and characterised. These complexes are of the type [Pt(I(L))(A(L))](2+), where I(L) is either dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or 2,3-dimethyl-dpq (23Me2dpq) and A(L) is one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SS-dach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RR-dacp). The CT-DNA binding of these complexes and a series of other complexes were assessed using fluorescent intercalator displacement assays, resulting in unexpected trends in DNA binding affinity. The cytotoxicity of the eight synthesised compounds was determined in the L1210 cell line; the most cytotoxic of these were [Pt(dpq)(SS-dach)]Cl2 and [Pt(dpq)(RR-dach)]Cl2, with IC50 values of 0.19 and 0.80 µM, respectively. The X-ray crystal structure of the complex [Pt(dpq)(SS-dach)](ClO4)2·1.75H2O is also reported.
