Integrated Circular Dichroism and Circularly Polarized Luminescence Measurements.

Circularly polarized luminescent (CPL) systems have a plethora of potential applications owing to their interesting excited-state properties. However, the progress in developing new chiral luminescence systems is significantly hindered by the lack of available instrumentation for the broader chemistry and materials science community to perform routine, reproducible measurements of chiral spectroscopies. In this work, we present data from an easy-to-use custom-built instrument based on a Jasco circular dichroism (CD) spectropolarimeter coupled with a CPL emission monochromator (CD/CPL hybrid system). The hybrid system measures CPL, fluorescence, CD, and absorbance on the same part of the sample without the need to move between the CD and CPL measurements. The instrument uses a xenon arc lamp as the light source, enabling a wide range of excitation wavelengths to support flexible development of new molecules and materials. Data obtained and presented for camphor, ruthenium metal complexes, the peptide gramicidin, and a DNA-ligand (4',6-diamidino-2-phenylindole, DAPI) system in this work highlight the ease of use and reproducibility of the results. The g-factors for CD and CPL obtained for the different compounds are shown to be the same for isolated transitions and some examples of how to use variations of g-factors with wavelength are demonstrated. The reliable and excellent benchmark results obtained from a custom-built commercial wavelength scanning CPL/CD hybrid instrument open up new avenues for the broader chemical and materials science community to intensify research on chiral luminescent systems.

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity.

Kinetically inert platinum(IV) complexes are a chemical strategy to overcome the impediments of standard platinum(II) antineoplastic drugs like cisplatin, oxaliplatin and carboplatin. In this study, we reported the syntheses and structural characterisation of three platinum(IV) complexes that incorporate 5-benzyloxyindole-3-acetic acid, a bioactive ligand that integrates an indole pharmacophore. The purity and chemical structures of the resultant complexes, P-5B3A, 5-5B3A and 56-5B3A were confirmed via spectroscopic means. The complexes were evaluated for anticancer activity against multiple human cell lines. All complexes proved to be considerably more active than cisplatin, oxaliplatin and carboplatin in most cell lines tested. Remarkably, 56-5B3A demonstrated the greatest anticancer activity, displaying GI50 values between 1.2 and 150 nM. Enhanced production of reactive oxygen species paired with the decline in mitochondrial activity as well as inhibition of histone deacetylase were also demonstrated by the complexes in HT29 colon cells.

Enhanced potency of a chloro-substituted polyaromatic platinum(II) complex and its platinum(IV) prodrug against lung cancer.

The present study investigates the anti-neoplastic activity of a platinum (II) complex, Pt(II)5ClSS, and its platinum (IV) di-hydroxido analogue, Pt(IV)5ClSS, against mesenchymal cells (MCs), lung (A549), melanoma (A375) and breast (MDA-MB-231) cancer cells. Both complexes exhibited up to 14-fold improved cytotoxicity compared to cisplatin. NMR was used to determine that ∼25 % of Pt(IV)5ClSS was reduced to Pt(II)5ClSS in the presence of GSH (Glutathione) after 72 h. The complex 1H NMR spectra acquired for Pt(II)5ClSS with GSH shows evidence of degradation and environmental effects (∼30 %). The prominence of the 195Pt peak at âˆ¼ -2800 ppm suggests that a significant amount of Pt(II)5ClSS remained in the mixture. Pt(II)5ClSS and Pt(IV)5ClSS have shown exceptional selectivity to cancer cells in comparison to MCs (IC50 > 150 µM). Western blot analysis of Pt(II)5ClSS and Pt(IV)5ClSS on A549 cells revealed significant upregulation of cleaved PARP-1, BAX/Bcl2 ratio, cleaved caspase 3 and cytochrome thus suggesting apoptosis was induced through the intrinsic pathway. Flow cytometry also revealed significant cell death by apoptosis. Treatment with Pt(II)5ClSS and Pt(IV)5ClSS also showed significant amounts of free radical production while the COMET assay showed that both complexes cause minimal DNA damage. Cellular uptake results via ICP-MS suggest a time-dependent active mode of transport for both complexes with Pt(II)5ClSS being transported at a higher rate compared to Pt(IV)5ClSS. A Dose Escalation Study carried out on BALB/c mice showed that Pt(II)5ClSS and Pt(IV)5ClSS were approximately 8- folds and 12.5-folds, respectively, more tolerated than cisplatin. The present study provides evidence that both complexes may have the characteristics of an efficient and potentially safe anti-tumor drug that could support NSCLC treatment.

Synthesis and Characterisation of Platinum(II) Diaminocyclohexane Complexes with Pyridine Derivatives as Anticancer Agents.

Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(PL)(AL)]Cl2 molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1H-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the PL; the AL is resolved diaminocyclohexane. Precursor [Pt(PL)(Cl)2] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(PL)(AL)]2+ complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1H-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS.

Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells.

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

Synthesis and Characterisation of Fluorescent Novel Pt(II) Cyclometallated Complexes with Anticancer Activity.

Cancer poses a significant threat to global health and new treatments are required to improve the prognosis for patients. Previously, unconventional platinum complexes designed to incorporate polypyridyl ligands paired with diaminocyclohexane have demonstrated anticancer activity in KRAS mutated cells, previously thought to be undruggable and have cytotoxicity values up to 100 times better than cisplatin. In this work, these complexes were used as inspiration to design six novel cyclometallated examples, whose fluorescence could be exploited to better understand the mechanism of action of these kinds of platinum drugs. The cytotoxicity results revealed that these cyclometallated complexes (CMCs) have significantly different activity compared to the complexes that inspired them; they are as cytotoxic as cisplatin and have much higher selectivity indices in breast cancer cell lines (MCF10A/MCF-7). Complexes 1b, 2a, and 3b all had very high selectivity indexes compared to previous Pt(II) complexes. This prompted further investigation into their DNA binding properties, which revealed that they had good affinity to ctDNA, especially CMCs 1a and 3b. Their inherent fluorescence was successfully utilised in the calculation of their DNA binding affinity and could be useful in future work.

Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents.

Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1-6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1-6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI50 values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI50 value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1-6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.

Novel Platinum(II) and Platinum(IV) Antitumor Agents that Exhibit Potent Cytotoxicity and Selectivity.

A novel platinum(II) complex 47OMESS(II) and its platinum(IV) derivative 47OMESS(IV) were synthesized and characterized. Cytotoxicity studies against mesenchymal cells (MCs) and lung (A549), breast (MDA-MB-231), and melanoma (A375) cancer cells demonstrated 7-20-fold superior activity for both complexes relative to cisplatin. Remarkably, 47OMESS(IV) demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs. Western blot analysis on A549 cells showed the involvement of the intrinsic apoptotic pathway. Cellular fractionation and uptake experiments in A549 cells using ICP-mass spectrometry (MS) indicated that 47OMESS(II) and 47OMESS(IV) cross the cellular membrane predominantly via active transport mechanisms. The significant improvement in selectivity that is exhibited by 47OMESS(IV) is reported for the first time for this class of complexes.

Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells.

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (2) exhibiting the lowest GI50 of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1-4; however, this was not always translated to the observed cytotoxicity.

Bioactive Platinum(IV) Complexes Incorporating Halogenated Phenylacetates.

A new series of cytotoxic platinum(IV) complexes (1-8) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes 1-8 were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely 4 and 6, eliciting an average GI50 value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, 4 exhibited the highest degree of potency amongst the derivatives, displaying a GI50 value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, 56MESS (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, 4 (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes' solubility, stability, lipophilicity, and reactive oxygen species production.

Novel Planar Pt(II) Cyclometallated Cytotoxic Complexes with G-Quadruplex Stabilisation and Luminescent Properties.

Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square-planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was determined in two of the major G-quadruplex structures formed in the human c-MYC promoter gene (c-MYC) and a human telomeric repeat sequence (H-Telo). The CMCs were found to stabilise H-telo more strongly than c-MYC, and the CMCs with the highest cytotoxic effect had a low-moderate correlation between H-telo binding capacity and cytotoxicity (R2 values up to 10 times those of c-MYC). The melting experiments further revealed that the stabilisation effect was altered depending on whether the CMC was introduced before or after the formation of QDNA. All CMCs' GI50 values were comparable or better than cisplatin in human cancer cell lines HT29, U87, MCF-7, H460, A431, Du145, BE2-C, SJ-G2, MIA, and ADDP. Complexes 6, 7, and 9 were significantly more cytotoxic than cisplatin in all cell lines tested and had good to moderate selectivity indices, 1.7-4.5 in MCF10A/MCF-7. The emission quantum yields were determined to be relatively high (up to 0.064), and emission occurred outside cellular autofluorescence, meaning CMC fluorescence is ideal for in vitro analyses.

Potent Chlorambucil-Platinum(IV) Prodrugs.

The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.

Cyclooxygenase-Inhibiting Platinum(IV) Prodrugs with Potent Anticancer Activity.

Platinum(IV) prodrugs of the [Pt(PL)(AL)(COXi)(OH)]2+ type scaffold (where PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI50 of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1-4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.

Photoactive and Luminescent Transition Metal Complexes as Anticancer Agents: A Guiding Light in the Search for New and Improved Cancer Treatments.

Cancer continues to be responsible for the deaths of more than 9 million people worldwide each year. Current treatment options are diverse, but low success rates, particularly for those with late-stage cancers, continue to be a problem for clinicians and their patients. The effort by researchers globally to find alternative treatment options is ongoing. In the present study, we focused on innovations in inorganic anticancer therapies, specifically those with photoactive and luminescent properties. Transition metals offer distinct advantages compared to wholly organic compounds in both chemotherapeutics and luminescence properties. Here we report on the characteristics that result from discrete structural changes that have been expertly used to fine-tune their properties, and how diverse inherent luminescent properties have been widely employed to monitor cellular localization to photodynamic therapy.

A Comparison of Immobilised Triphenylphosphine and 1-Hydroxybenzotriazole as Mediators of Catch-and-Release Acylation Under Flow Conditions.

Described herein is a comparative study of immobilised triphenylphosphine (PS-PPh3 ) and 1-hydroxybenzotriazole (PS-HOBt) to mediate amide couplings under continuous flow. Compared to Appel-type amidations (PS-PPh3 ), the developed 'catch-and-release' approach (PS-HOBt) afforded near-quantitative amide conversions. Utilising this strategy, sulfonyl chloride amenability enabled facile access to an expanded library of sulfonate and sulfonamides. Post-constructional peptide modification was also demonstrated, affording two Nß -functionalised pentapeptides in high yields and purities. In contrast to frequently utilised coupling agents, the PS-HOBt resin could be recycled six times without a reduction in efficacy or regeneration requirements.

Synthesis, characterisation and biological activity of the ruthenium(II) complexes of the N4-tetradentate (N4-TL), 1,6-di(2'-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz2).

A series of complexes of the type rac-cis-ß-[Ru(N4-TL)(N2-bidentates)]2+ (where N4-TL = 1,6-di(2'-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz2, N4-TL-2) and N2-bidentates = 1,10-phenanthroline (phen, Ru-2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, Ru-3), 7,8-dimethyl-dipyrido[3,2-a:2',3'-c] phenazine (dppzMe2,Ru-4), 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBz, Ru-5), 2-(p-tolyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzMe, Ru-6), 2-(4-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (phenpyrBzNO2,Ru-7), were synthesised and characterised and X-ray crystallography of Ru-5 obtained. The in vitro cytotoxicity assays revealed that Ru-6 was 5, 2 and 19-fold more potent than oxaliplatin, cisplatin, and carboplatin, respectively displaying an average GI50 value of ≈ 0.76 µM against a panel of 11 cancer cell lines.

A flow-based transition-metal-catalysed hydrogenolysis strategy to facilitate peptide side-chain deprotection.

Orthogonal deprotection methodologies are an invaluable tool for the construction of site-specially modified peptides. Here, we report a facile 10% Pd/CaCO3-based procedure to selectively mediate Nß-side-chain Cbz-lysis from extended peptide sequences in the presence of trityl and t-Butyl protecting groups.

Recent advances in platinum-based chemotherapeutics that exhibit inhibitory and targeted mechanisms of action.

Current platinum-based drugs used in chemotherapy, like cisplatin and its derivatives, are greatly limited due to side-effects and drug resistance. This has inspired the search for novel platinum-based drugs that deviate from the conventional mechanism of action seen with current chemotherapeutics. This review highlights recent advances in platinum(II) and platinum(IV)-based complexes that have been developed within the past six years. The platinum compounds explored within this review are those that display a more targeted approach by incorporating ligands that act on selected cellular targets within cancer cells. This includes mitochondria, overexpressed receptors or proteins and enzymes that contribute to cancer cell proliferation. These types of platinum compounds have shown significant improvements in anticancer activity and as such, this review highlights the importance of pursuing these new designed platinum drugs for cancer therapy, with the potential of undergoing clinical trials.

Immobilized Carbodiimide Assisted Flow Combinatorial Protocol to Facilitate Amide Coupling and Lactamization.

Through a screen of over one hundred and 30 permutations of reaction temperatures, solvents, carbodiimide resins, and carbodiimide molar equivalences, in the presence, absence, or combination of diisopropylamine and benzotriazole additives, a convenient and first reported carbodiimide polymer-assisted flow approach to effect amide coupling and lactamization was developed. The protocol entails injecting a single solution (1:9 dimethylformamide: dichloromethane) containing a carboxylic acid and an amine or linear peptide sequence into a continuous stream of dichloromethane. The protocol remained viable in the absence of base, did not require carboxylate preactivation which, and in concert with minimal workup requirements, enabled the isolation of products in high yields. Compared to the utilization of untethered carbodiimide reagents, the flow procedure was also observed to provide a degree of racemization safety.

A study of Pt(II)-phenanthroline complex interactions with double-stranded and G-quadruplex DNA by ESI-MS, circular dichroism, and computational docking.

The binding interactions of a series of square-planar platinum(II)-phenanthroline complexes of the type [Pt(PL)(AL)]2+ [where PL = variously methyl-substituted 1,10-phenanthroline (phen) and AL = ethane-1,2-diamine (en)] were assessed with a G-quadruplex DNA (5'-TTG GGG GT-3', G4DNA) and a double-stranded DNA (5'-CGC GAA TTC GCG-3', dsDNA) sequence by ESI-MS. The results indicate a strong correlation between G4DNA affinity and increasing phenanthroline methyl substitution. Circular dichroism (CD) spectroscopy and molecular docking studies also support the finding that increased substitution of the phenanthroline ligand increased selectivity for G4DNA. ESI-MS was used to probe the interaction of a range of square-planar Pt(II)-phenanthroline complexes with double-stranded and G-quadruplex DNA.