Chemotherapeutic Potential of Chlorambucil-Platinum(IV) Prodrugs against Cisplatin-Resistant Colorectal Cancer Cells.

Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the prodrugs have been previously found to induce changes in the microtubule cytoskeleton, specifically actin and tubulin of HT29 colon cells, while chlorambucil alkylates the DNA. These prodrugs demonstrate significant anticancer activity in 2D cell and 3D spheroid viability assays.

Anticancer Effect of PtPHEN, Pt5ME, Pt56ME and Their Platinum(IV)-Dihydroxy Derivatives against Triple-Negative Breast Cancer and Cisplatin-Resistant Colorectal Cancer.

Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast and colorectal cancer. Here, we compare the anticancer effect of novel complexes [Pt(1,10-phenanthroline)(1,2-diaminocyclohexane)](NO) (), [Pt(5-methyl-1,10-phenanthroline)(1,2-diaminocyclohexane)](NO) () and [Pt(5,6-dimethyl-1,10-phenanthroline)(1,2-diaminocyclohexane)](NO) () and their platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent than cisplatin in both 2D and 3D cell line cultures with increased selectivity for cancer cells over genetically stable cells.

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, , and were confirmed via spectroscopic means.

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).

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.

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.

Platinum(IV) Derivatives of [Pt(1,2-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(1,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS, ) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 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 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug.

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.

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 (-) 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 -.

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

A novel platinum(II) complex and its platinum(IV) derivative 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, demonstrated 17-22-fold greater selectivity toward the cancerous cells compared to the non-cancerous MCs.

Bioactive Platinum(IV) Complexes Incorporating Halogenated Phenylacetates.

A new series of cytotoxic platinum(IV) complexes (-) 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 - 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 and , eliciting an average GI value of 20 nM over the range of cell lines tested.

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, (where H is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A is 1,2-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, , , and , 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, , , and .

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).

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

Platinum(IV) prodrugs of the [Pt(P)(A)(COXi)(OH)] type scaffold (where P is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A is 1,2-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, , exhibited a GI 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.

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.

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-PPh ) and 1-hydroxybenzotriazole (PS-HOBt) to mediate amide couplings under continuous flow. Compared to Appel-type amidations (PS-PPh ), 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.

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/CaCO-based procedure to selectively mediate Nβ-side-chain Cbz-lysis from extended peptide sequences in the presence of trityl and -Butyl protecting groups.

Synthesis, characterisation and biological activity of the ruthenium(II) complexes of the N-tetradentate (N-T), 1,6-di(2'-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz).

A series of complexes of the type rac-cis-β-[Ru(N-T)(N-bidentates)] (where N-T = 1,6-di(2'-pyridyl)-2,5-dibenzyl-2,5-diazahexane (picenBz, N-T-2) and N-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 (dppzMeRu-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 (phenpyrBzNORu-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 GI value of ≈ 0.76 μM against a panel of 11 cancer cell lines.

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.

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.

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(P)(A)] [where P = variously methyl-substituted 1,10-phenanthroline (phen) and A = 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.

Synthesis, characterisation and potent cytotoxicity of unconventional platinum(iv) complexes with modified lipophilicity.

Novel platinum(iv) complexes were synthesised to examine the facile modulation of the lipophilicity of the complex by incorporating axial ligands of increasing length, ranging from 2-6 carbons. RP-HPLC was used to establish the lipophilicity of each complex. The in vitro cytotoxicities of all complexes were determined against a panel of malignant cell lines and a non-cancerous cell line.

Synthesis, characterisation and influence of lipophilicity on cellular accumulation and cytotoxicity of unconventional platinum(iv) prodrugs as potent anticancer agents.

Lipophilic platinum(iv) complexes were synthesised of the type [Pt(HL)(AL)(OH)(R)]2+ and [Pt(HL)(AL)(R)2]2+ (HL = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10-18)) from hydrophilic platinum(ii) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines.