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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. A notable production of reactive oxygen species has been observed in HT29 cells 72 h post treatment with prodrugs of this type, while the mitochondrial membrane potential was substantially reduced. The cellular uptake of the chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport was the primary uptake mechanism, with platinum localisation identified primarily in the cytoskeletal fraction. Apoptosis and necrosis were observed at 72 h of treatment as demonstrated by Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed significant changes in actin and tubulin intensity and in architecture. Western blot analysis of intrinsic and extrinsic pathway apoptotic markers, microtubule cytoskeleton markers, cell proliferation markers, as well as autophagy markers were studied post 72 h of treatment. The proteomic profile was also studied with a total of 1859 HT29 proteins quantified by mass spectroscopy, with several dysregulated proteins. Network analysis revealed dysregulation in transcription, MAPK markers, microtubule-associated proteins and mitochondrial transport dysfunction. This study confirms that chlorambucil-platinum(IV) prodrugs are candidates with promising anticancer potential that act as multi-mechanistic chemotherapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Conventional intravenous platinum(II) chemotherapy medications, including carboplatin, oxaliplatin and cisplatin, have demonstrated remarkable efficacy in treating several forms of cancer. Also, this therapy is frequently accompanied by toxicity and development of resistance. More potent platinum complexes with fewer side effects may be of benefit. This study compares the in vitro anticancer effect of novel platinum(II) complexes and their platinum(IV)-dihydroxy derivatives with cisplatin to understand the influence of different mechanisms of action on potency. The investigation of these complexes is expected to advance our understanding to support further research into their application as cancer therapeutics. 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)(1S,2S-diaminocyclohexane)](NO3)2 (PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII5MESS) and [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII56MESS) 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. ICP-MS studies showed cellular uptake occurred through an active transport mechanism with considerably altered platinum concentrations found in the cytoskeleton across all complexes after 24 h. Significant reactive oxygen species generation was observed, with reduced mitochondrial membrane potential at 72 h of treatment. Late apoptosis/necrosis was shown by Annexin V-FITC/PI flow cytometry assay, accompanied by increased sub-G0/G1 cells compared with untreated cells. An increase in S and G2+M cells was seen with all complexes. Treatment resulted in significant changes in actin and tubulin staining. Intrinsic and extrinsic apoptosis markers, MAPK/ERK and PI3K/AKT activation markers, together with autophagy markers showed significant activation of these pathways by Western blot. The proteomic profile investigated post-72 h of treatment identified 1597 MDA−MB−231 and 1859 HT29 proteins quantified by mass spectroscopy, with several differentially expressed proteins relative to no treatment. GO enrichment analysis revealed a statistically significant enrichment of RNA/DNA-associated proteins in both the cell lines and specific additional processes for individual drugs. This study shows that these novel agents function as multi-mechanistic chemotherapeutics, offering promising anticancer potential, and thereby supporting further research into their application as cancer therapeutics. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Research has been conducted on the Delta- and Lambda-enantiomer oligonucleotide binding to a metal complex. The results of the (super)1 H NMR spectroscopy and viscosity measurements are presented.

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 Nβ‐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. [ABSTRACT FROM AUTHOR]

An examination of the oligonucleotide binding of the delta enantiomers of (Ru(phen)2L)2+ indicates that all three ruthenium(II) polypyridyl complexes bind in the DNA minor groove. Results from one- and two-dimensional nuclear magnetic resonance experiments clearly indicate that delta-(Ru(phen)2dpq)2+ binds the hexanucleotide d(GTCGAC)2 by intercalation from the minor groove, or at the GA/TC site. With the dodecanucleotide d(TCGGGATCCCGA)2, the metal complex bound at a GG/CC site. This suggests that delta-(Ru(phen)2dpq)2+ may exhibit some sequence selectivity in its oligonucleotide binding.