Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

Pósa, Vivien; Stefanelli, Alessia; Nunes, Julia Helena Bormio; Hager, Sonja; Mathuber, Marlene; May, Nóra V.; Berger, Walter; Keppler, Bernhard K.; Kowol, Christian R.; Enyedy, Éva A.; Heffeter, Petra

doi:10.3390/cancers14184455

Cited by 19 publications

(20 citation statements)

References 50 publications

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“…Comparisons were made to (1) the negative control Fe(III) complex, [Fe(DFO)] that is redox inert under these conditions and does not significantly oxidize oxy-Mb; , and (2) the positive controls that demonstrate increasing ability to oxidize oxy-Mb in the order: [Fe(PPP44mT) 2 ] + < [Fe(DpC) 2 ] + < [Fe(Dp44mT) 2 ] + < [Fe(Triapine) 2 ] + . , The current experiments also investigated the Fe(III) complex of clinically trialed COTI-2, , whose ability to induce oxy-Mb oxidation has not been reported. Studies were performed by incubating purified oxy-Mb (40 μM) for 1–3 h with the agents (10 μM; Figure A).…”

Section: Resultsmentioning

confidence: 99%

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Wijesinghe,

Kaya,

Gonzálvez

et al. 2023

J. Med. Chem.

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The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), and Zn(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.

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Section: Resultsmentioning

confidence: 99%

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Wijesinghe,

Kaya,

Gonzálvez

et al. 2023

J. Med. Chem.

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“…In the following protocols, cells were stained with annexin V (AV) and propidium iodide (PI) for cell death analysis, with only PI for cell cycle analysis, or with 10 μg mL −1 JC-1 for evaluation of the mitochondrial membrane potential as previously described. 54,55 4.14. Western Blot.…”

Section: Synthesis Of the Silver Compounds Synthesis Of The Compounds...mentioning

confidence: 99%

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

Teixeira,

Stefanelli,

Pilon

et al. 2024

J. Med. Chem.

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In this work, we investigated the anticancer activity of several novel silver(I) 2,2′-bipyridine complexes containing either triphenylphosphane (PPh 3 ) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV−vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray singlecrystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppecontaining drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

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“…Although few small molecules have followed clinical development, p53-based therapy is still not clinically available for cancer treatment. Among the p53-activating small molecules in clinical trials for CRC ( Figure 1 ), Idasanutlin ( 1 , NCT03555149), Siremadlin ( 2 , NCT03714958), and CGM097 ( 3 , NCT01760525) effectiveness is limited only to wild-type (wt) p53 expressing CRC, and small molecule COTI-2 ( 4 , NCT02433626) is a mutant p53 activator which mechanism of action results still unclear [ 21 , 22 ]. Another relevant clinical candidate, APR-246 ( 5 ), retains a p53-independent inhibitory activity in CRC [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators

et al. 2023

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For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites’ identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS/MS), followed by their preparation and structural elucidation, it was possible to identify that the indole C2 and C3 are the main target of the cytochrome P450 (CYP)-promoted oxidative metabolism in the tryptophanol-derived isoindolinone scaffold. Based on these findings, to search for novel p53 activators a series of 16 enantiopure tryptophanol-derived isoindolinones substituted with a bromine in indole C2 was prepared, in yields of 62–89%, and their antiproliferative activity evaluated in human colon adenocarcinoma HCT116 cell lines with and without p53. Structural optimization led to the identification of two (S)-tryptophanol-derived isoindolinones 3.9-fold and 1.9-fold more active than hit SLMP53-1, respectively. Compounds’ metabolic stability evaluation revealed that this substitution led to a metabolic switch, with the impact of Phase I oxidative metabolism being minimized. Through differential scanning fluorimetry (DSF) experiments, the most active compound of the series in cell assays led to an increase in the protein melting temperature (Tm) of 10.39 °C, suggesting an effective binding to wild-type p53 core domain.

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Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

Cited by 19 publications

References 50 publications

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators

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