CF3 derivatives of the anticancer Ru(III) complexes KP1019, NKP-1339, and their imidazole and pyridine analogues show enhanced lipophilicity, albumin interactions, and cytotoxicity
Bibliographic record
Abstract
The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics.Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues have been synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes.Addition of CF3 groups also provided a spectroscopic handle for 19 F NMR studies of ligand exchange processes and protein interactions.The lipophilicities of the CF3 functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient at pH 7.4 (logD7.4).The solution behavior of the CF3-functionalized complexes was characterized in phosphate buffered saline (PBS) using 19 F NMR, electron paramagnetic resonance (EPR), and UV-Vis spectroscopies.These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA).From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA.These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species.EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation.19 F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA.In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity.Addition of CF3 groups enhances the activity of the indazole complex against A549 non-small cell lung carcinoma cells.Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line, but showed strong cytotoxicity with CF3 functionalization.Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".