Synthesis and characterization of the biological activity of the cisplatin analogs cis-PtCl2(dexrazoxane) and cis-PtCl2(levrazoxane) of the topoisomerase II inhibitors dexrazoxane (ICRF-187) and levrazoxane (ICRF-186).
Bibliographic record
Abstract
3077 The bisdioxopiperazines dexrazoxane and levrazoxane are strong catalytic inhibitors of mammalian DNA topoisomerase II. The individual stereoisomers of their platinum(II) complexes, cis-PtCl2(dexrazoxane) and cis-PtCl2(levrazoxane), were synthesized and their structures were determined by x-ray crystallography. Dexrazoxane and levrazoxane inhibit cell growth because they inhibit topoisomerase II, whereas cisplatin acts through the formation of DNA cross-links. It was hypothesized that platinum(II) complexes of dexrazoxane and levrazoxane would retain both activities and yield drugs with a dual mode of action. Both cis-PtCl2(dexrazoxane) and cis-PtCl2(levrazoxane) inhibited Chinese hamster ovary cell growth, but more weakly than dexrazoxane and levrazoxane did. Based on the inability of these platinum complexes to inhibit the catalytic activity of topoisomerase II it was concluded that these compounds did not inhibit cell growth by. targeting topoisomerase II. The recent x-ray structure of dexrazoxane bound to the ATPase region of a yeast topoisomerase II has been used to model the platinum complexes into the bisdioxopiperazine binding site. A comparison of the conformation of cis-PtCl2(dexrazoxane) to that of dexrazoxane bound to the dimer interface of topoisomerase II showed that the highly constrained cis-PtCl2(dexrazoxane) was in a highly unfavorable conformation for binding. Also neither of the platinum complexes were able to cross-link DNA. Thus the cell growth inhibitory activity of these complexes were also not likely due to any cisplatin-type cross-linking activity. Support: CIHR and a Canada Research Chair in Drug Development.
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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) | 0.001 | 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".