Abstract 3509: Design, synthesis and biological evaluation of a novel series of anthrapyrazoles linked with netropsin-like oligopyrrole carboxamides as anticancer agents
Bibliographic record
Abstract
Abstract Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. Combilexin molecules, which combine DNA minor groove binder and intercalator functionalities, have the potential for increased DNA binding affinity and increased cytotoxicity due to their dual mode of DNA binding. In this study DNA minor groove binder netropsin analogs containing either a mono-N-methylpyrrole carboxamide or two units of N-methylpyrrole carboxamide linked to DNA intercalating anthrapyrazoles were synthesized. Two of the hybrid molecules which possessed bis-methylpyrrole moities and amine head groups displayed submicromolar cytotoxicity towards K562 human leukemia cells. The synthesized hybrids were also evaluated for DNA binding by measuring the increase in DNA melting temperature, for DNA topoisomerase IIα-mediated double strand cleavage of DNA, for inhibition of DNA topoisomerase IIα decatenation activity, and for inhibition DNA topoisomerase I relaxation of DNA. Several of the compounds stabilized the DNA-topoisomerase IIα covalent complex, indicating that they acted as topoisomerase IIα poisons. The results indicate that the hybrid agents have higher affinity for DNA than the parent compounds. In conclusion, a novel group of compounds combining DNA intercalating anthrapyrazoles and minor groove binding netropsin analogs have been designed, synthesized and biologically evaluated as possible novel anticancer agents. Support: CIHR, a Canada Research Chair in Drug Development, National Institutes of Health grant CA090787 to J.C.Y., the Dishman Foundation at Southwestern University and the Robert A. Welsh Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3509.
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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 | 0.000 |
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".