The molecular docking-based design and biological evaluation of a novel series of bisintercalating DNA-binding bisanthrapyrazole compounds
Bibliographic record
Abstract
4737 Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of ester coupled bisanthrapyrazole (BisAP) derivatives of 7-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethylanthra[1,9-cd]pyrazol-6(2H)-one (AP9) were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should not be cardiotoxic like the anthracyclines. Based on the docking scores of a series of BisAPs with different sizes of linkers that were docked into an x-ray structure of double stranded DNA, several BisAP compounds were selected for synthesis (n = 1 - 5) and physical and biological evaluation. The synthesized compounds were evaluated for DNA binding by measuring ΔTm, the DNA melting temperature increase, and for growth inhibitory effects on the human erythroleukemic K562 cell line. All the BisAPs potently inhibited the growth of K562 cells. Some of the BisAP compounds bound to DNA more strongly than doxorubicin, an intercalating anticancer drug used as a positive control. This result suggests that the BisAPs bisintercalate into DNA. In conclusion, a novel group of bisintercalating anthrapyrazole compounds have be designed, synthesized and biologically evaluated as possible novel potent anticancer agents. Support: CIHR, a Canada Research Chair in Drug Development, the Dishman Foundation at Southwestern University and the Robert A. Welsh Foundation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".