MANNICH BASES OF CYCLOALKANONES AND RELATED COMPOUNDS AS CYTOTOXIC AGENTS
Bibliographic record
Abstract
Cancer chemotherapy is primarily limited by the non-selective action of drugs and hence toxicity to normal cells. Therefore one of the most important features of new drugs should be selectivity towards tumor cells. Mannich bases have been found to possess some degree of selective antineoplastic activity. These compounds demonstrate a greater affinity for the thiol groups than amino and hydroxy functions in biomolecules. Hence carcinogenic and mutagenic side effects may be avoided. The aim of the present investigation was to design and prepare a number of Mannich bases which could be screened against P388-D1 leukemia cells and also in the NCI screen. Thus the following series of compounds were designed and synthesized: • Mono Mannich bases of cycloalkanones which are potentially cytotoxic through conversion to the corresponding a,ß-unsaturated ketones. • Bis Mannich bases of cycloalkanones. These were designed to examine the theory of sequential cytotoxicity. • Quaternary ammonium salts of mono and bis Mannich bases with a view to attain a faster rate of deamination and hence greater cytotoxicity than the corresponding tertiary amines. • 2-(Arylmethylene)cycloalkanones and the corresponding Mannich bases. The Mannich bases of cyclopentanone and cyclohexanone generally demonstrated significant cytotoxicity against P388-D1 leukemia cells. However the activity is decreased with further increases in the size of the cycloalkanering. Thus the cyclododecanone mono and bis Mannich bases were in general far less active. The bis Mannich bases of cyclohexanone were found to be more cytotoxic in the P388-D1 screen than the corresponding mono derivatives. In order to investigate whether there is a correlation between the cytotoxicity and the basicity of the amino function and hence the rate of deamination, various series of mono and bis Mannich bases of cyclopentanone, cyclohexanone and cyclododecanone with different amino moieties having varying log Kb values were synthesized and evaluated. However, no correlation was observed between the predicted rates of deamination and cytotoxicity. A number of mono and bis Mannich bases of cycloalkanones synthesized in this project showed greater cytotoxicity and selectivity than melphalan in the NCI screen. 2-(Arylmethylene)cycloalkanone Mannich bases demonstrated greater cytotoxicity against P388-D1 leukemia cells than the corresponding 2-(aryl-methylene)cycloalkanones. The activities of the Mannich bases in which the aryl ring was unsubstituted or contained a 4-methyl group were similar to that of melphalan.
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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) | 0.002 | 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".