Metabolite profiling in human and mouse liver microsomes of the aminosteroid RM-581, a new orally active anticancer agent
Bibliographic record
Abstract
To progress towards clinical phase studies with orally active aminosteroid RM-581, it was necessary to address its metabolic stability. Analysis by ultra high-pressure liquid chromatography coupled with quadrupole time-of-flight-mass spectrometry (MS) showed the gradual disappearance of RM-581, making it possible to determine a half-life of 14 and 15 min in mouse and human liver microsomes, respectively, and the presence of 6 metabolites in varying proportions (M1 to M6). The MS/MS spectra of metabolites were investigated to assign sub-structures to fragment ions. These analyses made it possible to conclude that the amino acid proline in the C2-side chain of the steroid mestranol core was the main site of metabolism, and the following mass shift relative to the parent compound were observed for each metabolite relative to RM-581: M1(+34), M2(−2), M3(+16), M4(+18), M5(+32) and M6(+16). Suspecting the formation of RM-581 analogs whose pyrrolidine ring of proline has been opened, compound 8 (M4) was synthesized and characterized. Its chromatographic and MS properties made it possible to formally identify the metabolite M4 (M + H + = 665.3684; Rt = 9.11 min) as a primary alcohol derivative. This result also indirectly supports the proposed structures of the other metabolites M6 (aldehyde), M5 (carboxylic acid) and M1 (dihydroxylated quinoline ring). M4 (IC 50 = 12–454 μM) was found to be much less potent than RM-581 (IC 50 = 0.78–7.55 μM) when tested on 9 human pancreas and leukemia cancer cell lines. M4 (63 %) was also more present in plasma than RM-581 (37 %) when RM-581 was orally administered to rats.
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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".