I. Hybrid androgen receptor antagonist – Histone deacetylase inhibitors and II. development of an oxy-Cope / Michael cascade reaction
Bibliographic record
Abstract
Part I Prostate cancer treatment options have improved in recent years, but the disease remains prevalent in the elderly Canadian male population. Existing treatments for castration-resistant prostate cancer are inadequate and this necessitates innovation in treatment by drug co-administration or drug design. This century, and especially in the past decade, the concept of hybrid drug design has taken root in the literature. A series of hybrid compounds which combine key structural features of both androgen receptor antagonists and histone deacetylase inhibitors have been designed using the structure-activity relationship data available for each. Certain molecules are shown to inhibit the desired targets both in vitro and in cell assays. Furthermore, select hybrids were more effective in antiproliferation assays with prostate cancer cell lines than second-generation antiandrogen prostate cancer drug enzalutamide. Those hybrids also demonstrated less general cytotoxicity than known histone deacetylase inhibitors such as entinostat.Part IISince the discovery of massive rate enhancements with anionic conditions, the oxy-Cope reaction has proven immensely popular and useful in synthetic efforts. However, few methods have been developed for catalyzing the oxy-Cope reaction. Our group previously communicated the use of iminium catalysis in the Cope rearrangement of 1,5-hexadienes bearing 2-carboxaldehydes using diazepane hydrazide ammonium salts. This methodology has now been extended to the oxy-Cope rearrangement, resulting in catalysis not only of the sigmatropic shift, but also a subsequent Michael addition. The result is an oxy-Cope / Michael cascade reaction. We demonstrate ring expansions using 5 to 7-membered divinylcycloalkanes to access fused hydrindane, hydrazulene, and 8/5 bicycles in excellent yield with very high diastereoselectivity. We have also extended this to acyclic substrates which allow the synthesis of substituted cyclopentanes from linear hexadiene precursors. This has allowed us to study the reaction of enantioenriched linear substrates and confirm the mechanism of the transformation
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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) | 0.001 | 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 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".