Design, synthesis, and biological evaluation of selective estrogen receptor modulator/histone deacetylase inhibitor hybrid molecules
Bibliographic record
Abstract
Therapeutic options for the treatment of breast cancer have long been limited to invasive surgical procedures, or chemo- and radiotherapies that are plagued with detrimental side-effects. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are a large subclass of molecules that have been used in adjuvant therapies and have provided substantial clinical benefits as preventative and long-term treatment options. Despite their success, endocrine therapies face several challenges including the development of endocrine resistance and, in the case of tamoxifen, the increased risk of endometrial cancer. Recent studies have shown that dual administration of SERMS and histone deacetylase inhibitors (HDACis) in vitro have led to cooperative effects such as increased drug potency, the resensitization of endocrine resistant cell lines, and an overall decrease in the risk of endometrial cancer development. In an effort to combine the cooperative effects of SERMs and HDACis, this project focuses on the design, synthesis, and biological evaluation of a series of hybrid SERM/HDACi molecules that combine the pharmacophores of both drug classes.The design of the hybrids was based on previous research projects investigating hybrid antiestrogens within the Gleason group. This project expanded on a promising subsetof 4-OHT based hybrids and began with in silico screening of a virtual library using the FORECASTOR docking platform. Seven compounds were chosen for synthesis and a previously devised route was unsuccessfully attempted using a McMurry cross-coupling as the key step. An alternate route to the triphenylethylene scaffold is hinged on a highly convergent and modular three-component coupling reaction was designed and successfully carried out. Four hybrids were synthesized and purified by preparatory HPLC prior to biological evaluation.Fluorogenic HDACi assays to determine the hybrid affinities of HDACs 3 and 6 were carried out by the author within the Gleason lab. Three of the four hybrids showed lowmicromolar HDAC 3 potencies (IC50) and the fourth showed submicromolar potency, and suggested that increased chain-lengths led to a higher degree of HDAC inhibition. HDAC 6 inhibition results trended similar to those of HDAC 3 and three of the four hybrids showed submicromolar potencies. Cell-based bioluminescence resonance energy transfer (BRET) and luciferase transactivation assays were conducted by the Mader lab at Université de Montréal to evaluate the ER affinity and antagonism profile of the hybrids. Each hybrid exhibited full antagonism against the ER and three of the hybrids showed submicromolar IC50 values with regards to their ER affinity. MCF-7 breast cancer cell growth curves were carried out and a single hybrid outperformed 4-hydroxytamoxifen (4-OHT), tamoxifen, and endoxifen. The ER data alongside the HDACi results are suggestive of a hybrid SERM/HDACi that was capable of eliciting a cooperative antiproliferative effect against the breast cancer cell line.The final chapter of this thesis presents a brief project regarding the design of a 3-acyl-1,5-diene substrate for the organocatalytic Cope rearrangement. A novel diazepanecarboxylate organocatalyst capable of catalyzing the Cope rearrangement of hindered aldehydes via iminium catalysis was recently reported by the Gleason group. DFT calculations suggested that iminium ion formation of 3-acyl-1,5-dienes would accelerate the Cope rearrangement. The final 3-acyl-1,5-diene substrate was shown to be capable of undergoing the Cope rearrangement under simple thermal conditions and future work will investigate the potential for organocatalytic rate acceleration.
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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 | 0.000 |
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".