Design, synthesis and evaluation of selective estrogen receptor modulator/histone deacetylase inhibitor merged bifunctional ligands
Bibliographic record
Abstract
Breast cancer remains one of the most persistent threats to women's health in the Western world. The selective estrogen receptor modulator (SERM) tamoxifen is a front-line treatment for the disease, but suffers from a high rate of acquired resistance and an increased risk of endometrial cancer. As such, improved small molecule inhibitors with the ability to overcome antiestrogen resistance while limiting adverse side effects are valuable pharmaceutical targets. Histone deacetylase inhibitors (HDACi) have recently emerged as versatile anticancer agents with antiproliferative activity in breast cancer cells. Combination therapy of SERMs and HDACi has demonstrated enhanced cytotoxicity and the ability to restore tamoxifen sensitivity to antiestrogen-resistant cancer cell lines. This research project describes a novel approach to overcoming antiestrogen resistance by combining the anticancer properties and cooperative activity of SERMs and HDACi into compact, merged bifunctional ligands. Previous research by the Gleason laboratory indicated that HDACi functionality, in the form of zinc-chelating hydroxamic acids, could be integrated into the polar side chain of SERMs while maintaining antiestrogenicity at micromolar concentrations. Building from these preliminary results, a series of novel hybrid molecules was designed with zinc-binding groups incorporated into the aliphatic side chain or the triphenylethylene core structure of the active tamoxifen metabolite 4-hydroxytamoxifen (4-OHT). The resulting structures were investigated in silico using the molecular docking program FITTED. Twelve hybrid compounds were then synthesized by geminal Suzuki coupling and McMurry coupling procedures. Despite the propensity of the compounds to isomerize around the central double bond, the majority of the syntheses proceeded diastereoselectively and HPLC purification furnished the final products as a single isomer or in good diastereomeric excess. The HDAC inhibition and ER antagonism of the bifunctional molecules were evaluated in collaboration with the Mader laboratory of the Université de Montréal. Side chain-substituted hybrid compounds demonstrated good affinity for the ER binding pocket and nanomolar ER inhibitory activity. In addition, long-chain chimeric ligands possessing amide linkers exhibited significant HDAC 6 inhibition, with one compound displaying inhibitory activity at sub-micromolar concentrations. However, these side-chain substituted hybrids also exhibited substantial ER agonism in the absence of estradiol, which limited their effectiveness as antiestrogens. Conversely, a compound containing a phenyl hydroxamic acid in the aromatic core of 4-OHT acted as a full antagonist at micromolar concentrations and displayed no estrogenic behaviour. The core-substituted hybrid also exhibited modest HDAC inhibition, though it lacked the strong activity of its side chain counterparts. The synthesized SERM/HDACi molecules therefore displayed encouraging results and provided important structural insight into the future creation of bifunctional ligands.A brief side project is also described as a contribution towards the total synthesis of (R)-puraquinonic acid. The enantioselective synthesis of this natural product was previously accomplished by the Gleason group using a novel lactam auxiliary alkylation sequence to set the molecule's sole stereocenter. However, the specific rotation of the final product was opposite that expected and contradicted previous stereochemical assignments of the alkylation sequence. To address this inconsistency, a convergent stereochemical proof was completed which allowed direct comparison of alkylation products to auxiliary-based Mannich addition products that could be characterized by X-ray diffraction. The absolute stereochemistry of the sequence was thereby unambiguously assigned and strongly supported the conclusion that our group had successfully synthesized (R)-puraquinonic acid.
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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".