Rational design, synthesis and biological evaluation of natural product mimics
Bibliographic record
Abstract
This dissertation describes the design and synthesis of molecules mimicking bioactive portions of peptides, nucleoside bases and bioactive natural products. Chapter 1 details the design and implementation of catechol based peptidomimetics of urotensin II (U-II), based on the identified 3D pharmacophore. The synthesis describes orthogonal protecting group strategies for phenols. Chapter 2 summarizes an efficient protocol to annulate the 5,6-fused 2-pyridones, a ring system similar to those found in nucleoside bases. A tandem procedure comprising the condensation of propiolamide and cyclic β-ketomethyl esters in water, followed by acid or base promoted intramolecular ring closure and decarboxylation was developed. Chapter 3 provides a strategy for the design of truncated analogs of (+)-spongistatin 1 preserving conformational properties of the natural product. The solution conformers of (+)-spongistatin 1 were studied in detail leading to the design of AB- and ABEF-ring analogs. An ABEF-ring analog with low nanomolar activity was found to act through the same mode of action as (+)-spongistatin 1, proving that the bioactive portion of the molecule comprise a linear version of the ABEF-ring system. Finally Chapter 4 describes the design and synthesis of novel (+)-discodermolide analogs with improved potency. Detailed investigation of the earlier SAR and photolabeling data, combined with solution structure and docking studies revealed a possible binding mode of (+)-discodermolide that occupies known taxane binding site on β-tubulin. Attachment of aromatic side-chains mimicking the taxol tail furnished one of the most potent (+)-discodermolide analog series reported to date.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".