Synthesis and Evaluation of Agelastatin Derivatives as Potent Modulators for Cancer Invasion and Metastasis
| Autor: | Alyssa H. Antropow, Rachel J. Buchsbaum, Mohammad Movassaghi, Kun Xu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Molecular Conformation
Context (language use) 010402 general chemistry Thioester 01 natural sciences Article Metastasis Mice Structure-Activity Relationship Alkaloids Breast cancer Tumor Cells Cultured medicine Animals Humans Structure–activity relationship Oxazolidinones Cell Proliferation chemistry.chemical_classification Dose-Response Relationship Drug 010405 organic chemistry Chemistry Alkaloid Organic Chemistry Cancer Neoplasms Experimental Fibroblasts medicine.disease Antineoplastic Agents Phytogenic Coculture Techniques 0104 chemical sciences Biochemistry Breast cancer cells Drug Screening Assays Antitumor |
| Zdroj: | The Journal of Organic Chemistry. 82:7720-7731 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/acs.joc.7b01162 |
| Popis: | The synthesis of new agelastatin alkaloid derivatives and their anticancer evaluation in the context of the breast cancer microenvironment is described. A variety of N1-alkyl and C5-ether agelastatin derivatives were accessed via application of our strategy for convergent imidazolone synthesis from a common thioester along with appropriately substituted urea and alcohol components. These agelastatin derivatives were evaluated in our three-dimensional co-culture assay for the effects of mammary fibroblasts on associated breast cancer cells. We have discovered that agelastatin alkaloids are potent modulators for cancer invasion and metastasis at non-cytotoxic doses. Herein we discuss the increased potency of (−)-agelastatin E as compared to (−)-agelastatin A in this capacity, in addition to identification of new agelastatin derivatives with activity that is statistically equivalent to (−)-agelastatin E. The chemistry described in this report provides a platform for the rapid synthesis of agelastatin derivatives with excellent potency (50–100 nM) as modulators for cancer invasion and metastasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|