Multicomponent assembly of 4-aza-podophyllotoxins: A fast entry to highly selective and potent anti-leukemic agents
| Autor: | Stéphane P. Roche, Nagalakshmi Jeedimalla, Madison Flint, Lyndsay Smith, Dmitriy Minond, Alberto Haces |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
Stereochemistry Antineoplastic Agents Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Humans Structure–activity relationship IC50 Etoposide Cell Proliferation Podophyllotoxin Pharmacology Leukemia Dose-Response Relationship Drug Molecular Structure Cell growth Chemistry Organic Chemistry HEK 293 cells Trypan Blue General Medicine medicine.disease Combinatorial chemistry HEK293 Cells Toxicity Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 106:167-179 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2015.10.009 |
| Popis: | The aim of this study was the synthesis and lead structure selection of a best anti-leukemic agent from a library of aza-podophyllotoxin analogues (APTs). To this end, we report a scalable, modified multicomponent reaction using a "sacrificial" aniline partner as a more general route to rapidly construct the pivotal library of 50 APT analogues. Our preliminary structure activity relationship studies for anti-leukemic activity also address the innate toxicity of these compounds against non-malignant cells. As a result, we identified 2 novel compounds 2ca' and 2jc' more potent than etoposide 1 (25-60 fold) having high selectivity against the human THP-1 leukemia cell line and a minimal toxicity (IC50 of 9.3 ± 0.8 and 19.6 ± 1.4 nM respectively) which represent the best candidates for further pharmacological optimization. |
| Databáze: | OpenAIRE |
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