A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents
Over the last decades, much effort has been devoted to the design of the “ideal” library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing underst...
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todo:paper_18607179_v13_n16_p1732_Alonso2023-10-03T16:33:20Z A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents Alonso, F. Quezada, M.J. Gola, G.F. Richmond, V. Cabrera, G.M. Barquero, A.A. Ramírez, J.A. antiproliferative agents molecular complexity multicomponent reactions natural product mimics phenanthrenes antineoplastic agent phenanthrenoid derivative unclassified drug antiproliferative activity apoptosis Article cell survival comparative study cyclization drug design drug mechanism drug screening drug synthesis electrospray mass spectrometry HT-29 cell line human human cell IC50 in vitro study leukemia cell molecular library nonhuman nuclear magnetic resonance spectroscopy plant response priority journal protein conformation proton nuclear magnetic resonance structure activity relation Over the last decades, much effort has been devoted to the design of the “ideal” library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged—in a minimalist way—by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_18607179_v13_n16_p1732_Alonso |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
antiproliferative agents molecular complexity multicomponent reactions natural product mimics phenanthrenes antineoplastic agent phenanthrenoid derivative unclassified drug antiproliferative activity apoptosis Article cell survival comparative study cyclization drug design drug mechanism drug screening drug synthesis electrospray mass spectrometry HT-29 cell line human human cell IC50 in vitro study leukemia cell molecular library nonhuman nuclear magnetic resonance spectroscopy plant response priority journal protein conformation proton nuclear magnetic resonance structure activity relation |
| spellingShingle |
antiproliferative agents molecular complexity multicomponent reactions natural product mimics phenanthrenes antineoplastic agent phenanthrenoid derivative unclassified drug antiproliferative activity apoptosis Article cell survival comparative study cyclization drug design drug mechanism drug screening drug synthesis electrospray mass spectrometry HT-29 cell line human human cell IC50 in vitro study leukemia cell molecular library nonhuman nuclear magnetic resonance spectroscopy plant response priority journal protein conformation proton nuclear magnetic resonance structure activity relation Alonso, F. Quezada, M.J. Gola, G.F. Richmond, V. Cabrera, G.M. Barquero, A.A. Ramírez, J.A. A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| topic_facet |
antiproliferative agents molecular complexity multicomponent reactions natural product mimics phenanthrenes antineoplastic agent phenanthrenoid derivative unclassified drug antiproliferative activity apoptosis Article cell survival comparative study cyclization drug design drug mechanism drug screening drug synthesis electrospray mass spectrometry HT-29 cell line human human cell IC50 in vitro study leukemia cell molecular library nonhuman nuclear magnetic resonance spectroscopy plant response priority journal protein conformation proton nuclear magnetic resonance structure activity relation |
| description |
Over the last decades, much effort has been devoted to the design of the “ideal” library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged—in a minimalist way—by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
| format |
JOUR |
| author |
Alonso, F. Quezada, M.J. Gola, G.F. Richmond, V. Cabrera, G.M. Barquero, A.A. Ramírez, J.A. |
| author_facet |
Alonso, F. Quezada, M.J. Gola, G.F. Richmond, V. Cabrera, G.M. Barquero, A.A. Ramírez, J.A. |
| author_sort |
Alonso, F. |
| title |
A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| title_short |
A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| title_full |
A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| title_fullStr |
A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| title_full_unstemmed |
A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents |
| title_sort |
minimalist approach to the design of complexity-enriched bioactive small molecules: discovery of phenanthrenoid mimics as antiproliferative agents |
| url |
http://hdl.handle.net/20.500.12110/paper_18607179_v13_n16_p1732_Alonso |
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