A Minimalist Approach to the Design of ComplexityEnriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents

FERNANDO ALONSO; MARIA JOSEFINA QUEZADA; GABRIEL F. GOLA; VICTORIA RICHMOND; GABRIELA M. CABRERA; ANDREA A. BARQUERO; JAVIER A. RAMIREZ

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2018 vol. 13 p. 1732 - 1740

1860-7179

Over the last decades, much effort has been devoted to thedesign of the ?ideal? library for screening, the most promisingstrategies being those which draw inspiration from biogeniccompounds, as the aim is to add biological relevance to suchlibraries. On the other hand, there is a growing understandingof the role that molecular complexity plays in the discovery ofnew bioactive small molecules. Nevertheless, the introductionof 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 simpleguidelines during the design process along with the application of multicomponent reactions as key steps in the syntheticprocess. Natural phenanthrenoids, a class of plant aromaticmetabolites, served as inspiration for the synthesis of a libraryin which complexity-enhancing features were introduced infew steps using multicomponent reactions. These resultingchemical entities were not only more complex than the parentnatural products, but also interrogated an alternative region ofthe chemical space, which led to an outstanding hit rate in anantiproliferative assay: four out of twenty-six compoundsshowed in vitro activity, one of them being more potent thanthe clinically useful drug 5-fluorouracil