Identification of Novel Human Breast Carcinoma (MDA-MB-231) Cell Growth Modulators from a Carbohydrate-Based Diversity Oriented Synthesis Library.

Elena Lenci,Francesca Bianchini,Andrea Trabocchi,Riccardo Innocenti,Alessio Biagioni,Gloria Menchi

doi:10.3390/molecules21101405

Elena Lenci, Francesca Bianchini + Show 4 more

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https://doi.org/10.3390/molecules21101405

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Journal: Molecules (Basel, Switzerland)	Publication Date: Oct 20, 2016
Citations: 1	License type: CC BY 4.0

Affiliation: University of Florence

Abstract

The application of a cell-based growth inhibition on a library of skeletally different glycomimetics allowed for the selection of a hexahydro-2H-furo[3,2-b][1,4]oxazine compound as candidate inhibitors of MDA-MB-231 cell growth. Subsequent synthesis of analogue compounds and preliminary biological studies validated the selection of a valuable hit compound with a novel polyhydroxylated structure for the modulation of the breast carcinoma cell cycle mechanism.

Highlights

In the last 25 years, target-based drug discovery has become a paradigm in both the pharmaceutical industry and in academia
The diversity-oriented synthesis of six polyhydroxylated nitrogen-containing scaffolds was achieved by the combination of two building blocks, obtained from D-mannose, with glycinederived aminoacetaldehyde (Figure 2)
Small molecules drug discovery and development became a highly challenging field, and in this view we have identified potential novel drug compounds starting from library compounds and investigated their effect on a malignant human tumor cell line

Summary

Introduction

In the last 25 years, target-based drug discovery has become a paradigm in both the pharmaceutical industry and in academia. Considering that it has proved hard to increase the number of truly innovative new drugs, the interest towards phenotypic screening of large small molecule libraries is growing fast [1,2] In this context, Diversity-Oriented Synthesis (DOS) [3,4,5]. The application of carbohydrates in traditional combinatorial chemistry has been reported since the nineties [12,13,14], they remain rather underexplored in DOS strategies, mainly because of their need for transitional protection/deprotection stages [15,16,17,18,19,20,21] In this context, we have reported the use of D-mannose in combination with glycine-derived aminoacetaldehyde for the synthesis of an array of novel skeletally different polyhydroxylated nitrogen-containing scaffolds [22]. The relevance of these compounds was attested by the widespread distribution of polyhydroxylated nitrogen-containing natural products in plants and microorganisms (Figure 1)

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