First-in-Class Phosphorus Dendritic Framework, a Wide Surface Functional Group Palette Bringing Noteworthy Anti-Cancer and Anti-Tuberculosis Activities: What Lessons to Learn?

Serge Mignani,Jean-Pierre Majoral,Xiangyang Shi,Jérôme Bignon

doi:10.3390/molecules26123708

Abstract

Based on phenotypic screening, the major advantages of phosphorus dendrimers and dendrons as drugs allowed the discovery of new therapeutic applications, for instance, as anti-cancer and anti-tuberculosis agents. These biological activities depend on the nature of the chemical groups (neutral or cationic) on their surface as well as their generation. As lessons to learn, in the oncology domain, the increase in the generation of metallo-dendrimers is in the same direction as the anti-proliferative activities, in contrast to the development of polycationic dendrimers, where the most potent anti-tuberculosis phosphorus dendrimer was observed to have the lowest generation (G0). The examples presented in this original analysis of phosphorus dendrimers and dendrons provide support for the lessons learned and for the development of new nanoparticles in nanomedicine.

Highlights

Biocompatible dendrimers incorporating phosphorus account for over 100 families of dendrimers [1], and within the dendrimer space concept, as a continuum chemical space defined by us in 2013 [2]
Synthesis of highly branched phosphorus dendrimers with well-defined size, shape, molecular weight and monodispersity versus the non-globular structure of linear polymers of the same molecular weight can be performed under mild reaction conditions, releasing by-products such as water and sodium salts that can be removed without the use of any sophisticated techniques
Medicinal chemists are like painters, they spread their ideas onto their palette in order to conceive new medicines according to their aesthetic and imaginative space and their background

Summary

Introduction

Biocompatible dendrimers incorporating phosphorus account for over 100 families of dendrimers (globular tree-like structures) [1], and within the dendrimer space concept, as a continuum chemical space defined by us in 2013 [2]. Nanoparticles in general, and dendrimers in particular, that encapsulate or conjugate biologically active molecules or drugs can be considered best-in-class when used clinically This strategy is based on the host–guest properties of dendrimers [24]. Modification of the nature of the groups on the surface of phosphorus dendrimers crucially influences the in vitro and in vivo biological activities and delineates new ‘druggable’ clusters within the chemical space The purpose of this original manuscript is to review and analyze our recent first-inclass development of neutral and cationic phosphorus dendrimers and dendrons, active per se, in the oncology and anti-tuberculosis domains. These observations have never been published before, and constitute a lesson learned

Neutral Phosphorus Dendrimers as Anti-Cancer Agents

As Anti-Tuberculosis Agents

Conclusions and Perspectives