One-Pot Synthesis of Phosphinylphosphonate Derivatives and Their Anti-Tumor Evaluations.

Jade Dussart-Gautheret,Evelyne Migianu-Griffoni,Maelle Monteil,Thibaut Legigan,Marc Lecouvey,Julia Deschamp

doi:10.3390/molecules26247609

Abstract

This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by 31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).

Highlights

The synthesis of phosphorus-containing compounds still represents a major challenge in the development of more efficient therapeutics [1,2,3]
We have recently reported the efficient synthesis of substituted HMBPi III by developing a convenient one-pot methodology [12,13,14]
Inspired by our previous works on HMBPs II or HMBPi III, we focused on the synthesis of the hydroxymethylene(phosphinyl)phosphonate scaffold

Summary

Introduction

The synthesis of phosphorus-containing compounds still represents a major challenge in the development of more efficient therapeutics [1,2,3]. 1-hydroxymethylene-1,1-bisphosphonates (HMBPs II) are C-substituted pyrophosphate I analogues used to treat and prevent osteoporosis, cancer and bone metastasis (Figure 1) [4,5,6]. These molecules have shown interesting antitumor properties on in vitro and in vivo models of soft tissue primary tumor [7,8,9]. The synthesis of more lipophilic analogues such as hydroxy-methylenebis(H-phosphinates) (HMBPi III) or hydroxymethylene(phosphinyl)phosphonates (HMPPs IV) should overcome these drawbacks (Figure 1)

Methods

Results

Conclusion