Three-Component Reaction of Diamines with Triethyl Orthoformate and Diethyl Phosphite and Anti-Proliferative and Antiosteoporotic Activities of the Products.

Patrycja Petruczynik,Jan Kuryszko,Ewa Chmielewska,Mateusz Psurski,Zdzisław Kiełbowicz,Paweł Kafarski,Joanna Wietrzyk

doi:10.3390/molecules25061424

Abstract

A three-component reaction between diamines (diaminobenzenes, diaminocyclohexanes, and piperazines), triethyl orthoformate, and diethyl phosphite was studied in some detail. In the case of 1,3- and 1,4-diamines and piperazines, products of the substitution of two amino moieties—the corresponding tetraphosphonic acids—were obtained. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This is most likely the result of the formation of hydrogen bonding between the phosphonate oxygen and a hydrogen of the adjacent amino group, which caused a decrease in the reactivity of the amino group. Most of the obtained compounds inhibited the proliferation of RAW 264.7 macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells, with 1, trans-7, and 16 showing broad nonspecific activity, which makes these compounds especially interesting in the context of anti-osteolytic treatment and the blocking of interactions and mutual activation of osteoclasts and tumor metastatic cells. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid, which were used as controls. However, studies of sheep with induced osteoporosis carried out with compound trans-7 did not support this assumption.

Highlights

The synthesis of bisphosphonic acids was described as early as the 19th century, the interest in these compounds is still growing, rooted in their promising and variable physiological activities [1]
The reaction of 1,4-diaminobenzene with triethyl orthoformate and diethyl phosphite (Figure 1) readily provided 1,4-di-substituted tetrabisphosphonic acid, which appeared to be relatively stable if stored at low temperature while protected against moisture
When 1,2-diaminobenzene was used, a mixture of products containing mono- and di-substituted compounds was obtained, with the mono-substituted produce the major one, we did not succeed in their isolation from the reaction mixture. 1,3-Diaminobenzene gave a complex mixture of inseparable products, most likely di- and mono-substituted compounds

Summary

Introduction

The synthesis of bisphosphonic acids was described as early as the 19th century, the interest in these compounds is still growing, rooted in their promising and variable physiological activities [1]. Most commonly, their regulation of bone growth has been exploited for the design and preparation of antiosteoporotic drugs that can be used to treat skeletal complications of Molecules 2020, 25, 1424; doi:10.3390/molecules25061424 www.mdpi.com/journal/molecules. We have synthesized hundreds of these compounds and screened their anti-proliferative activity towards mouse macrophage

Methods

Results

Conclusion