Hybrid Quinolinyl Phosphonates as Heterocyclic Carboxylate Isosteres: Synthesis and Biological Evaluation against Topoisomerase 1B (TOP1B).

Asier Selas,Birgitta R Knudsen,Concepcion Alonso,Francisco Palacios,Yolanda Pérez-Pertejo,Rafael Balaña-Fouce,María Fuertes,Estela Melcón-Fernández,Rosa M Reguera

doi:10.3390/ph14080784

Asier Selas, Birgitta R Knudsen + Show 7 more

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https://doi.org/10.3390/ph14080784

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Abstract

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action.

Highlights

Cancer is one of the most devastating diseases in spite of the substantial advances in the research of antitumor therapies
Povarov reaction a highly convenient approach for the synthesis of quinoline derivatives, giving place to a wide-ranging chemical diversity arising to the large reactant scope able to get involved in the Povarov reaction [25]. In light of these considerations and following with our previous work in the synthesis of new TOP1B inhibitors, we report the synthesis of novel hybrid quinoline derivatives with dialkylphosphonate substituents through the Povarov reaction between aminophenylphosphonates, aromatic aldehydes, and styrenes or acetylenes, and their biological evaluation as candidates for TOP1B inhibitors with antiproliferative and antileishmanial activities
The synthesis was performed by a [4 + 2] cycloaddition reaction from the corresponding phosphorated anilines, aromatic aldehydes, and olefins, by a two-step or MCR protocol, and subsequent oxidation of the quinoline derivatives with DDQ or directly by a [4 + 2] cycloaddition reaction with acetylenes used as dienophiles

Summary

Introduction

Cancer is one of the most devastating diseases in spite of the substantial advances in the research of antitumor therapies. The incidence of cancer worldwide is over 18 million people and the mortality near 10 million people (in 2018) [1], and research and discovery of new effective and selective drugs/therapies remains a challenge nowadays. Leishmaniasis is a neglected tropical disease, caused by parasitic protozoa of the Leishmania genus. Leishmaniasis is endemic in tropical and subtropical areas with annual case incidence ranging from 0.7 to 1 million and over 1 billion people living at risk [2]. The visceral form causes 20,000–30,000 deaths per year mostly in Sub-Saharan African countries. The current treatment of leishmaniasis is complicated and all existing drugs have significant side effects [3]

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