Hybrid quinolinyl phosphonates as heterocyclic carboxylate isosteres: Synthesis and biological evaluation against topoisomerase 1B (TOP1B)

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

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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.

Original languageEnglish
Article number784
JournalPharmaceuticals
Volume14
Issue8
Number of pages24
ISSN1424-8247
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Antiproliferative effect
  • Enzyme inhibition
  • Leishmaniosis effect
  • Quinolinyl phosphonates
  • Topoisomerase 1B

Fingerprint

Dive into the research topics of 'Hybrid quinolinyl phosphonates as heterocyclic carboxylate isosteres: Synthesis and biological evaluation against topoisomerase 1B (TOP1B)'. Together they form a unique fingerprint.

Cite this