Synthesis of N-methylarylnitrones derived from alkyloxybenzaldehydes and antineoplastic effect on human cancer cell lines

Débora S S Costa; Thiago Martino; Fernanda C Magalhães; Graça Justo; Marsen G P Coelho; Julio C F Barcellos; Victor B Moura; Paulo R R Costa; Kátia C C Sabino; Ayres G Dias

doi:10.1016/j.bmc.2015.03.014

Synthesis of N-methylarylnitrones derived from alkyloxybenzaldehydes and antineoplastic effect on human cancer cell lines

Bioorg Med Chem. 2015 May 1;23(9):2053-61. doi: 10.1016/j.bmc.2015.03.014. Epub 2015 Mar 10.

Affiliations

¹ Laboratório de Química Bioorgânica, IPPN, CCS, s H1027, Cidade Universitária, Universidade Federal do Rio de Janeiro, Brazil.
² Laboratório Imunologia Aplicada e Bioquímica de Proteínas e Produtos Naturais, IBRAG, Universidade do Estado do Rio de Janeiro, Brazil.
³ Laboratório de Química Orgânica, Instituto de Química, Universidade do Estado do Rio de Janeiro, Brazil.
⁴ Laboratório de Química Orgânica, Instituto de Química, Universidade do Estado do Rio de Janeiro, Brazil. Electronic address: ayres.dias@gmail.com.

PMID: 25813896
DOI: 10.1016/j.bmc.2015.03.014

Abstract

New O-isoprenylated-N-methylarylnitrones derived from isomeric o, m and p-hydroxybenzaldehydes have been prepared and the antineoplastic effects on human cancer cell lines were evaluated. The O-geranylated nitrone LQB-278 (1b) and its isomers 2b and 3b inhibited the NO production, but the anti-leukemic activity was drastically dependent on nitrone isomer, with the 1b being the most effective one (IC₅₀ of 6.7 μM) on Jurkat leukemia cell, by MTT assay. In addition, 1b up-regulated p21CIP1/WAF1/Sdi1 protein expression (flow cytometry), a cell cycle inhibitor, reduced cell growth, and induced DNA fragmentation (increased sub-G1 phase cells) and phosphatidylserine externalization in plasmatic membrane (increased annexin V positive cells). Finally, the 1b up-regulation of p21 expression and apoptosis induction seem to be the mechanisms by which it promotes its anti-leukemic effects, making this new molecular architecture a promising prototype for leukemia intervention.

Keywords: Apoptosis; Cancer; Leukemia; Nitrones; O-Isoprenylated derivatives; p21CIP1/WAF1/Sdi1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzaldehydes / chemistry*
Cell Cycle / drug effects
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
K562 Cells
Mice
Molecular Structure
NIH 3T3 Cells
Nitric Oxide / antagonists & inhibitors
Nitric Oxide / biosynthesis
Nitrogen Oxides / chemical synthesis*
Nitrogen Oxides / chemistry
Nitrogen Oxides / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzaldehydes
Nitrogen Oxides
nitrones
Nitric Oxide