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Open AccessArticle

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Lexões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal
ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Química Orgânica, Produtos Naturais e Agroalimentares (QOPNA), Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
Department of Biochemistry, FCUP—Faculty of Sciences of the University of Porto, 4169-007 Porto, Portugal
Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
Author to whom correspondence should be addressed.
Mar. Drugs 2018, 16(8), 261;
Received: 11 June 2018 / Revised: 13 July 2018 / Accepted: 26 July 2018 / Published: 31 July 2018
(This article belongs to the Special Issue Synthesis of Marine-Derived Compounds)
Many fungal quinazolinone metabolites, which contain the methyl-indole pyrazino [1,2-b]quinazoline-3,6-dione core, have been found to possess promising antitumor activity. The purpose of this work was to synthesize the enantiomeric pairs of two members of this quinazolinone family, to explore their potential as antitumor and their ability to revert multidrug resistance. The marine natural product fiscalin B (4c), and antienantiomers (4b, 5b, and 5c) were synthesized via a one-pot approach, while the syn enantiomers (4a, 4d, 5a, and 5d) were synthetized by a multi-step procedure. These strategies used anthranilic acid (i), chiral N-protected α-amino acids (ii), and tryptophan methyl esters (iii) to form the core ring of pyrazino[2,1-b]quinazoline-3,6-dione scaffold. Four enantiomeric pairs, with different enantiomeric purities, were obtained with overall yields ranging from 7 to 40%. Compounds 4ad and 5ad were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5ad displayed GI50 values ranging from 31 to 52 μM, which are lower than those of 4ad. Nevertheless, no effect on P-glycoprotein (P-gp) modulation was observed for all compounds. This study disclosed new data for fiscalin B (4c), as well as for its analogues for a future development of novel anticancer drug leads. View Full-Text
Keywords: antitumor; enantiomers; fiscalins; quinazolinones; synthesis antitumor; enantiomers; fiscalins; quinazolinones; synthesis
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MDPI and ACS Style

Long, S.; Resende, D.I.S.P.; Kijjoa, A.; Silva, A.M.S.; Pina, A.; Fernández-Marcelo, T.; Vasconcelos, M.H.; Sousa, E.; Pinto, M.M.M. Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products. Mar. Drugs 2018, 16, 261.

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