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Mar. Drugs 2018, 16(8), 261; https://doi.org/10.3390/md16080261

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

1
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
2
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
3
ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
4
Química Orgânica, Produtos Naturais e Agroalimentares (QOPNA), Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
5
i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
6
Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
7
Department of Biochemistry, FCUP—Faculty of Sciences of the University of Porto, 4169-007 Porto, Portugal
8
Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
*
Author to whom correspondence should be addressed.
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)
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Abstract

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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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