Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-07-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/16/8/261 |
| _version_ | 1811277848495783936 |
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| author | Solida Long Diana I. S. P. Resende Anake Kijjoa Artur M. S. Silva André Pina Tamara Fernández-Marcelo M. Helena Vasconcelos Emília Sousa Madalena M. M. Pinto |
| author_facet | Solida Long Diana I. S. P. Resende Anake Kijjoa Artur M. S. Silva André Pina Tamara Fernández-Marcelo M. Helena Vasconcelos Emília Sousa Madalena M. M. Pinto |
| author_sort | Solida Long |
| collection | DOAJ |
| description | 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 4a–d and 5a–d were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5a–d displayed GI50 values ranging from 31 to 52 μM, which are lower than those of 4a–d. 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. |
| first_indexed | 2024-04-13T00:24:06Z |
| format | Article |
| id | doaj.art-fff3188f455242068df7dd5b511d8012 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-13T00:24:06Z |
| publishDate | 2018-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-fff3188f455242068df7dd5b511d80122022-12-22T03:10:39ZengMDPI AGMarine Drugs1660-33972018-07-0116826110.3390/md16080261md16080261Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural ProductsSolida Long0Diana I. S. P. Resende1Anake Kijjoa2Artur M. S. Silva3André Pina4Tamara Fernández-Marcelo5M. Helena Vasconcelos6Emília Sousa7Madalena M. M. Pinto8Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalInterdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Lexões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, PortugalQuímica Orgânica, Produtos Naturais e Agroalimentares (QOPNA), Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugali3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugali3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugali3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalLaboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, PortugalMany 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 4a–d and 5a–d were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5a–d displayed GI50 values ranging from 31 to 52 μM, which are lower than those of 4a–d. 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.http://www.mdpi.com/1660-3397/16/8/261antitumorenantiomersfiscalinsquinazolinonessynthesis |
| spellingShingle | Solida Long Diana I. S. P. Resende Anake Kijjoa Artur M. S. Silva André Pina Tamara Fernández-Marcelo M. Helena Vasconcelos Emília Sousa Madalena M. M. Pinto Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products Marine Drugs antitumor enantiomers fiscalins quinazolinones synthesis |
| title | Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products |
| title_full | Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products |
| title_fullStr | Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products |
| title_full_unstemmed | Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products |
| title_short | Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products |
| title_sort | antitumor activity of quinazolinone alkaloids inspired by marine natural products |
| topic | antitumor enantiomers fiscalins quinazolinones synthesis |
| url | http://www.mdpi.com/1660-3397/16/8/261 |
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