Antitumor activity of quinazolinone alkaloids inspired by marine natural products

• Autor(a) principal: Long S.
• Data de Publicação: 2018
• Outros Autores: Resende D.I.S.P., Kijjoa A., Silva A.M.S., Pina A., Fernández-Marcelo T., Helena Vasconcelos M., Sousa E., Pinto M.M.M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/120483
• topic: 4 (1h indol 3 ylmethyl) 1 isobutyl 2h pyrazino[2,1 b]quinazolin 3,6 (1h,4h) dione; 4 (1h indol 3 ylmethyl) 1 isobutyl 2h pyrazino[2,1 b]quinazoline 3,6 (1h,4h) dione; 4 (1h indol 3 ylmethyl) 1 isopropyl 2h pyrazino[2,1 b]quinazolin 3,6 (1h,4h) dione; 4 (1h indol 3 ylmethyl) 1 isopropyl 2h pyrazino[2,1 b]quinazoline 3,6 (1h,4h) dione; ABC transporter subfamily B; antineoplastic agent; fiscalin B; natural product; pyrazino[2,1 b]quinazoline 3,6 dione; quinazolinone derivative; unclassified drug; alkaloid; antineoplastic agent; biological product; quinazolinone derivative; antineoplastic activity; Article; chirality; controlled study; drug screening; drug structure; drug synthesis; enantiomer; enzyme modification; GI50; human; human cell; marine species; multidrug resistance; tumor cell line; aquatic species; chemical structure; chemistry; synthesis; Alkaloids; Antineoplastic Agents; Aquatic Organisms; Biological Products; Cell Line, Tumor; Humans; Molecular Structure; Quinazolinones

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. © 2018 by the authors.