Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

Abstract

Many fungal quinazolinone metabolites, which contain the methyl-indole pyrazino [1,2-<i>b</i>]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 (<b>4c</b>), and antienantiomers (<b>4b</b>, <b>5b</b>, and <b>5c</b>) were synthesized via a one-pot approach, while the syn enantiomers (<b>4a</b>, <b>4d</b>, <b>5a</b>, and <b>5d</b>) were synthetized by a multi-step procedure. These strategies used anthranilic acid (<b>i</b>), chiral <i>N</i>-protected α-amino acids (<b>ii</b>), and tryptophan methyl esters (<b>iii</b>) to form the core ring of pyrazino[2,1-<i>b</i>]quinazoline-3,6-dione scaffold. Four enantiomeric pairs, with different enantiomeric purities, were obtained with overall yields ranging from 7 to 40%. Compounds <b>4a</b>⁻<b>d</b> and <b>5a</b>⁻<b>d</b> were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and <b>5a</b>⁻<b>d</b> displayed GI₅₀ values ranging from 31 to 52 μM, which are lower than those of <b>4a</b>⁻<b>d</b>. Nevertheless, no effect on P-glycoprotein (P-gp) modulation was observed for all compounds. This study disclosed new data for fiscalin B (<b>4c</b>), as well as for its analogues for a future development of novel anticancer drug leads.