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 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.
Highlights
During the past ten years, great attention has been focused on drug development from MarineNatural Products (MNPs) as well as on their synthetic and semi-synthetic analogues
There are two main methods to synthesize compounds containing this scaffold (i) the Eguchi-aza Wittig approach that consists of a selective acylation of diketopiperazines with o-azidobenzoyl chloride, followed by dehydrative cyclization [23]; and (ii) the Mazurkiewicz–Ganesan approach, consisting of coupling of linear tripeptides followed by the isomerization of 4-imino-4H-3,1-benzoxozines to obtain the corresponding quinazolin-4-ones [24,25]
This marine-inspired synthesis can bring new insights into discovery of new lead compounds in the oncology area
Summary
Natural Products (MNPs) as well as on their synthetic and semi-synthetic analogues. While terrestrial sources such as higher plants and microorganisms have reached the limelight, the marine environment increasingly becomes the newest and untapped resource of bioactive compounds [1]. Approximately 80 secondary metabolites of this subclass, covering structurally diverse compounds, have been isolated from fungi, mainly of marine origin. These include (i) compounds containing only a substituted piperazine ring such as glyantrypine (2), isolated from the culture broth of the mangrove-derived fungus Cladosporium sp
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