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Author(s): Long S.
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.
Title: Antitumor activity of quinazolinone alkaloids inspired by marine natural products
Publisher: MDPI
Issue Date: 2018
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. © 2018 by the authors.
Subject: 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
antineoplastic agent
biological product
quinazolinone derivative
antineoplastic activity
controlled study
drug screening
drug structure
drug synthesis
enzyme modification
human cell
marine species
multidrug resistance
tumor cell line
aquatic species
chemical structure
Antineoplastic Agents
Aquatic Organisms
Biological Products
Cell Line, Tumor
Molecular Structure
Source: Marine Drugs, vol. 16(8):261
Related Information: info:eu-repo/grantAgreement/FCT/5876/147268/PT
Document Type: Artigo em Revista Científica Internacional
Rights: openAccess
Appears in Collections:CIIMAR - Artigo em Revista Científica Internacional

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