Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products

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.

Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects

“…The reaction carried out using microwave with high temperature resulted not only in low yields of the products in the range of 2.2 to 21.7%, but also with a high degree of epimerization (Scheme 1). Contrary to what has been found in our previous study [16] that the reaction under a microwave irradiation was regioselective and yielded only anti isomers, the synthesis of 8 , by a microwave irradiation, produced also its syn epimer, 9 [4-(benzyloxy)-1-methylbenzyl at C-1], with a 22% yield. This study suggested that microwave irradiation is beneficial for the synthesis of quinazolinone alkaloids with bulky substituents at C-1 which was previously reported as unsuccessful by Mazurkiewicz-Ganesan method [17].…”

“…Surprisingly, 4 and 5 , with three stereogenic centers, gave a higher enantiomeric ratio (er) of 99%. Similar to the previous report for fiscalin B analogs [16], the multi-step approach gave a better yield and, in most cases, higher enantiomeric ratios due to milder conditions; nonetheless, the one-pot reaction is a faster alternative to provide anti enantiomers with diversity of substituents at C-1.…”

“…The oxazole intermediates were obtained by adding the dehydrating agent, triphenylphosphine (Ph 3 P), and I 2 to dehydrate β-keto amide v or ix , and N-deprotection by 20% piperidine afforded 1 and 2 . On the other hand, a highly effective and environmentally friendly approach using a microwave-assisted multicomponent polycondensation of amino acids was used to prepare a series of the anti enantiomers of pyrazinoquinazoline alkaloids [18], as described in our previous work [16]. This methodology was used to synthesize new derivatives of fiscalin B ( 3 ) and fumiquinazoline G ( 1 ), 4, 5, 6 , 7 , and 8 (Scheme 1B).…”

“…[15] reported that proteomimetic l -tyrosine of l -DOPA is cytotoxic in vitro and capable of generating protein aggregation, whereas non-protein amino acid β-methylamino- l -alanine (BMAA) has been linked to neurological diseases such as amyotrophic lateral sclerosis (ALS) and PD since BMAA was detected in brain protein of LAS and PD patients. In the previous work, we have described syntheses of a series of fiscalin B derivatives, which showed weak to moderate antitumor activity against non-small cell lung cancer (NCI-H460) and colorectal adenocarcinoma (HCT-15) cell lines [16]. These findings led us to develop a small library of proteomimetic quinazolinone-derived compounds (Figure 1B) with different configurations at C-1 and C-4 to investigate their action on neurodegenerative disorders as well as to further explore their potential as tumor cell growth inhibitors, putting in evidence the influence of the stereochemistry of the derivatives.…”

Evodiamine Induces Apoptosis in SMMC-7721 and HepG2 Cells by Suppressing NOD1 Signal Pathway

“…Therefore, the development of novel and less toxic therapeutic agents is imperative to reduce high morbidity and mortality rates associated with HCC. Over the years, the antitumor effect of natural products has been a key therapeutic strategy for treatment of cancers [ 32 , 33 , 34 ]. Alternation of oncogenes and tumor suppressor genes could induce transformation of normal cells and tumor cells in the process of tumorigenesis [ 35 ].…”