Chemistry of the fumiquinazolines and structurally related alkaloids

Resende, Diana I. S. P.; Boonpothong, Papichaya; Sousa, Emı́lia; Kijjoa, Anake; Pinto, Madalena

doi:10.1039/c8np00043c

Cited by 59 publications

(56 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Marine-derived indolylmethylpyrazinoquinazoline alkaloids, with a pyrazino[2,1- b ]quinazoline-3,6-dione linked to an indole moiety (Figure 1), have attracted our attention due to their promising antitumor activities [3], with epi -fiscalin A [4], fumiquinazoline A [5,6,7,8,9], fumiquinazoline G [7], and versiquinazolines [10] as the most active analogs. Moreover, the response of fiscalins A-C [11] and (−)-spiroquinazoline [12] (Figure 1A) as substance P inhibitors was also reported as a novel neuroprotective therapy in the intrastriatal 6-hydroxydopamine model of early stage of Parkinson’s disease (PD) [13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs by the Mazurkiewicz-Ganesan approach. The neuroprotection capacity of these compounds on the rotenone-damage human neuroblastoma cell SH-SY5y was evaluated using the MTT assay. Compounds 1, 3, 5, and 7 showed more than 25% protection. The antitumor activity was investigated using the sulforhodamine B assay and some compounds were tested on the non-malignant MCF-12A cells. Fumiquinazoline G (1) was the most potent compound, with GI50 values lower than 20 µM. Compounds 5, 7, and 11 were more active in all tumor cell lines when compared to their enantiomers. Compounds 5, 7, 10, and 11 had very little effect in the viability of the non-malignant cells. Differences between enantiomeric pairs were also noted as being essential for these activities the S-configuration at C-4. These results reinforce the previously described activities of the fiscalin B (3) as substance P inhibitor and fumiquinazoline G (1) as antitumor agent showing potential as lead compounds for the development of drugs for treatment of neurodegenerative disorders and cancer, respectively.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…These fumiquinazolines consist of a quinazolinone core fused to a piperazine or spiro ring. Their biochemical origin entails anthranilic acid, l-tryptophan, and l-alanine, and their biosynthesis was recently reviewed by Resende and colleagues [88]. The BGC of fumiquinazolines in A. fumigatus contains, among others, a transporter (Af12040), a monomodular NRPS (Af12050), an FAD-dependent monooxygenase (Af12060), an FAD-dependent oxidoreductase (Af12070), and a trimodular NRPS (Af12080) [89].…”

Section: Indolesmentioning

confidence: 99%

Alkaloids from Marine Fungi: Promising Antimicrobials

et al. 2020

View full text Add to dashboard Cite

Resistance of pathogenic microorganisms against antimicrobials is a major threat to contemporary human society. It necessitates a perpetual influx of novel antimicrobial compounds. More specifically, Gram− pathogens emerged as the most exigent danger. In our continuing quest to search for novel antimicrobial molecules, alkaloids from marine fungi show great promise. However, current reports of such newly discovered alkaloids are often limited to cytotoxicity studies and, moreover, neglect to discuss the enigma of their biosynthesis. Yet, the latter is often a prerequisite to make them available through sufficiently efficient processes. This review aims to summarize novel alkaloids with promising antimicrobial properties discovered in the past five years and produced by marine fungi. Several discovery strategies are summarized, and knowledge gaps in biochemical production routes are identified. Finally, links between the structure of the newly discovered molecules and their activity are proposed. Since 2015, a total of 35 new antimicrobial alkaloids from marine fungi were identified, of which 22 showed an antibacterial activity against Gram− microorganisms. Eight of them can be classified as narrow-spectrum Gram− antibiotics. Despite this promising ratio of novel alkaloids active against Gram− microorganisms, the number of newly discovered antimicrobial alkaloids is low, due to the narrow spectrum of discovery protocols that are used and the fact that antimicrobial properties of newly discovered alkaloids are barely characterized. Alternatives are proposed in this review. In conclusion, this review summarizes novel findings on antimicrobial alkaloids from marine fungi, shows their potential as promising therapeutic candidates, and hints on how to further improve this potential.

show abstract

“…In the marine world, amino acids are important building blocks associated with diverse structures with medley complexity, particularly alkaloids from marine-derived fungi. Studies on the isolation, biosynthesis, synthesis, and biological activities of the pyrazino[2,1- b ]quinazoline-3,6-dione core linked to an indole moiety have been increasing significantly in the last 20 years [ 1 , 2 , 3 , 4 ]. Structurally, these quinazolinone alkaloids have been classified from simple to complex structures and consist of three different building blocks—anthranilic acid, α-amino acids, and tryptophan moieties that merge into a simple ring system [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Naturally occurring and synthetic fiscalin B ( 1 ) have been reported for their activities such as substance P inhibition [ 12 ], neuroprotective [ 14 ], antitumor [ 15 ], and antimalarial [ 16 ]. However, the ADME profile of pyrazino[2,1- b ]quinazoline-3,6-diones, including these bioactive fungi-derived compounds, has not yet been reported [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones and Study of Their In Vitro Metabolic Profile

et al. 2021

Self Cite

View full text Add to dashboard Cite

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.

show abstract

Chemistry of the fumiquinazolines and structurally related alkaloids

Cited by 59 publications

References 106 publications

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

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

Alkaloids from Marine Fungi: Promising Antimicrobials

Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones and Study of Their In Vitro Metabolic Profile

Contact Info

Product

Resources

About