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Molecules. 2019 Feb 1;24(3). pii: E534. doi: 10.3390/molecules24030534.

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

Author information

1
Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. up201502099@ff.up.pt.
2
Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. dresende@ff.up.pt.
3
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal. dresende@ff.up.pt.
4
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal. ankijjoa@icbas.up.pt.
5
ICBAS-Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal. ankijjoa@icbas.up.pt.
6
Organic Chemistry and Natural Products Unit (QOPNA), Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. artur.silva@ua.pt.
7
Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal. ricardojorgefernandes@gmail.com.
8
Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal. ricardojorgefernandes@gmail.com.
9
Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal. cristinax@ipatimup.pt.
10
Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal. cristinax@ipatimup.pt.
11
Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal. hvasconcelos@ipatimup.pt.
12
Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135, Porto, Portugal. hvasconcelos@ipatimup.pt.
13
Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. hvasconcelos@ipatimup.pt.
14
Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. esousa@ff.up.pt.
15
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal. esousa@ff.up.pt.
16
Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. madalena@ff.up.pt.
17
Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Matosinhos, Portugal. madalena@ff.up.pt.

Abstract

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.

KEYWORDS:

antitumor; enantioselectivity; fiscalin B; fumiquinazoline; neuroprotection; quinazolinones

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