Aim: The aim of this work was to synthesize fiscalin B, to pursuit the development of a library of derivatives and to investigate the derivatives for their potential antitumor activity.
Introduction: Marine organisms provided numerous novel compounds with sensational multiple pharmacological properties. The necessity of novel therapeutics has gain more importance especially because of the resistance associated to the current therapeutics and the inexistent treatments for incurable diseases. Fiscalin B is a fungal metabolite with a pyrazino[2,1-b]quinazoline-3,6-dione system reported to have significant biological activities.
Methods: Two methods were studied for synthesis – double cyclization and microwave assisted procedures. First method started with coupling reactions to form tripeptide of tryptophan methyl ester linked to N-Fmoc-valine via anthranilic acid. Then, the dehydrative cyclization was performed using formamide to form the intermediate oxazine. The coupling reaction to form the fiscalin B were achieved after deprotection.1 The second method is the coupling of anthranilic acid with N-Boc-valine to form Boc-protected benzoxazin-4-one by thermal heating conditions. Then, the addition of tryptophan methyl ester hydrochloride led to 4-quinazoline-3,6-dione scaffold by microwave irradiation.2 The cell growth inhibitory effect was investigated by the Sulforhodamine B assay.
Results: The use of amino acids with different configurations and different side chains or even the derivatization of the existing functional groups were enable the application of this synthetic methodology for a library of fiscalin B analogues. The formation yields of fiscalin B analogues were low, ranging from 3 to 16%. Eight derivatives were tested on non-small cell lung cancer (H460), colon adenocarcinoma (HCT15) and breast cancer (MCF7) human cell lines and showed moderate cytotoxic effects, with GI50 concentrations ranging from 30 to 80μM.
Conclusion: Significant differences were obtained between enantiomeric pairs.
Acknowledgements: To national funds provided by FCT, ERDF, and COMPETE under the projects PEst-C/MAR/LA0015/2013, QOPNA (FCT UID/QUI/00062/2013), PTDC/MAR-BIO/4694/2014 (POCI-01-0145-FEDER-016790), PTDC/AAG-TEC/0739/2014 (POCI-01-0145-FEDER-016793), and INNOVMAR, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR and grant reference NOVELMAR/BPD_2/2016-019. To University of Aveiro and FCT/MEC for the financial support to the QOPNA research project (UID/QUI/00062/2013) financed by national funds and co-financed by FEDER under the PT2020, and to the Portuguese NMR Network. S.L. thanks Erasmus Mundus Action 2 (LOTUS+, LP15DF0205) for full PhD scholarship.