Study On Synthesis Of Aspergiolide A And Its Analogues

Aspergiolide A is isolated from filamentous fungi Aspergillus glaucus HB-19ofmarine origin. It is a multi-target anti-cancer lead compounds which has a novelnaphtho[1,2,3-de]chromene-2,7-dione. In view of the unique structure and activitiesof aspergiolide A, we explored the total synthesis of Aspergiolide A and its analoguesto explore the structure-activity relationships and determine the active groups.Part1: Study on synthesis of aspergiolide ABasing on the biosynthetic pathway of Aspergiolide A, we synthesized1,3-dihydroxy-9,10-anthraquinone to conduct model reactions. i) we testedknoevenagel reaction of anthraquinone79with ethyl acetoacetate form theaspergiolide A skeleton; ii) we explored Reformatsky reaction of α-bromo butyrate ofanthraquinone79to obtain the aspergiolide A skeleton; iii) In addition, wesynthesized two1,4-anthraquinone as a substrate for the Hetero-Diels-Alder reactionto obtain aspergiolide A, Unfortunately, our efforts are not rewarded.Part2: Synthesis of analogues of aspergiolide ANaphtho[1,2,3-de]quinoline-2,7-diones are the anthraquinone derivativeswhich have four coplanar rings. Studies have shown that such compounds not onlypossess anti-tumor activity and anti-multidrug resistance activity, but also exhibitapoptosis signal-regulating kinase1(ASK1) inhibitory activity. Based on the structureand activity characteristics of aspergiolide A and Naphtho[1,2,3-de]quinoline-2,7-dione compounds, analogues of aspergiolide A using emodin as core structure weredesigned. Thus, we made4-amino emodin by means of regioselctive nitration ofemodin and reduction of nitro group. Finally,4-amino emodin reacted with11aliphatic and aromatic β-keto esters followed by removal of benzyl and methyl groupsas well as derivatization of nitro functionality to give rise to21analogues ofaspergiolide A which have3H-naphtho[1,2,3-de]quinoline-2,7-dione skeleton. Theirbioactive are being tested.Above all, we synthesized three key intermediates and explored their applications in the synthesis of Aspergiolide A. More importantly,21analogues ofaspergiolide A with the skeleton of3H-naphtho[1,2,3-de]quinoline-2,7-dione usingemodin as starting material were achieved, which open up a new opportunity fordiscovering new bioactive these commpounds.