Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and structure-activity relationship studies

Abstract

Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.

Troponoid Compounds as Therapeutic Agents and as Targets and Templates for Chemical Synthesis

“…16,27 Colchicine derivatives also hold some promise as immunosuppressive agents. 28 Compounds embodying the -hydroxy--tropolone motif (30) (Figure 6), and that not only include puberulic acid (17) and manicol (19) (see above) but also puberulonic acid (31) and the xenovulene A metabolite 32, are notable for their broad range of biological activities that include anti-malarial, 12,29 antibacterial, 30 anti-fungal 31 and anti-viral ones. 32 The benzotropolone purpurogallin (33) (Figure 7), a readily prepared synthetic analogue 34 and the natural product -thujaplicin (13) have each recently been reported to display usefully selective cytotoxic properties.…”

“…Compounds embodying the α′-hydroxy-α-tropolone motif ( 30 ) (Figure 6 ), that not only include puberulic acid ( 17 ) and manicol ( 19 ) (see above) but also puberulonic acid ( 31 ) and the xenovulene A metabolite 32 , are notable for their broad range of biological activities that include antimalarial, 12 29 antibacterial, 30 antifungal 31 and antiviral ones. 32…”

“…11 Stipitatic acid (16) 1b and its hydroxylated counterpart puberulic acid (17) are mold metabolites displaying pronounced antifungal effects. More recently the latter has been identified as a notable antimalarial agent 12,13 while its co-metabolite viticolin C ( 18) is much less active in this regard. 13 As with other polyhydroxylated tropones (see below), the sesquiterpene manicol (19) 14 possesses both antiviral and cytotoxic properties.…”

Antiviral activity of amide-appended α-hydroxytropolones against herpes simplex virus-1 and -2

“…19 Meanwhile, HSV-1 pUL12 has alkaline nuclease activity essential for in vivo function. 20 One challenge associated with developing aHTs as drugs has been the scarcity of synthetic methods available to make structural variants of them, 21 and up until very recently 22 all synthetic chemistry-driven structure-function studies on the chemotype relied on direct modication of either 3,7-dihydroxytropolone 23 or manicol. 24 Of late, oxidopyrylium cycloaddition/ring-opening strategies have emerged that are highly effective for aHTs synthesis 25 and the strategy has been exploited in various medicinal chemistry-based pursuits, including against HSV-1 and -2.…”

Synthesis and biological assessment of 3,7-dihydroxytropolones

“…7 During the preparation of this manuscript, a galactose-based method previously used by Sunazuka and Omura to synthesize puberulic acid 8 was further adapted to develop a small library of both 3,7-dHTs and αHTs (Scheme 1B), as well as other related troponoids. 9 Testing of these molecules for their antimalarial activity revealed that a carboxylic acid was key to providing selectivity against Plasmodium falciparum K1 versus MRC-5 cells, and it did so whether on an αHT or a 3,7-dHT, but provided more selectivity with 3,7-dHT. These studies highlight the value in a divergent, unifying strategy in SAR determination of oxygenated troponoids, and their importance in assessing the inhibitory potential of these oxygenated troponoids.…”