Synthesis and biological assessment of 3,7-dihydroxytropolones

Abstract

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

“…Based on the requirement for divalent metal (Mg ++ ) at the DNA polymerase and RNase H active sites of HBV P protein, α–HTs, which we [ 11 ], and others [ 9 , 13 , 15 , 25 , 26 , 39 ] have studied extensively as viral RNase H inhibitors, were a logical starting choice. However, despite showing good activity against recombinant HBV RNase H, α–HTs were poorly active in inhibiting minus-strand priming.…”

“…Compounds 196 , 272 , and 362 were reported Hirsch et al [ 39 ] (as compounds 6a, 6c, and 6e, respectively), 111 , 113 , 146 , and 335 , by Lomonosova et al [ 26 ], compounds 231 , 232 , 233 , 234 , and 235 by Berkowitz et al [ 43 ], and compound 055G by D’Erasmo et al [ 44 ] (as compound 4n). N -hydroxypyridinediones 514 and 667 have been reported by Tavis et al [ 30 ].…”

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile

“…3). 8 While studies are ongoing to establish the likely mechanism of action, certain aHTs are known to inhibit at least two HSV-1 nucleases, UL15 19 and UL12, 20 and also act synergistically with current antivirals. 14 aHTs also have demonstrable activity against other herpesviruses including human cytomegalovirus 5b and Kaposi's sarcoma-associated herpesvirus, 21 as well as several animal herpesviruses.…”

“…7 This strategy is highly effective at installing a variety of functionalities at position 4 (inset, Scheme 1). However, installing functionality at the 3 position, adjacent to the metalbinding oxygens, is more laborious using this strategy, 8 and it is not clear at present how the method could install functionality at both the 3-and 6-positions. Given this proximity, it would be expected that molecules with appendages at the 3 and/or 6 positions would more readily engage protein targets either positively or negatively, and as a result have a more dynamic biological activity prole.…”

Oxidopyrylium [5+2] cycloaddition chemistry: Historical perspective and recent advances (2008–2018)

“…Our group has been interested in oxidopyrylium cycloaddition chemistry for the synthesis of hydroxytropolones, which have a broad range of therapeutic potential owing to their ability to inhibit various therapeutically relevant dinuclear metalloenzymes. 86 We have recently expanded upon this synthetic work to include 3,7-dihydroxytropolones, 87 which are found in the natural products puberulic and puberulonic acid. 88 Inspired by recent studies by Cox and coworkers on the biosynthesis of the related natural products stipitatonic and stipitatic acid, 89 we synthesized the 3,7-dihydroxytropolone analog of stipitalide ( 47.1 ) through a related approach (Scheme 47).…”