Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

Dusan Sladic,Miroslav Gasic

doi:10.3390/11010001

Abstract

A review of results of bioactivity and reactivity examinations of marine sesquiterpene (hydro)quinones is presented. The article is focused mostly on friedo- rearranged drimane structural types, isolated from sponges of the order Dictyoceratida. Examples of structural correlations are outlined. Available results on the mechanism of redox processes and examinations of chemo- and regioselectivity in addition reactions are presented and, where possible, analyzed in relation to established bioactivities. Most of the bioactivity examinations are concerned with antitumor activities and the mechanism thereof, such as DNA damage, arylation of nucleophiles, tubulin assembly inhibition, protein kinase inhibition, inhibition of the arachidonic cascade, etc. Perspectives on marine drug development are discussed with respect to biotechnological methods and synthesis. Examples of the recognition of validated core structures and synthesis of structurally simplified compounds retaining modes of activity are analyzed.

Highlights

The general structure of the first rearranged drimane containing sesquiterpenes, namely avarol (1), avarone (2) and their derivatives, was established by standard analytical methods, chemical degradation [13,14,15] and later by stereocontrolled synthesis [16]
The error was later corrected [8] by chemical degradation and correlation of the circular dichroism (CD) measurement data of the obtained products with those of compounds with firmly established stereochemistry to show that sesquiterpenoids 1, 2 and 3 have the same absolute stereochemistry, i.e. 5S,8S,9R,10S
Along with the efforts to correlate the stereochemistry of drimane- and 4,9-friedodrimane sesquiterpene quinones by instrumental methods, it was shown that through adequate reasoning and the use of simple chemical reactions, relevant conclusions can be reached concerning chirality, at particular carbon atoms

Summary

Structure

The general structure of the first rearranged drimane containing sesquiterpenes, namely avarol (1), avarone (2) and their derivatives, was established by standard analytical methods, chemical degradation [13,14,15] and later by stereocontrolled synthesis [16]. Along with the efforts to correlate the stereochemistry of drimane- and 4,9-friedodrimane sesquiterpene quinones by instrumental methods, it was shown that through adequate reasoning and the use of simple chemical reactions, relevant conclusions can be reached concerning chirality, (i.e. absolute stereochemistry) at particular carbon atoms. In this respect, by an acid catalyzed rearrangement of ilimaquinone (3) and isospongiaquinone (4), and of 5-epi-ilimaquinone (7) and 5epi-isospongiaquinone (8) (and vice versa), it was confirmed that both pairs yield the same mixture of products, unambiguously connected to ilimaquinone (Scheme 1) [17]. It is interesting to note that in acid catalyzed reactions of both ilimaquinone and avarol, a reversal of a friedo-like rearrangement takes place; formation of the tricyclic product 12 by avarol alkylation at C-1 (Scheme 3) was suggested to occur by a 1,2-H shift [17], involving an a priori less stable carbocation intermediate 11

Biosynthesis

Reactivity

H CH3 10

Marine pharmacology: perspectives

Findings

59 O HN CH COOH