Aplysqualenols A and B: Squalene-Derived Polyethers with Antitumoral and Antiviral Activity from the Caribbean Sea Slug Aplysia dactylomela

Abstract

The novel bromotriterpene polyethers aplysqualenol A (1) and aplysqualenol B (2) have been isolated from the Caribbean sea slug Aplysia dactylomela collected in Puerto Rico, and their structures and relative configurational assignments established from spectroscopic data aided by quantum mechanical calculations of NMR chemical shifts. Although both these compounds may be conceived as polyoxycyclic derivatives of the C30 squalene skeleton, remarkably 1 and 2 possess an unprecedented C15 to C24 flexible chain of 14S* spatial disposition that contains a unique ether bridge between C16 and C19. Biological activity screening tests revealed that, although aplysqualenol A (1) does not have significant anti-infective properties, it possesses potent antitumoral and antiviral activities.

Keywords: Antitumor activity; Antiviral activity; Aplysia dactylomela; Polyether; Sea slug.

Figure 1

Diagnostic fragment ions (m/z) of aplysqualenol A (1) detected in the EI mass spectrum.

Figure 2

Plausible conformations of rings A–B–C–D in 1 showing selected NOESY correlations.

Figure 3

Minimum energy configurations of the four stereoisomer models 1a–1d considered for quantum mechanical calculations of ¹³C NMR isotropic shifts. The hydrogen atoms have been omitted for clarity. Oxygen atoms are indicated in red. Hydrogen bonds are represented as dashed lines between the donor hydrogen and the acceptor atom. Bonds with less than ideal geometry are displayed with a blue tint. The intensity of the colour increases as the bond becomes less ideal.

Figure 4

Deviations from the average of the carbon chemical shifts of distereomers 1a-1d. The x and y axes represent position number and Δδ in parts per million, respectively. To discriminate between stereoisomers 1a and 1b (the two most likely structures for aplysqualenol A on the basis of the calculation results shown in Table 3), a careful analysis was done on individually calculated ¹³C chemical shifts for carbons C22 and C30, which were expected to experience larger variations upon inversion of configuration at C22. As shown here, very large differences in the Δδ ¹³C values of 1a and 1b were observed for C22 and C30 (+11.9 vs +4.0 and −7.8 vs −3.0, respectively), suggesting again the exclusion of stereoisomer 1a.

Scheme 1

Proposed biogenetic pathway for aplysqualenol A (1).