Cytotoxic Plakortides from the Brazilian Marine Sponge Plakortis angulospiculatus

Abstract

Three new plakortides, 7,8-dihydroplakortide E (1), 2, and 10, along with known natural products 3, 4, spongosoritin A (5), 6-8, and plakortide P (9), were isolated from Brazilian specimens of Plakortis angulospiculatus. Compounds 2, 3, 5, and 7-9 displayed cytotoxic activities with IC50 values ranging from 0.2 to 10 μM. Compounds that contained a dihydrofuran ring were generally less active and displayed time dependence in their activity. The activities of compounds 2 and 7-9, carboxylic acids bearing a common six-membered endoperoxide, were higher overall than for compounds 3 and 5. The modes underlying the cytotoxic actions of plakortides 2, 3, 5, 7, and 9 were further investigated using HCT-116 cells. While dihydrofurans 3 and 5 induce a G0/G1 arrest, six-membered peroxides 2, 7, and 9 delivered a G2/M arrest and an accumulation of mitotic figures, indicating a distinctly different antimitotic response. Confocal analysis indicated that microtubules were not altered after treatment with 2, 7, or 9, therein suggesting that the mitotic arrest may be unrelated to cytoskeletal targets. Overall, we find that two related classes of natural products obtained from the same extract offer cytostatic activity, yet they do so through discrete pathways.

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation

“…The residue obtained after acidic workup was further purified via preparative RP-HPLC to yield the pure acid ( 1 ). The structure of the compound was analyzed by 1 H, 13 C, correlation spectroscopy (COSY), and nuclear Overhauser exchange spectroscopy (NOESY) nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry and, according to the literature [29,33] and NOESY data, the pure acid was identified as a diastereomer of plakortide H acid, namely the 6-epimer. In fact, the NOESY data and coupling constants are in agreement with those found for plakortides M and N [29] and are in agreement with the literature [33] and thus, the same configuration was also assumed for the isolated compound, namely the ( R )-configuration at the 6-position and the ( R )-configuration at the carbon atom 10 [33].…”

“…The residue was purified using preparative RP-HPLC. Yellow viscous oil (4.1 mg); ${false[\mathrm{sans-serif\alpha }false]}_{\mathrm{D}}^{23}$ = −157.84 ( c 0.0037, CHCl 3 ) (reference [33] reports ${false[\mathrm{sans-serif\alpha }false]}_{\mathrm{D}}^{20}$ = −145 ( c 1.1, CHCl 3 )); ESI-MS: m/z 375.25 [M + Na] + , calcd. for C 21 H 36 O 4 , 352.51.…”

“…From a sample of this sponge, we isolated plakortide E ( 2 , Figure 1) and found that it was also active against trypanosomes [31]. Here, we report the cytotoxicity towards the drug-sensitive leukemia CCRF-CEM cell line (human Caucasian acute lymphoblastic leukemia, childhood T acute lymphoblastic leukemia) and its multi-drug resistant subline CEM/ADR5000 (multi-drug resistant CCRF cell line) (Table 2), of seven derivatives (Figure 1): the 6-epimer of the plakortide H acid ( 1 ) [32,33] along with the endoperoxides plakortide E ( 2 ), plakortin ( 3 ) [34,35,36], and dihydroplakortin ( 4 ) [36,37] that have been isolated from a sample of the Caribbean sponge Plakortis halichondrioides . In addition, the acid of plakortin, namely plakortic acid ( 5 ) [38,39], as well as the esters plakortide E methyl ester ( 6 ) [40,41] and the ester 6-epi-plakortide H ( 7 ) were synthesized by hydrolysis (plakortic acid) and Steglich esterification (plakortide E methyl ester and 6-epi-plakortide H), respectively, to perform a comparative study.…”

PPAR Modulating Polyketides from a Chinese Plakortis simplex and Clues on the Origin of Their Chemodiversity

“…However, the chemical and biological potential of Plakortis sponges is undoubtedly associated to their prolific production of 1,2-dioxane derivatives, exemplified by the antimalarial plakortin 5 and related plakortides. 6 These molecules are believed to share a propionate/butyrate-based polyketide biosynthetic origin, an hypothesis supported by the co-occurrence of analogues differing for the ketide unit (e.g. propionate in place of butyrate etc.)…”

“…Similarly, the structural elucidation of the new plakilactone I (7), was aided by comparison with data of plakilactone A (6). The molecular formula of 7 (C 15 H 26 O 2 ) lacked only a -CH 2 -unit compared to that of 6.…”