Halogenated Diterpenes with In Vitro Antitumor Activity from the Red Alga Sphaerococcus coronopifolius

Abstract

Eight new (1-8) structurally diverse diterpenes featuring five different carbocycles were isolated from the organic extracts of the red alga Sphaerococcus coronopifolius collected from the coastline of the Ionian Sea in Greece. The structures of the new natural products, seven of which were halogenated, and the relative configuration of their stereocenters were determined on the basis of comprehensive spectroscopic analyses, including NMR and HRMS data. Compounds 5 and 8 were found to possess in vitro antitumor activity against one murine and five human cancer cell lines with mean IC 50 values 15 and 16 µM, respectively.Cancer is one of the most serious, complicated to cure and frequently deadly diseases, and carries huge economic impact in modern societies. The estimated number of cancer cases in the world accounts for approximately 15% of worldwide mortality. Ominous predictions of a 68% increase in cancer incidents globally by 2030 necessitate the discovery of novel chemotherapeutic agents [2]. Over 60% of antineoplastic drugs, including approved pharmaceuticals and molecules under clinical evaluation, can be traced back to natural sources [3].Sphaerococcus coronopifolius Stackhouse 1797, a bright, scarlet red seaweed, growing on rock subtidal habitats, with a wide distribution throughout the Mediterranean Sea and the East Atlantic Ocean, has shown to be a prolific source of structurally interesting diterpenes, most of which possess at least one bromine atom . These secondary metabolites have exhibited a wide range of bioactivities, such as antibacterial [20,22,25,26,28,29], cytotoxic/antitumor [18,21,24,28], antimalarial [20], anti-inflammatory [30], and antifouling [27].As part of our ongoing interest in the discovery of novel bioactive metabolites of natural origin from marine organisms, we have focused on the chemical constituents of the red alga S. coronopifolius, which is sporadically encountered along the rocky Greek coastlines. A population of this alga previously collected in Liapades Bay at Corfu island afforded three structurally unique diterpenes, including spirosphaerol, anthrasphaerol and corfusphaeroxide [31]. Herein, we report the isolation and structure elucidation of eight new diterpene alcohols (1-8) (Figure 1) from another population collected later from another site in the Ionian Sea, including (i) four tetracyclic halogenated diterpenes, namely iodocoronol (1), the 14-iodo-substituted derivative of coronopifoliol [13], bromocoronol (2), the corresponding 14-bromo-substituted analogue, bromotetrasphaereniol (3), the ∆ 3,18 unsaturated 14-deoxy derivative of bromotetrasphaerol [14], and the methoxy derivative 4 of ioniol I [26], (ii) two bicyclic diterpenes, corotrienone (5) featuring the sphaerococcenol-like [5] α,β-unsaturated ketone analogue of bromocorodienol [12], and the double-bond positional isomer iso-bromocorodienol (6), and (iii) two brominated 6/6/6 tricyclic diterpenes, debromosphaerol (7), the unusual B/C cis-fused 17-debromo analogue of bromosphaerol [4], and the methoxy deri...

Marine natural products

“…406 Eight new halo-diterpenoids 913-920 were isolated from a Sphaerococcus species. 407 Other reports of red algal metabolites were published but the structures are inconsistent with the experimental data reported and are not shown here. 408,409 The total synthesis of laurendecumallene B has been achieved.…”

Antifouling Activity of Halogenated Compounds Derived from the Red Alga Sphaerococcus coronopifolius: Potential for the Development of Environmentally Friendly Solutions

“…A series of chromatographic separations of the CH 2 Cl 2 / MeOH extract of the red alga S. coronopifolius, collected in Agios Giannis bay off Parga in Greece, resulted in the isolation of 14 diterpenes (1-14) and one sesquiterpene (15) as the major constituents. By comparison of their spectroscopic and physical characteristics with those reported in the literature, the isolated metabolites were identified as bromosphaerol (1) [33,34], 12S-hydroxybromosphaerol (2) [35,36], 12R-hydroxy-bromosphaerol (3) [36,37], sphaerococcinol A (4) [38,39], 14R-hydroxy-13,14-dihydro-sphaerococcinol A (5) [36], 8-methoxy-dihydrosphaerococcenol (6) [40], 2S-hydroxy-isobromosphaerol (7) [41], bromosphaerol B (8) [36], bromosphaerodiol (9) [42], 1S-hydroperoxy-12S-hydroxy-bromosphaerodiol B (10) [36], 1S-hydroperoxy-12R-hydroxy-bromosphaerodiol B (11) [36], 1S-hydroxy-1,2-dihydrobromosphaerol (12) [41,43], bromotetrasphaerol (13) [37], 12R-hydroxy-bromocorodienol (14) [44] and allo-aromadendrene (15) [45] (Figure 1).…”

Anticancer Compounds Derived from Marine Diatoms

“…The discovery of cancer therapies from marine sources is highly relevant to combat cancer. More than 60% of anti-tumor drugs are derived from natural sources, including the confirmed pharmaceuticals and molecules, which are currently under clinical trials [6]. Biologically-active molecules isolated from nature have greatly contributed towards the development of new drugs for different human diseases [7].…”