Anticancer and Anti-inflammatory Sulfur-Containing Semisynthetic Derivatives of Sarcophine

Abstract

Cembranoids, compounds with 14-membered macrocyclic skeleton, are known to exhibit a wide range of biological activities including anticancer properties.1) Since 1998, sarcophine (1), a cembranoid diterpene, has been investigated for its potential as a chemopreventive agent. 2)Bioconversion of (1) yielded several hydroxylated metabolites.2) These metabolites showed improved activity, compared not only to sarcophine, but also to sarcophytol A (2), which is a structurally related and well established chemopreventive cembranoid.2,3) Despite the promising results, there was one additional attempt toward optimizing the anticancer activity of sarcophine.4) This attempt involved semisynthetic transformation of sarcophine and its lactone opened derivative yielding potent hydroxylated derivatives. 4)The Red Sea soft coral Sarcophyton glaucum is a rich source of sarcophine with yields up to 3% of animal, dry weight.5) The high yield along with promising bioactivity makes sarcophine an ideal target for semisynthetic modifications. Hence our goal is to generate a structurally diverse library of sarcophine derivatives and test their biological activities. Previous reports involved generation of oxygenated and nitrogen containing sarcophine derivatives.2,4,6) Our first attempt towards semisynthetic modification involved oxymercuration-demercuration and halogenation of sarcophine. 7)This study targets the generation of sulfur-containing derivatives of sarcophine by targetting the epoxide ring. Sulfurcontaining functionalities are known to confer anticancer properties to several natural and synthetic products.8-10) For example, the anticancer potential of garlic is attributed to its organic sulfides including allicin.10) Sulfur-containing compounds are known to promote detoxification, which helps the liver to breakdown carcinogenic substances.11) The anticancer potential of sarcophine and its derivatives was evaluated by studying their effect on the highly malignant ϩSA mammary epithelial cell proliferation. Finally, the potential of NSAID's in reducing the risk of several malignancies prompted the investigatation of the effect of the chemopreventive sarcophine and its derivatives on the release of inflammatory mediators like thromboxane B 2 and superoxide anion in activated rat neonatal microglia. 12) Results and DiscussionReaction of 1 with ammonium thiocyanate in the presence of antimony trichloride yielded two sulfur and nitrogen-containing derivatives 3 and 4 in reasonable yields.The HR-MS spectrum 3 displayed a molecular ion peak [MϩH] ϩ at m/z 376.1940, suggesting the molecular formula C 21 H 29 NO 3 S, and eight degrees of unsaturation. The IR absorption band at 2159 cm Ϫ1 indicated the presence of a thio- Sarcophine (1), a cembranoid diterpene is known to inhibit the process of tumorigenesis. Sarcophine can be isolated in large amounts from the Red Sea soft coral Sarcophyton glaucum and hence is an ideal target for semisynthetic or biocatalytic modifications. Hydroxylated derivatives of 1 were reported to improve its...

Antiproliferative potential of sarcophine and its semisynthetic sulfur-containing derivatives against human mammary carcinoma cell lines

“…Our previous studies supported that at lower concentrations; sarcophine may exert its antiproliferative potential by inducing the cyclindependent kinase (CDK) inhibitor, p21 WAF1/Cip1 expression, and residual DNA repair in the MCF-7 cells [11,12]. In this study, we further explored the anticancer activity of sarcophine and its sulfurcontaining derivatives (2)(3)(4)(5)(6) in two human mammary carcinoma cell lines (MCF-7 and MDA-MB-231), using various cell cycle progression markers.…”

“…The thiocyanate and 1,3-oxathilane-2-imine derivatives 2 and 3 were the most effective in arresting the cells in G0/G1 phase. A concomitant decrease in the cell populations at S and G2+M phases was also noticed with sarcophine and derivatives (2)(3)(4)(5). The derivative 6 was ineffective in both of the cell lines, probably because of its cis configuration, which resulted in a folded structure, thus preventing its binding with its targeted receptor site.…”

“…Figure 1 is a schematic representation of the preparation of sulfur-containing derivatives of sarcophine. The details of the structure elucidation for the compounds 2-6 are reported elsewhere [3].…”

“…3). On the other hand, mutant p53 does not induce the p21 WAF1/Cip1 expression [17], which could be the reason for why the MDA-MB-231 cells (1) and its sulfur-containing derivatives (2)(3)(4)(5)(6). Briefly, the cells were treated with the test compounds (100 lM) for 72 h, followed by flow cytometric analysis using CellQuest Pro software (Table 2).…”

“…In order to synthesize new derivatives with enhanced antiproliferative potential, several semisynthetic derivatives (2-6) of sarcophine ( Fig. 1) were generated by targeting the epoxide ring for the introduction of sulfur-containing functionalities [3]. The reaction of sarcophine with ammonium thiocyanate afforded cis thiocyanohydrin and 1,3-oxathilane-2-imine derivatives (2 and 3), whereas reaction with Lawesson's reagent yielded a thiol (4) and two cyclic phosphonate diester derivatives (5 and 6).…”