Chemical transformation and biological studies of marine sesquiterpene (S)-(+)-curcuphenol and its analogs

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Abstract

Chemical transformation studies of the marine sesquiterpene phenol (S)-(+)-curcuphenol (1), isolated from the Jamaican sponges Myrmekioderma styx, were accomplished. In order to optimize the activity and better understand the SAR of (S)-(+)-curcuphenol, nineteen semisynthetic analogs were prepared and evaluated for activity against infectious diseases. A number of analogs showed significant activity against Mtb and Leishmania donovani, while showed good to moderate activities in antibacterial and antifungal assays as well as against Plasmodium falciparium (D6 clone) and (W2 clone). The analogs a, c, h, and r exhibited Mtb activity with MICs of 24.6, 41.2, 6.90, and 50.5 μM, respectively. Analog f showed enhanced activity against L. donovani with an IC50 of 0.6 μM and IC90 of 40 μM respectively.

Introduction

(S)-(+)-Curcuphenol (1) is a biologically active sesquiterpene phenol that has been isolated from the marine sponges Didiscus oxeata, Didiscus flavus, Myrmekioderma styx, and Epipolasis sp. [1], [2], [3], [4]. (S)-(+)-Curcuphenol has shown activity against several human cancer cell lines (A-549, HCT-8, and MDAMB) with MIC's of 0.1–10 μg/mL [3]. A recent investigation showed 1 to have cytotoxicity against cancer cell lines in a manner independent of a p53 mechanism [18]. Additionally, (S)-(+)-curcuphenol inhibited activity of gastric H+, K+-ATPase by 50% at concentrations of 8.3 μM and 23 μM, respectively [4]. Both (+) and (−)-curcuphenol have been reported to have antimicrobial activity against Staphylococcus aureus [1], [5]. Furthermore, (S)-(+)-curcuphenol has shown activity against Candida albicans [1], [3], Cryptococcus neoformans [1], and methicillin-resistant S. aureus [1]. (S)-(+)-Curcuphenol and the closely related (S)-(+)-15-hydroxycurcuphenol (2) also display in vitro antimalarial activity against Plasmodium falciparium (D6 clone) and P. falciparium (W2 clone) (Fig. 1) [1]. The enantiomer, (R)-(−)-curcuphenol, has been isolated from the gorgonian soft coral Pseudopterogorgia rigida [5] and the terrestrial plant Lasianthaea podocephata [6], [7] and has shown activity against S. aureus and Vibrio anguillarum [5]. (R)-(−)-curcuquinone (3) and (R)-(−)-curcuhydroquinone (4) have also displayed activity against S. aureus and V. anguillarum. The closely related compound xanthorrhizol (5) has shown protective effects against cisplatin induced cytotoxicity and eliminated any cisplatin-induced DNA-binding activity of NF-κB [8]. Additionally, xanthorrhizol (5) has reported activity against C. albicans, toxicity to Artemia salina, and cytotoxicity against a human nasopharyngeal carcinoma cell line (KB) [9]. An enhancement of the antituberculosis activity of 1 was observed during administration with cyanthiwigin B (6) [2]. A recent study by Takamatsu et al. found 1 to have strong antioxidant activity but concluded that it may not enter into cells due to poor cellular uptake or reduced medium solubility [10]. Total enantioselective synthesis of curcuphenol and closely related compounds has been accomplished by numerous groups [11], [12], [13], [14], [15], [16], [17].

Semisynthetic studies of natural products have been a reliable method for the generation of more active and less toxic derivatives and establishment of structure–activity relationships (SAR) (Table 1). In an attempt to improve the activity and understand the SAR of (S)-(+)-curcuphenol (1), we report herein the chemical modification of 1 at the C1 position (Scheme 1). The twenty analogs reported here were evaluated for biological activity against several infectious diseases. The results from these assays can be seen in Table 2, Table 3, Table 4 and Table 5 of the Appendix.

The esterification of curcuphenol with a variety of carboxylic acids in the presence of N,N′-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) produced twenty analogs in yields greater than 90%. In all cases, the reactions proceeded efficiently at ambient temperatures and were complete within 20–24 h. Reactions using dichloromethane as a solvent yielded the best results. Esterification produced a number of cyclic and heterocyclic ester and the results are presented in Table 1. This method was effective for coupling of both simple as well as complex carboxylic acids, and it is noteworthy, that two of the carboxylic acids used in the coupling of curcuphenol are clinically used drugs. Diflunisal (used in formation of l) is a nonsteroidal analgesic, anti-inflammatory, and antipyretic drug. Chlorambucil (used in formation of m) is chemotherapeutic agent that is given as a treatment for some types of cancer.

Section snippets

General procedure

(S)-(+)-Curcuphenol (1) (0.75 mmol) was dissolved in dry methylene chloride (1.5 mL). To this solution, the carboxylic acid (0.75 mmol) and DMAP (catalytic amount) was added and stirred for about 5 min followed by the addition of DCC (0.75 mmol). The reaction was stirred at room temperature and the reaction progress was monitored using thin layer chromatography (TLC). The reaction was complete after 24 h. The reaction mixture was filtered and evaporated. The residue was fractionated on silica

Anti-HIV-1

Isoquinoline derivatives have previously been patented for treatment of HIV-1 through inhibition of HIV-1 reverse transcriptase [23], as HIV protease inhibitors [24], and even as viral entry inhibitors against HIV [25]. Additionally, indole alkaloids have been patented as HIV-1 reverse transcriptase inhibitors [26] and indole substitution has been reported to dramatically increase anti-HIV-1 activity [27]. It is therefore not surprising that analogs a, c, j, and r showed activity (EC50 31.2,

Conclusions

Recent investigations into curcuphenol and related compounds have yielded a variety of activity profiles and stereoselective strategies for its synthesis. Our study has reported derivatives of curcuphenol with increased activity against tuberculosis, anti-HIV-1, leishmania, and cancer. The most impressive of these activities is that of compound f with activity against leishmania almost a log order better than pentamidine. In addition, we report the lowest energy conformation for curcuphenol and

Acknowledgments

We gratefully acknowledge Dr. B. Avula for acquiring ESIMS. We are also indebted to J. Trott, S. Sanders and B. Smiley from the National Center for Natural Products Research (NCNPR) for antimicrobial testing and B. Tekwani for leishmania and malarial assays. Additionally, we are grateful to S. Franzblau and F. Zhang for Mtb assays and R. Schinazi, S. Wirtz, and P. Tharnish for the anti-HIV-1 assays. We appreciate J. Fiechtl assistance in the preparation of this manuscript. This work was

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