Original article
Total synthesis and biological evaluation of clavaminol-G and its analogs

https://doi.org/10.1016/j.ejmech.2013.07.001Get rights and content

Highlights

  • First total synthesis of clavaminol-G (1) and 1-aminoundecan-2-ol (2).

  • Synthesized derivatives of 2 with COOCH3 (3), COOH (4) and OH (5) functional groups.

  • All compounds (15) were evaluated for cytotoxic and antimicrobial activities.

  • 1-Aminoundecan-2-ol (2) exhibited promising cytotoxic and antimicrobial activities.

Abstract

The first total synthesis of clavaminol-G (1) and 1-aminoundecan-2-ol (2) has been achieved from 10-undecenoic acid using epoxidation, regioselective azidolysis and in situ detosylation and reduction reactions as key steps. The methodology is extended for the synthesis of 1-aminoundecan-2-ol derivatives; namely, methyl 11-amino-10-hydroxyundecanoate (3), 11-amino-10-hydroxyundecanoic acid (4) and 11-aminoundecan-1,10-diol (5). Among these, 1-aminoundecan-2-ol (2) exhibited good antimicrobial activity and promising cytotoxicity towards HeLa, MDA-MB-231, MCF-7 and A549 cell lines with IC50 values of 4.36, 4.02, 3.88 and 6.78 μM, respectively. Compound 3 exhibited good activity against HeLa cells (IC50 = 3.59 μM), while compound 5 showed moderate activity towards HeLa and A549 cell lines. Clavaminol G (1) and compound 4 showed no activity towards all the cell lines.

Graphical abstract

The total synthesis of clavaminol-G (1) and its derivatives was accomplished for the first time from 10-undecenoic acid (6) and they were further evaluated for cytotoxic and antimicrobial activities.

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Introduction

Amino alcohol functional groups are often found in many bioactive compounds with significant applications in synthetic and pharmaceutical chemistry. Different compounds containing amino alcohol moiety have been synthesized for use in various diseases [1]. Among the numerous amino alcohols, clavaminols A–N are a new class of 2-amino-3-alkanols with a wide range of bioactivities, such as anti-inflammatory, antibacterial, anticancer, anti-protozoal, anathematic and antifungal activities [2]. Structurally, these compounds are related to the widely distributed amphiphilic sphingosine derivatives. Due to the wide spectrum of biological activities, the clavaminols family has attracted increased attention by both synthetic organic chemists and biologists. Recently, marine organisms and ascidians (tunicates) have been identified as an enriched bioresource for these compounds. Searching for new bioactive compounds from marine origin, Aiello et al. reported clavaminols A–F [3], with cytotoxic properties against A549, T47D and AGS cell lines. Recently, Aiello et al. [4] isolated six new amino alcohols, clavaminols G–N from the Mediterranean ascidian Clavelina phlegrea. Clavaminol G (1) and its hydrolyzed product 1-aminoundecan-2-ol (2) are the marine-derived bioactive compounds isolated by Aiello and co-workers from the Mediterranean ascidian C. phlegrea. Clavaminol G and 1-aminoundecan-2-ol are the sphingoid-type bases, which contains a long saturated C11 alkyl chain with 1,2-aminoalcohol moiety. These naturally-occurring bioactive compounds exhibited moderate to good cytotoxicity against A549 (lung carcinoma) and AGS (gastric carcinoma) cell lines [4]. Due to these interesting structural pattern and bioactivities, the synthesis of clavaminol G and 1-aminoundecan-2-ol is considered important for the organic chemists. In continuation to our previous work [5] on the construction of bioactive naturally-occurring compounds, in the present study, we synthesized clavaminol G (1) and 1-aminoundecan-2-ol (2) from 10-undecenoic acid, which is derived from a renewable feedstock, castor oil. In addition, we also synthesized the compounds methyl 11-amino-10-hydroxyundecanoate (3), 11-amino-10-hydroxyundecanoic acid (4) and 11-aminoundecan-1,10-diol (5), the derivatives of 1-aminoundecan-2-ol (2) with –COOCH3, –COOH and –OH terminal functional groups, respectively. All these synthesized compounds, 15 were further evaluated for their biological activities. To the best of our knowledge, this is the first report on the total synthesis and biological evaluation of clavaminol G (1) and 1-aminoundecan-2-ol (2).

Section snippets

Chemistry

Our retrosynthetic analysis of compounds 1 and 2 is illustrated in Scheme 1. As indicated, compounds 1 and 2 could be synthesized from the azido tosylate 10, which in turn could be obtained from the epoxy alcohol 8. Compound 8 would be derived from readily available 10-undecenoic acid 6.

The synthesis of clavaminol G (1) and 1-aminoundecan-2-ol (2) (Scheme 2) was initiated with commercially available fatty acid namely, 10-undecenoic acid 6 which was converted to alcohol 7 in high yield (97%) by

Conclusion

In conclusion, we have developed a simple route for the total synthesis of a natural bioactive compounds clavaminol G (1) and 1-aminoundecan-2-ol (2) starting from commercially available 10-undecenoic acid. The key transformations involved in the synthesis are epoxidation, azidolysis and one-pot reduction of azido tosylate 10. All the steps involved in the present synthesis are high yielding and the applied reagents are readily available. This proposed synthetic route is straightforward,

General experimental

All reagents used were of analytical grade and were used as obtained from different commercially sources without any further purification. All dry reactions were carried out under nitrogen environment in oven-dried glassware using standard gas-light syringes, cannulas, and septa. Reactions were carried out using anhydrous solvents and were monitored on silica gel TLC plates (coated with TLC grade silica gel, obtained from Merck) employing iodine vapors for detection of spots. Column

Acknowledgments

The authors acknowledge the financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, India, in the form of Senior Research Fellowships (SRF) to T.V.K. Reddy and P. Sujitha.

References (17)

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