Original articleDiastereoselective synthesis and bioactivity of long-chain anti-2-amino-3-alkanols
Graphical abstract
Highlights
▸ An improved diastereoselective synthesis of anti-2-amino-3-alkanols is reported. ▸ Seven long-chain anti-2-amino-3-alkanol natural products have been synthesized. ▸ In vitro study in human glioblastoma cell line SHG-44 undertook. ▸ These compounds induced cell death and inhibited cell proliferation.
Introduction
Sphingoid bases (also called sphingosines) are a class of naturally occurring long-chain 2-amino-3-alkanols. Since the first isolation of sphingosine (1) (Fig. 1), hundreds of sphingoid bases with considerable structural diversity have been isolated from plants and animals [1]. Due to the wide spectrum of biological activities, this family has attracted a lot of attention by both biologists and synthetic organic chemists [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Recently, marine organisms, ascidians (tunicates) and marine sponges have also been found to be the enriched sources of 1-deoxy-sphingoid bases [1]. In spite of their structural simplicity, these long-chain amino alcohols exhibit remarkable bioactivities, and are promising for the development of new anti-tumor agents [13]. 1-Deoxy-sphingoid bases have been shown to be more cytotoxic than sphingosine against HT29 cells [14]. In this context, spisulosine (2) (also referred as “ES-285”), isolated from the marine clam Spisula polynyma by Caudros et al. [15], is considered to be a novel anti-tumor compound and currently in Phase I clinical trial against solid tumor in Europe [16], [17]. Specially, spisulosine has shown the inhibition of cell proliferation in numerous tumor cell lines due to the disruption of actin stress fibers through Rho signaling pathway [15]. It has also been found to activate caspases 3 and 12 and to modify the phosphorylation of p53 [18]. In addition, clavaminols A ∼ N, a family of fourteen members isolated from the Mediterranean ascidian Clavelina phlegraea, also displayed biological cytotoxicity. Opposite to the 2S,3R-configuration of sphingosine, clavaminols A ∼ N possess 2R,3S-configuration in the anti-2-amine-3-alkanol motif [19], [20]. Clavaminols A–C and F were tested for their cytotoxic and pro-apoptotic properties and clavaminol A (3) was shown to be the most potent cytotoxic compound of this series in inducing cell death through activation of the apoptotic machinery. Interestingly, while clavaminols G–N have shown no significant cytotoxicity, the unnatural deacetylated product (8) of clavaminol N (6) showed a cytotoxic effect comparable to that of clavaminol A (IC50 ≈ 5 μg/mL) on two different tumor cell lines, human lung adenocarcinomic epithelial cells A549 and human gastric adenocarcinoma epithelial cell AGS. Similarly, the deacetylated product (7) of clavaminol H (5) showed significant cytotoxic activity in AGS cells, while it has no effect on lung cancer cell line A549 [19], [20]. Moreover, (2S,3R)-2-aminododecan-3-ol (9), the enantiomer of clavaminol A (3), is an antifungal agent isolated from the ascidian Clavelina oblonga in Brazil [21]. This compound displayed antifungal activity against Candida albicans ATCC 10231 and Candida glabrata with a MIC of 0.7 μg/mL and 30 μg/mL, respectively. Furthermore, xestoaminol C (10), isolated together with its congeners xestoaminols A and B from a Fijisponge xestospongia, sp., was extremely active in assay against reverse transcriptase with 95% inhibition at 1 mg/mL [22]. Apart from those mentioned above, many other bioactive long-chain 2-amino-3-alkanols have also been reported [23], [24].
In recent years, several synthetic approaches to these amino alcohols have been reported [8], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], including seven for spisulosine (2) [25], [26], [27], [28], [29], [30], [31], two for the deacetylated products (7) of clavaminol H [28], [32], and three for xestoaminol C (10) [8], [33], [34]. As a continuation of our longstanding interest in the synthesis of N-containing bioactive molecules [35], [36], [37], and in conjunction with our recent interest in the development of anti-tumor agents [38], [39], we were engaged in the synthesis of above-mentioned long-chain amino alcohols. In present study, we used Reetz approach [40], [41] with modification to synthesize sphingoid bases (Fig. 1), including spisulosine (2), clavaminols A and B (3 and 4), as well as the deacetylated products of clavaminols H and N (7 and 8), antifungal compound (9), and xestoaminol C (10). Moreover, we tested the effect of these synthetic compounds on cell toxicity and proliferation to elucidate their biological and pharmacological roles as anti-cancer agents.
Section snippets
Chemistry
All the molecules shown in Fig. 1 are vicinal amino alcohols with an anti stereochemistry and with either (2S,3R) or (2R,3S) configuration. Biosynthetically they are originated from l or d-alanine or serine [19], [20], [21]. Thus α-amino acids would afford a convenient starting point to access these compounds and the homologues and analogs thereof via the addition of an organometallic reagent to the α-amino aldehydes (Scheme 1) [42]. Among the methods available for the conversion of α-amino
Pharmacology
Cancer therapies predominantly focus on the anti-proliferation strategy as a number of studies have demonstrated and supported that tumor growth occurred upon imbalance between cell proliferation and apoptosis. It has been suggested that marine organisms be the potential sources for antineoplastic agents [59] and several compounds isolated from marine crops have been portrayed as anti-cancer candidates [60], [61], [62], [63]. Although recent reports showed that sphingosine and its derivatives
Results and discussion
In SHG-44 cells, all compounds were capable to induce cell toxicity at 50 μM and compounds 7, 9, 10 were found of the strongest effect among these compounds (10 μM of compound 7, 9, 10 inhibited cell growth with 60%, 80% and 100%, respectively) (Fig. 2). The extended studies showed that compound 7, 9, 10 demonstrated anti-proliferation property in SHG-44 cell with IC50 of 4.41 μM, 7.96 μM and 4.5 μM, respectively (Fig. 3). In contrast, compounds 4 and 8 were lack of anti-proliferation activity,
Conclusion
In summary, by the development of a one-pot Swern oxidation-organometallic reagent addition procedure, the Reetz’s method for the asymmetric synthesis of β-amino alcohols has been improved. Using this concise and versatile method, the asymmetric syntheses of seven naturally occurring or derived cytotoxic long-chain anti-2-amino-3-alkanols, including the first stereoselective synthesis of clavaminol B (4) and (2R,3S)-deacetylclavaminol N (8), have been achieved in ≥99% diastereoselectivities and
General methods
Melting points (M.p.) were determined on a Yanaco MP-500 micro melting point apparatus and were uncorrected. Infrared spectra were measured with a Nicolet Avatar 360 FT-IR spectrometer using film KBr pellet techniques. 1H and 13C NMR spectra were recorded in CDCl3 or CD3OD on a Bruker 400 spectrometer with tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield from TMS. Mass spectra were recorded by a Bruker Dalton ESquire 3000 plus liquid
Conflict of interest
None.
Acknowledgments
The authors are grateful to the National Basic Research Program (973 Program) of China (Grant No. 2010CB833200), the NSF of China (20832005), NFFTBS (No. J1030415), Fujian Province Health-Education Research Projects (WKJ2008-2-45) and Xiamen Science and Technology Key Program Grant (No. 3502Z20100006) for the financial support.
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