Conformationally constrained sphingolipids such as anhydrophytosphingosines represented by jaspine B (also known as pachastrissamine) and its stereoisomers have become an attractive and timely target ...for total synthesis due to their significant biological activity as well as the unique structures. This review article describes the biological activity and chemistry of the natural jaspine B and its seven stereoisomers.
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A short and flexible construction of novel dihydrosphingosine-type analogues has been accomplished. The pivotal step of this approach was a cascade 3,3-sigmatropic rearrangement of a ...tris(imidate) substrate, which provided the core motif of our final compounds with three carbon–nitrogen bonds, including two consecutive stereocentres, starting from an l-erythrofuranose chiron. The subsequent cross-metathesis scenario allowed for the instalment of an alkyl side chain unit. Antiproliferative/cytotoxic screening of the target derivative revealed its capacity to alter the viability of both leukaemia and solid tumour cell lines.
In this paper we describe the efficient synthesis of d-ribo-phytosphingosine and its analogues commencing from the easily available l-erythrose chiron, which already contained the future C-3 and C-4 ...stereocentres of our target compounds. Construction of the remaining C-2 stereochemistry relied on aza-Claisen rearrangements to establish the desired vicinal aminoalcohol motif. The aliphatic chain was introduced by means of an olefin cross metathesis process. Completion of this phytosphingolipid synthesis was then achieved through the suitable selection of functional group interconversions, accompanied by selective deprotection protocols. Preliminary in vitro experiments revealed higher antiproliferative activity of the unnatural d-arabino-phytosphingosine 3. HCl in comparison to cisplatin against three of the five cancer cell lines evaluated, with IC50 values ranging from 4.17 μM to 7.63 μM. Moreover, compound 3. HCl has better inhibitory effects on the proliferation of the aforementioned malignant cell lines than its natural stereochemical congener 2. HCl.
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•An approach to d-ribo-phytosphingosine and its analogues was achieved.•The strategy relied on sigmatropic rearrangements and OCM reaction.•The stereochemistry was assigned via X-ray analysis.•The target compounds were screened for anticancer activity.
A short synthetic route towards novel cytotoxic FTY720 analogues bearing a variously substituted azobenzene unit was developed. The target compounds were constructed either via a Wittig olefination ...or Mills reaction as the key processes. Preliminary biological screening revealed the antiproliferative activity of several newly synthesised derivatives against Jurkat, HeLa and HCT-116 cells to be quite promising, comparable or higher than the potency of cisplatin (Brinkmann et al., 2010) 1. The structure-activity relationship showed that a loss of the alkyl side chain on the azobenzene core or its substitution with hydroxymethyl moiety seem to be detrimental for the resulting cytotoxic profile in this series of derivatives. To probe the photochromic properties of the final derivatives, the reversible E/Z isomerisation and thermal relaxation rate were determined.
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A short synthetic approach to constructing pyrrolidine-containing sphingolipid-like derivatives has been accomplished. The cornerstone feature of the synthesis was a 3,3-heterosigmatropic ...rearrangement of an imidate derived from l-tartaric acid chiron, which completed the core motif of the target sphingomimetics carrying three consecutive stereocentres and a terminal vinyl. A late-stage olefin cross metathesis reaction installed an alkyl side chain with the flexibility for analogue construction. The results obtained from biological screening have completed the structure-activity relationships in a series of eight prepared stereoisomeric C-alkyl pyrrolidinediols and elucidated the role of the stereochemistry on the heterocyclic skeleton towards the studied anticancer profile.
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A successful strategy for the construction of novel isomeric aza-analogues 13. HCl and 14. HCl of natural jaspine B was developed by constructing a vicinal diamino motif via a sequential Overman ...rearrangement, followed by a pyrrolidine core formation through SN2 type cyclisation. The olefin cross metathesis reaction was selected to incorporate the alkyl side chain unit. Based on an antiproliferative/cytotoxic evaluation study, it was observed that the final products display significant potency on Jurkat and HeLa cell lines, with IC50 values in the low micromolar range.
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•Synthesis of novel aza-analogues of jaspine B was achieved.•The used strategy relied on sequential and simple 3,3-sigmatropic rearrangements, the OCM reaction and SN2 cyclisation.•The stereochemistry of key substructures was determined via crystallographic analysis.•The target pyrrolidines exhibit an ability to inhibit cancer cell proliferation.
Straightforward access to enantiomerically pure 3,4-diamino-3,4-dideoxyphytosphingosines, as novel analogues of natural d-ribo-phytosphingosine was accomplished, starting from two available chirons: ...dimethyl l-tartrate and d-isoascorbic acid. A sequential Overman rearrangement followed by late-stage introduction of the alkyl side chain moiety via olefin cross-metathesis is the cornerstone of this approach. The preliminary evaluation study of the synthesised sphingomimetics, based on their ability to inhibit a proliferation of human cancer cells, showed promising cytotoxicity against Jurkat and HeLa cells for (2R,3R,4S)-2,3,4-triaminooctadecan-1-ol trihydrochloride.
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•Construction of a small library of phytosphingomimetics was achieved.•Cascade rearrangement and metathesis were involved as pivotal steps.•The relative stereochemistry was determined via chemical correlations.•The target compounds were evaluated on a series of cancer cell lines (BLM/A2058, MCF-7, HCT-116, Jurkat, HeLa).
Straightforward access to a series of the cytotoxic sphingolipid-derived alkaloids possessing a pyrrolidine unit and a long hydrophobic side chain was accomplished. Two simple carbohydrate chirons, ...protected d- and l-erythrofuranose, were chosen as the starting material, and 3,3-sigmatropic rearrangements, a late stage cross metathesis and an intramolecular nucleophilic substitution were involved as the key transformations. The final analogues of natural broussonetines were evaluated for their capacity to alter the proliferation of cancer cells.
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•Synthesis of novel straight side chain broussonetine analogues was accomplished.•The used strategy relied on 3,3-sigmatropic rearrangements, the OCM reaction and SN2 cyclization.•The stereochemistry of a key substructure was determined via crystallographic analysis.•The target pyrrolidine-based alkaloids exhibit an ability to inhibit cancer cell proliferation.
A straightforward approach to a novel phytosphingosine-like ceramide has been accomplished. The cornerstone features of this divergent synthesis are a cascade Overman rearrangement of tris(imidate) ...to introduce three desired stereogenic centres via sequential chirality transfer and an effective olefin cross-metathesis to install a long side chain. The final unusual phytoceramides were evaluated for their capacity to inhibit the proliferation of cancer cell lines. The preliminary results revealed that compound 21 exhibits promising anticancer activity against HeLa and HCT-116 cells as well as the excellent selectivity in cytotoxicity (malignant vs non-malignant cell lines).
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•An approach to a phytosphingosine-like analogue was achieved.•The strategy relied on a cascade rearrangement and OCM reaction.•All stereocentres were installed with the complete chirality transfer.•The target compounds were screened for anticancer activity.
The chiron approach to pyrrolidine-containing isophytosphingosine base-like compounds 21.HCl-23.HCl was developed from the known d-glucofuranose template. The key step of the synthesis was a highly ...diastereoselective aza-Claisen rearrangement, which created the cornerstone of the target molecules carrying three consecutive stereocentres. Subsequent cross metathesis reaction allowed the installation of a long-chain unit. The five-membered ring formation was accomplished via an intramolecular SN2 process. A single crystal X-ray analysis of the key intermediates confirmed the (2R,3R,4R)- and (2S,3R,4R)-configuration seen in the final derivatives. A comparison of the cytotoxic activity of the novel sphingomimetics (21.HCl-23.HCl) with recently described analogues (compounds 61, 62 and their antipodes) revealed that their antiproliferative profile strongly depends on the stereochemistry of the pyrrolidine substituents as well as the length of the side chain unit. Moreover, with regard to their structure and recent literature findings, compound 22.HCl may possess β-GCase inhibitory activity.
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•The preparation of novel C-alkyl pyrrolidine-diols as sphingomimetics was achieved.•The used strategy relied on the aza-Claisen rearrangement, the OCM reaction and SN2 type cyclisation.•Stereochemistry of the key substructure was determined via crystallographic analysis.•The target compounds exhibit the ability to inhibit cancer cell proliferation.
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