Elsevier

Carbohydrate Research

Volume 344, Issue 13, 8 September 2009, Pages 1628-1631
Carbohydrate Research

First total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol—a glycoglycerolipid of a marine alga with a high inhibitor activity against human Myt1-kinase

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Abstract

The first total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol, a glycoglycerolipid isolated from a marine alga extract, is described. Starting from α-methylglucopyranoside the multistep strategy allows the stereoselective synthesis of the final compound using various protective group procedures as well as derivatization of partial molecule domains. The latter offers the development of lead structures for inhibitors of human Myt1-kinase.

Graphical abstract

The first total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol as potential Myt1-kinase inhibitor in 13 steps starting with α-methyl-d-glucopyranoside is described.

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Introduction

Resulting from a systematic search of potential anti-cancer agents from plants and marine organisms a range of constituents were isolated which showed a high activity in a human Myt1-kinase inhibition assay. Complex structure determination of the crude extract led to glycoglycerolipids including the most active compound (IC50 of 4 μg/mL) 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol (Scheme 1; compound 14).1

The human Myt1-kinase is a Thr-14 and Tyr-15 specific regulator of Cdc2-kinase activity. The inhibitory phosphorylation of Cdc2 is important for timing the entry into mitosis. Various studies have shown that premature activation of Cdc2 would lead to mitotic dysfunction and apoptosis.2 Inhibition of Myt1-kinase is predicted to cause premature activation of Cdc2.3, 4 Therefore inhibitors of Myt1-kinase are supposed to kill rapidly proliferating cells and interfere with cell cycle checkpoints. Such inhibitors could represent an extension to conventional chemotherapy and could help overcoming resistance.

The rapid development in the field of kinase inhibitors is demonstrated by the commercial launch of imatinib and lapatinib recently. So the current research activity is promoted and accelerated by the development of suitable inhibitors as well as the conception of appropriate biochemical assays.2, 3 Thus, an innovative fluorescence polarization assay for Wee1- and Myt1-kinases was described by Rudolph and Kristjansdottir that was established and expanded in our group for current measurements.5 All known selective (e.g., imatinib and lapatinib) and non-selective kinase inhibitors (e.g., staurosporine and K-252a) work by binding the ATP binding site of the kinases and therefore lead to inhibition of the enzyme activity of the protein competitively. There are only a few studies that deal with the interaction of glycolipids and kinases. Recently it could be shown by X-ray crystallography and surface plasmon resonance that simple glycolipids and fatty acid derivatives can bind to kinases and act as activators and inhibitors depending on the structural variation.6 For p38α kinase was shown that three molecules of n-octyl-β-d-glucopyranose can bind near the ATP binding site as well as in a lipid binding site. Based on a comparison of p38α crystal structures and our homology model of Myt1-kinase we can find structure analogies in the areas of the binding sites. Therefore we hypothesize that simple glycolipids as well as the marine glycoglycerolipids have a similar binding mode in Myt1-kinase.

Searching for potential Myt1 inhibitors the isolated glycoglycerolipid represents an attractive target for neosynthesis and derivatization of molecule domains. Development of analogues as lead structures is in continuation of our work to glycolipids and is based on our knowledge on neosynthesis of natural products. Here we describe the first total synthesis of the title compound in 13 steps which strategy is shown in Scheme 1.7, 8, 9

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Results and discussion

Starting point of our synthesis was the commercially available and inexpensive α-methylglucopyranoside 1 which is characterized by stereoselective protection of the anomeric carbon atom.10 A modified method for tritylation of the primary hydroxyl group with triphenylmethylchloride (TrCl) in absolute pyridine and catalytic amounts of DMAP leads to compound 2 as considerable intermediate for selective derivatization of position C6.11 Benzylation of the secondary hydroxyl groups by use of a large

Conclusions

We describe the first total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol in a multistep strategy starting from α-methylglucopyranoside. The strategy also allows the selective modification of defined structure moieties of the synthesized glycoglycerolipid. The aim of our prospective investigations is the systematical derivatization of the carbohydrate domain, variances of length of the fatty acids and substitution of the core-structure. The

General methods

Mass spectra (MS) were recorded off-line with nano-ESI (Proxeon emitters, Odense, Denmark) on a LTQ-Orbitrap XL (Thermo Fisher Scientific, San Jose, USA). 1H NMR spectra were obtained with a Varian Inova 500 spectrometer operating at 500 MHz; all values are reported in ppm (δ) downfield from solvent. Polarimetric measurements were accomplished by an Eloptron/Polartronic E (Schmid+Haensch GmbH & Co.). Chromatography was performed on silica gel (Merck Silica Gel 60, 40–63 mesh) by MPLC. Therefore

Acknowledgement

This work was supported by research funds from ‘Kultusministerium des Landes Sachsen-Anhalt’.

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