Solid-phase synthesis and biological activity of a combinatorial cross-conjugated dienone library

The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50<0.05 microM). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.     

Diastereoselective solution and multipin-based combinatorial array synthesis of a novel class of potent phosphinic metalloprotease inhibitors

The solution-phase synthesis and resolution of new phosphinopeptidic building blocks containing a triple bond was realized in high yields and optical purities (units 3 a-d). The absolute configuration of the target compounds was unambiguously established by NMR studies. A post-assembly diversification strategy of these blocks was developed through 1,3-dipolar cycloaddition of a variety of in situ prepared nitrile oxides. This strategy led to the rapid and efficient diastereoselective preparation of a novel class of isoxazole-containing phosphinic peptides (peptides 5 a-i). Solid-phase version of this strategy was efficiently achieved on multipin solid technology, by developing a new protocol for the coupling of P-unprotected dipeptidic blocks with solid supported amino acids in a quantitative and diastereoselective manner. Optimization of dipolar cycloadditions onto pin-embodied phosphinic peptides allowed the convenient preparation of this new class of pseudopeptides. The crude phosphinic peptides (9 a-k) were obtained in high yields and purity as determined by RP-HPLC. Inhibition assays of some of these peptides revealed that they behave as very potent inhibitors of MMPs, outmatching previously reported phosphinic peptides, in terms of potency (K(i) in the range of few nM).     

Total synthesis of macrosphelide A by way of palladium-catalyzed carbonylative esterification

We achieved the total synthesis of macrosphelide A, as part of a combinatorial library of its analogues. The key intermediate, the seco-acid derivative, was prepared from the corresponding vinyl iodide using sequential carbonylative esterification.     

Combinatorial library of low molecular-weight organo- and hydrogelators based on glycosylated amino acid derivatives by solid-phase synthesis

A combinatorial approach for the synthesis of supramolecular gelators as new organic materials is described herein. In the course of the development of a convenient and flexible solid-phase synthesis of the artificial glycolipids, some of these compounds were accidentally found to act as low molecular-weight gelators toward organic solvents. Using this combinatorial solid-phase synthesis of glycosylated amino acetates, screening and optimization of low molecular-weight organo/hydro-gelators were efficiently carried out. We found that an N-acetyl-galactosamine-appended amino acid ester (GalNAc-aa) efficiently gelates a broad spectrum of organic solvents. More interestingly, some GalNAc-aa derivatives displayed an excellent hydrogelation capability. Transmission electron microscopy, scanning electron microscopy, confocal laser scanning microscopy, and FT-IR were used for characterization of the gel structure. It is indicated that supramolecular fibers supported by strong hydrogen-bonding networks are entangled so that the resulting spaces can immobilize a number of solvent molecules effectively. In addition, the supramolecular hydrogel consisting of GalNAc-suc-glu(O-methyl-cyc-pentyl)(2) is stable even under high salt concentrations probably due to its nonionic character and as a result, a native protein is successfully entrapped in the gel matrix without denaturation.     

Chemical synthesis of a glycolipid library by a solid-phase strategy allows elucidation of the structural specificity of immunostimulation by rhamnolipids

The first synthesis of a glycolipid library by hydrophobically assisted switching phase (HASP) synthesis is described. HASP synthesis enables flexible switching between solution-phase steps and solid-supported reactions conducted with molecules attached to a hydrophobic silica support. A library of glycolipids derived from the lead compound 1-a strongly immunostimulatory rhamnolipid--with variations in the carbohydrate part, the lipid components, and the stereochemistry of the 3-hydroxy fatty acids was designed and synthesized. The enantioselective synthesis of the 3-hydroxy fatty acid building blocks was achieved by employing asymmetric hydrogenation of 3-oxo fatty acids. Glycolipids were prepared by this approach without any intermediary isolation steps, mostly in excellent yields. Final deprotection to the carboxylic acids was accomplished by enzymatic ester cleavage. All prepared rhamnolipids were tested for their immunostimulatory properties against human monocyte cells by assaying the secretion of the cytokine tumor necrosis factor alpha (TNFalpha) into the medium. The observed structure-activity relationships of rhamnolipids indicate a specific, recognition-based mode of action, with small structural variations in the rhamnolipids resulting in strong effects on the immunostimulatory activities of the rhamnolipids at low micromolar concentrations.     

Tubulin-guided dynamic combinatorial library of thiocolchicine-podophyllotoxin conjugates

The use of tubulin as a target to influence the composition of the mixture from a dynamic combinatorial library, based on the disulfide bond exchange reaction, is described. ESI-FT-ICR-MS was used to determine the composition of the library. The heterodimeric compound amplified by this approach was used to design the homologous derivative with a two-carbon spacer in place of the disulfide function. The ability of the compounds to inhibit tubulin polymerization is reported and compared to thiocolchicine.     

A library of chiral imidazoline-aminophenol ligands: discovery of an efficient reaction sphere

A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)- or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a Friedel-Crafts alkylation of indole and nitroalkene to give the adduct in up to 83 % ee.     

Development of the traceless phenylhydrazide linker for solid-phase synthesis

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.     

Ketenes in polymer-assisted synthesis

Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.     

固相有机合成小分子化合物库

从杂环化合物库和非杂环化合物库两方面介绍了组合化学中采用固相合成技术所构建的小分子化合物库。