Synthesis of novel Gn-RH analogues using Ugi-4MCR

An efficient method for the synthesis of some Gn-RH analogues based on Ugi reaction has been developed. Four-component reaction of N- and C-terminus peptides, aromatic aldehydes and isocyanides affords novel Gn-RH analogues derived from triptorelin and gonadorelin. All of the products were purified using preparative HPLC and the structures were assigned according to MALDI-mass spectrometry data.     

An efficient one-pot synthesis of polyphenolic amino acids and evaluation of their radical-scavenging activity

A simple and efficient procedure for the synthesis of N-acyl 4-hydroxy, 4-hydroxy-3-methoxy and 3,4-dihydroxy phenylglycine amides by a strategy based on the multicomponent Ugi reaction is proposed. Hydroxybenzaldehyde derivatives were reacted with 4-methoxybenzylamine, cyclohexyl isocyanide and benzoic acid or 2-naphthylacetic acid to give Ugi adducts that were treated with trifluoroacetic acid yielding N-acyl hydroxyphenylglycine amides in good yields. The same procedure using as acid component protocatechuic acid or hydrocaffeic acid gave N-catechoyl 3,4-dihydroxyphenylglycine amides. The use of N-benzyloxycarbonylglycine as acid component allowed the preparation of a 3,4-dihydroxyphenylglycyl dipeptide derivative. Radical-scavenging activity studies of the polyphenolic amino acid derivatives showed a sharp increase in activity with the increase in number of hydroxyl or catechol groups present. Cyclic voltammetry experiments established a correlation between oxidation peak potentials and the radical-scavenging activity.     

Multicomponent synthesis of novel amino acid-nucleobase chimeras: a versatile approach to PNA-monomers

This paper describes a multicomponent approach to novel totally protected precursors of PNA-monomers via Ugi 4CC. The obtained bisamides are converted into several partially protected PNA-monomers or derivatives thereof using three different procedures. Methods for hydrolysis are shown to be dependent on the nature of the isocyano component required for Ugi 4CC. Several novel monomers suitable for oligomer synthesis are prepared demonstrating the high versatility of the reaction sequence.     

Solution-phase synthesis of a combinatorial monocyclic β-lactam library: Potential protease inhibitors

A 126-member library of monocyclic β-lactams was generated in parallel fashion by solution-phase Ugi four-component condensation reaction between β-amino acids, aldehydes, and isocyanides. The library was designed to identify potential human leukocyte elastase inhibitors. The approach is also capable of optimizing the lead compounds generated in the original library.     

Multicomponent reactions in crop protection chemistry

An overview is given of the significance of multicomponent reactions in the synthesis of agrochemicals. The most important applications of multicomponent condensations, such as the Biginelli reaction, Bucherer-Bergs reaction, Hantzsch dihydropyridine synthesis, Kabachnik-Fields reaction, Mannich reaction, Passerini reaction, Petasis reaction, Strecker reaction, Ugi reaction and Willgerodt-Kindler reaction, to the synthesis of herbicidally, fungicidally and insecticidally active compounds are presented. Also the mode of action and biological activity of these multicomponent reaction products are reported.     

A polymer-supported [1,3,2]oxazaphospholidine for the conversion of isothiocyanates to isocyanides and their subsequent use in an ugi reaction

The design and synthesis of a new polymer supported reagent for the clean conversion of isothiocyanates to isocyanides under microwave conditions was accomplished. The structurally diverse isocyanides generated were used in an Ugi 3CC, allowing the rapid generation of 2-isoindolinone-7-carboxamide analogues.     

Chemoenzymatic construction of a four-component Ugi combinatorial library

The chemoenzymatic preparation of a nine-member Ugi condensation library is described. The carboxylic acid and amine precursors are based on 3-hydroxybutyrate and 4-amino-1-butanol, respectively, and have been acylated selectively using a variety of acyl donors catalyzed by porcine pancreatic lipase. The enzyme is selective for the hydroxyl functionalities on both precursors, thereby yielding 3-acyl-butyric acid and 4-amino-1-acyl compounds. These enzymatically generated derivatives were then subjected to a four-component Ugi condensation reaction in the presence of acetaldehyde and methyl isocyanoacetate. Isolated yields of the alpha-(acylamino)amide Ugi products ranged from 72-95%. The inherent chemoselectivity of enzymatic catalysis may play an increasingly important role in expanding the structural diversity that can be achieved by chemical multicomponent condensation reactions.     

Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent

A class of cyclic acyldepsipeptide antibiotics collectively known as the enopeptins has recently attracted much attention because of their activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These antibiotics are further distinguished by their novel mechanism of action in which they bind and deregulate the tightly controlled activity of the cytoplasmic protease ClpP. Although the natural products have poor pharmacological properties, a synthetic derivative called acyldepsipeptide 4 (ADEP 4) showed remarkable antibacterial activity both in vitro and in mouse models of bacterial infections. A novel route to the ADEP 4 peptidolactone core structure, featuring the Joullié-Ugi three-component reaction, was developed. This multicomponent reaction and a related multicomponent reaction, the Ugi four-component reaction, were used to prepare analogs that were designed using the principles of conformational analysis. These cyclic acyldepsipeptides were tested for their activity against drug-resistant, clinical isolates of Staphylococci and Enterococci. One ADEP 4 analog in which the pipecolate was replaced by 4-methyl pipecolate exhibited in vitro antibacterial activity against Enterococci that was fourfold higher than the parent compound.     

Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC₅₀ range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.     

Synthesis of 4-azasteroids by an intramolecular Ugi reaction

In this paper we report the use of an intramolecular Ugi reaction to synthesize new 4-azacholestanes diversely substituted both at N-4 and C-5. Both the scope and the stereochemical outcome of this approach were studied by varying the nature of the components necessary for this multicomponent reaction. In sight of our results we concluded that this methodology can be applied to obtain 4-azasteroids targeted to find new biologically active compounds.     

Multicomponent synthesis of 4,4-dimethyl sterol analogues and their effect on eukaryotic cells

Most sterols, such as cholesterol and ergosterol, become functional only after the removal of the two methyl groups at C-4 from their biosynthetic precursors. Nevertheless, some findings suggest that 4,4-dimethyl sterols might be involved in specific physiological processes. In this paper we present the synthesis of a collection of analogues of 4,4-dimethyl sterols with a diamide side chain and a preliminary analysis of their in vitro activity on selected biological systems. The key step for the synthesis involves an Ugi condensation, a versatile multicomponent reaction. Some of the new compounds showed antifungal and cytotoxic activity.     

Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers

Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.     

Isosteric exchange of the acylsulfonamide moiety in Abbott's Bcl-XL protein interaction antagonist

A multi-component reaction strategy was used for the fast and efficient synthesis of amide isosteres of known Bcl-2 inhibitors capable of disrupting protein–protein interactions. Ugi reaction and a subsequent nucleophilic aromatic substitution reaction provide a versatile path to libraries of compounds similar to Abbott’s acylsulfonamides. Modeling arguments are used to explain the inferior activity of the amide as opposed to the sulfonamide series.     

New cross-linked and sulfated derivatives of partially deacetylated hyaluronan: synthesis and preliminary characterization

Partial chemical deacetylation of hyaluronan (HA) has been carried out using known procedures and carefully controlled experimental conditions in order to minimize chain degradation. The sample described herein (deHA) has a degree of deacetylation of about 17%, which corresponds to what required for its further use, but a molecular weight of about 1/25 with respect to the native, starting material. Chemical gels have been prepared with different degrees of cross-linking by means of a Ugi multicomponent condensation reaction involving aqueous deHA, formaldehyde, and cyclohexylisocyanide: the gels are mechanically stable and exhibit good water uptake strongly dependent on the extent of cross-linking, as expected. deHA samples have also been selectively N-sulfated or O-sulfated: the former exhibit anticoagulant properties well exceeding those of the latter and not too inferior to heparin.     

Polypeptoids synthesis based on Ugi reaction: Advances and perspectives

Polypeptoids are peptidomimetic polymers invented in the early 1990s. Although polypeptoid chemistry is developing rapidly, the simple synthesis of polypeptoids and sequence-controlled polypeptoids still remains a challenge. Fortunately, we have seen a drastic rising trend in the area of Ugi reaction for polypeptoid chemistry. In the following article, recent examples of the Ugi reaction for polypeptoids synthesis will be presented, as will their suitability for sequence-defined peptide-peptoid hybrids. The advantages and limitations of the Ugi reaction will be discussed, which is important for the simple and general synthesis of polypeptoids.     

Ugi multicomponent-reaction: Syntheses of cytotoxic dehydroabietylamine derivatives

Isocyanide-based multicomponent reactions – especially the standard four component Ugi reaction – provide an easy and powerful access to compounds with an auspicious pharmacological potential. Therefore, a set of 16 novel derivatives of the diterpene dehydroabietylamine was synthesized by the Ugi-4CR. The subsequent screening of the synthesized α-acylamino carboxamides in colorimetric sulforhodamine B assays revealed an in vitro cytotoxicity towards several human tumor cell lines. Particularly, the rhodamine B conjugates 14–16 showed a remarkable cytotoxic activity, characterized by EC₅₀ values in a low three-digit nanomolar range. The screening of rhodamine B amide 17 that was obtained for comparison by a Schotten-Baumann reaction showed that the linkage of the rhodamine B moiety and the diterpene influences significantly its cytotoxic potency. While 14 was highly cytotoxic and acted as a mitocan, compound 17 was not cytotoxic at all. This observation underlines the importance of the type of coupling between the diterpene and the rhodamine part. The presence of a rhodamine B moiety in the molecules doesn’t necessarily guarantee that the compound is cytotoxic.     

Structure–activity relationships of the aromatic site in novel anticonvulsant pyrrolo[1,2-a]pyrazine derivatives

Novel, chiral derivatives of pyrrolo[1,2-a]pyrazine with aromatic substituents at carbon C-4 were synthesized by a short synthetic sequence involving Ugi multicomponent reaction. The compounds were evaluated for their in vivo efficacy in animal models of epilepsy within the Anticonvulsant Screening Program (ASP). High activity in ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests was characteristic for meta-substituted analogs. On the other hand, efficacy of compounds in the 6 Hz model of pharmacoresistant limbic seizures was only marginally affected by the orientation of substituents in the phenyl moiety. The most active derivative, 5a, displayed an ED₅₀ value of 32.24 mg/kg and a protective index of 6.6 (PI) in the 6 Hz test. It was also active in a pilocarpine-induced status prevention model of pharmacoresistant status epilepticus.     

Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor

Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC₅₀ for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.     

Synthesis of artemisinin dimers using the Ugi reaction and their in vitro efficacy on breast cancer cells

The Ugi four-component reaction was used to prepare a series of artemisinin monomers and dimers. We found that the endoperoxide group in artemisinin remains intact during the reaction. The new artemisinin dimers showed potent anti-cancer activity against two human breast cancer cell lines, MDA-MB-231 and BT-474. One of the Ugi artemisinin dimers showed an IC₅₀ value of 12 nM when tested on BT474 cells, more than 600 times more potent than artesunate. Furthermore, the same Ugi artemisinin dimer showed a low toxicity when tested on MCF10A, a nontumorigenic cell line, resulting in a selectivity index of more than 8000.     

A focused sulfated glycoconjugate Ugi library for probing heparan sulfate-binding angiogenic growth factors

A library of small molecule heparan sulfate (HS) mimetics was synthesized by employing the Ugi four-component condensation of d-mannopyranoside-derived isocyanides with formaldehyde as the carbonyl component and a selection of carboxylic acids and amines, followed by sulfonation. The library was used to probe the subtle differences surrounding the ionic binding sites of three HS-binding angiogenic growth factors (FGF-1, FGF-2 and VEGF). Each compound features 3 or 4 sulfo groups which serve to anchor the ligand to the HS-binding site of the protein, with a diverse array of functionality in place extending from C-1 or C-6 to probe for adjacent favorable binding interactions. Selectivity of binding to these proteins was clearly observed and supported by molecular docking calculations.