From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase.

Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (), whose structure could be optimized into the potent CJ2-150 (). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation.

Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1.

With the aim to develop new chemical tools based on simplified natural metabolites to help deciphering the molecular mechanism of necroptosis, simplified benzazole fragments including 2-aminobenzimidazole and the 2-aminobenzothiazole analogs were prepared during the synthesis of the marine benzosceptrin B. Conpounds inhibiting the RIPK1 protein kinase were discovered. A library of 54 synthetic analogs were prepared and evaluated through a phenotypic screen using the inhibition of the necrotic cell death induced by TNF-α in human Jurkat T cells deficient for the FADD protein.

Molecular Iodine-Catalyzed Aerobic α,β-Diamination of Cyclohexanones with 2-Aminopyrimidine and 2-Aminopyridines.

Molecular iodine is shown to be an excellent catalyst for aerobic oxidative α,β-diamination of cyclohexanones with 2-aminopyrimidine/2-aminopyridines. This α,β-C-H functionalization is remarkable for its simplicity in both substrates and conditions, involving one and a half oxygen molecules and releasing three water molecules as the only byproduct. In addition, the functionalized products including protected 2-aminoimidazoles introduced without aromatization can serve as useful building blocks for natural product synthesis and medicinal chemistry.

Redox condensation of o-halonitrobenzene with 1,2,3,4-tetrahydroisoquinoline: involvement of an unexpected auto-catalyzed redox cascade.

A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles as a building block, base and a double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the α-methylene group and condensation.

Elements as Direct Feedstocks for Organic Synthesis: Fe/I2/O2 for Diamination of 2-Cyclohexenones with 2-Aminopyrimidine and 2-Aminopyridines.

Elements as feedstocks for organic synthesis, the trio of metallic iron, molecular iodine, and dioxygen, were found to be an excellent tool for oxidative regioselective diamination of conjugated enones with 2-aminopyrimidine (a guanidine surrogate) and 2-aminopyridines leading to unaromatized coupled products in moderate to good yields.

Concise Access to 2-Aroylbenzothiazoles by Redox Condensation Reaction between o-Halonitrobenzenes, Acetophenones, and Elemental Sulfur.

A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine. This three-component nitro methyl coupling was found to occur in an excellent atom-, step-, and redox-efficient manner in which elemental sulfur played the role of nucleophile building block and redox moderating agent to fulfill electronic requirements of the global reaction.

Elemental sulfur disproportionation in the redox condensation reaction between o-halonitrobenzenes and benzylamines.

The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.

Concise synthesis of didebromohamacanthin A and demethylaplysinopsine: addition of ethylenediamine and guanidine derivatives to the pyrrole-amino acid diketopiperazines in oxidative conditions.

Oxidative nucleophilic addition of ethylenediamine and guanidine derivatives to pyrrole-amino acid diketopiperazines was shown to provide substituted 5,6-dihydro-2(1H)-piperazinones, quinoxalinones, and 2-aminoimidazolones. On the basis of this methodology, a concise approach to natural products didebromohamacanthin A and demethylaplysinopsine has been demonstrated.

Three-component reaction between alkynes, elemental sulfur, and aliphatic amines: a general, straightforward, and atom economical approach to thioamides.

A general, straightforward, and atom-economical three-component synthesis of thioamides from alkynes, elemental sulfur, and aliphatic amines has been developed.

Cobalt- and iron-catalyzed redox condensation of o-substituted nitrobenzenes with alkylamines: a step- and redox-economical synthesis of diazaheterocycles.

A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.

Nitro-methyl redox coupling: efficient approach to 2-hetarylbenzothiazoles from 2-halonitroarene, methylhetarene, and elemental sulfur.

A simple, straightforward, and atom economic approach to 2-hetarylbenzothiazoles starting from 2-halonitroarene, methylhetarene, and elemental sulfur under mild conditions is described. The method is highlighted by the direct redox nitro-methyl reaction for carbon-nitrogen bond formation without an added oxidizing or reducing agent.

Unprecedented biomimetic homodimerization of oroidin and clathrodin marine metabolites in the presence of HMPA or phosphonate salt tweezers.

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors.

Iron sulfide catalyzed redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups: a straightforward atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

Iron sulfide generated in situ from elemental sulfur and iron was found to be highly efficient in catalyzing a redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups. This method represents a straightforward and highly atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

Benzazoles from aliphatic amines and o-amino/mercaptan/hydroxyanilines: elemental sulfur as a highly efficient and traceless oxidizing agent.

A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.

Efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur.

An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur under solvent-free conditions has been developed.

Boric acid: a highly efficient catalyst for transamidation of carboxamides with amines.

A novel method of transamidation of carboxamides with amines using catalytic amounts of readily available boric acid under solvent-free conditions has been developed. The scope of the methodology has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliphatic, aromatic, cyclic, acyclic, primary, and secondary amines.

Agelastatin E, agelastatin F, and benzosceptrin C from the marine sponge Agelas dendromorpha.

The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2-aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity.

Axiphenylalaninium and axityrosinium, modified amino acids from the Mediterranean marine sponge Axinella polypoides.

Two new modified amino acids, axiphenylalaninium (1) and axityrosinium (2), along with four known metabolites, C2-alpha-D-mannosylpyranosyl-L-tryptophan (3), N3,5'-cycloxanthosine (4), palythine (5), and taurine, were isolated from the marine sponge Axinella polypoides collected in the Mediterranean Sea. The structures were determined by spectroscopic studies and confirmed by X-ray analysis and chemical modifications.

N-Terminal 2,3-diaminopropionic acid (Dap) peptides as efficient methylglyoxal scavengers to inhibit advanced glycation endproduct (AGE) formation.

2,3-Diaminopropionic acid (Dap) and N-terminal Dap peptides have been found to inhibit in vitro protein-modifications by methylglyoxal (MG), one of the highly reactive alpha-dicarbonyl compounds. MG scavenging potency of the newly synthesized N-terminal Dap peptides is demonstrated by RP-HPLC, SDS-PAGE and non-denaturing PAGE analysis, assays for enzymatic activity and cell viability study and was compared with that of known AGE inhibitors, such as aminoguanidine, pyridoxamine, metformin and carnosine. Two addition products of MG and L-Dap-L-Leu are separated by HPLC and their chemical structures are characterized by (1)H and (13)C NMR spectroscopy to indicate that both of them are pyrazines derived from 2 molecules of MG and 1 molecule of L-Dap-L-Leu.

Diastereoselective synthesis of all eight l-hexoses from L-ascorbic acid.

[reaction: see text] A novel versatile method for the synthesis of all eight diastereomerically pure L-hexoses was developed. L-Ascorbic acid was converted to two diastereomers A. These alpha-hydroxy esters were transformed into four gamma-alkoxy-alpha,beta-unsaturated esters C via the intermediates B and subsequent Wittig olefination reactions.

[New aspects of diabetes].

Type II diabetes is a serious, insidious disease which is growing at an impressive rate, with 200 million diabetics worldwide and as many who ignore their state. Having been seriously studied over more than a century and a half, an enormous quantity of knowledge regarding this disease has been accumulated. The research we are conducting has allowed us to identify the most important actors responsible for diabetes.