First asymmetric synthesis of (-)-lintetralin via intramolecular Friedel-Crafts-type cyclization

The asymmetric synthesis of an aryltetralin lignan, (-)-lintetralin, was achieved with an overall yield of 29% with seven steps. Key features of the synthesis are an asymmetric Strecker reaction, a diastereoselective Michael addition of the lithiated amino nitrile product to 5H-furan-2-one, and an intramolecular carbocationic cyclization to provide the desired ring skeleton with the correct configuration.     

Conserved tyr residues determine functions of Alicyclobacillus acidocaldarius squalene-hopene cyclase

The catalytic cavity of Alicyclobacillus acidocaldarius squalene-hopene cyclase is mainly lined by aromatic amino acids. In recombinant cyclases, three out of four tyrosine residues (Y) have been mutated to phenylalanine residues (F). The mutant cyclases Y495F and Y612F had less activity than the wild-type cyclase, but a wild-type product pattern. Mutant Y609F had wild-type activity but a drastically altered product pattern with hopene and significant amounts of bicyclic alpha-polypodatetraene and different tetracyclic triterpenes (dammaradienes and eupha-7,24-diene). The experiments demonstrated that Y495 and Y612 may be involved in the initiation of the cyclization reaction and Y609 in the stabilization and/or positioning of the intermediate carbocations.     

Novel method for the synthesis of urea backbone cyclic peptides using new Alloc‐protected glycine building units

Cyclization of bioactive peptides, utilizing functional groups serving as natural pharmacophors, is often accompanied with loss of activity. The backbone cyclization approach was developed to overcome this limitation and enhance pharmacological properties. Backbone cyclic peptides are prepared by the incorporation of special building units, capable of forming amide, disulfide and coordinative bonds. Urea bridge is often used for the preparation of cyclic peptides by connecting two amine functionalized side chains. Here we present urea backbone cyclization as an additional method for the preparation of backbone cyclic peptide libraries. A straightforward method for the synthesis of crystalline Fmoc‐N^α [ω‐amino(Alloc)‐alkyl] glycine building units is presented. A set of urea backbone cyclic Glycogen Synthase Kinase 3 analogs was prepared and assessed for protein kinase B inhibition as anticancer leads. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model

An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.     

Nicotine inhibition of carotenoid cyclization in Cucurbita ficifolia cotyledons

Nicotine inhibits carotenoid cyclization in greening cucurbit cotyledons resulting in the accumulation of acyclic and monocyclic carotenes. Chlorophyll synthesis is also inhibited by the alkaloid.     

PIFA–BF3·OEt2 mediated intramolecular regioselective domino cyclization of ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H)-ones

The transition metal-free intramolecular regioselective domino cyclization of N-Boc protected ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-ones in moderate to good yields.     

High yield synthesis of tentoxin, a cyclic tetrapeptide.

Tentoxin is a naturally occurring phytotoxic cyclic tetrapeptide excreted by fungi of the Alternaria alternata family. The four total syntheses of tentoxin published to date give poor total yields, mainly owing to two difficulties, the introduction of the dehydro amino acid and more especially the cyclization step. Here we describe a method that stereospecifically introduces Z-dehydrophenylalanine (deltaZPhe) by a modified Erlenmeyer aldolization reaction. The linear tetrapeptide, Boc-R1Ala-Leu-R2deltaZPhe-G1y-OMe (R1, R2: CH3, 14CH3), the precursor of tentoxin, was obtained in a 72% yield from Boc-Leu-Gly-OH. This linear tetrapeptide, labelled with carbon-14, was used for a comparative study of four cyclization reagents DPPA, DCC-PfpOH, HBTU and HATU. This last was the most effective and gave tentoxin in a 81% cyclization yield. The activated ester formed with this reagent displayed an enhanced capacity for cyclization, permitting cyclization in concentrated medium (10 mM). This new synthetic route gave tentoxin in a 60% yield from Boc-Leu-Gly-OH and offers a means of achieving the synthesis of hitherto elusive analogues.     

Cyclic insulin-regulated aminopeptidase (IRAP)/AT4 receptor ligands.

The angiotensin IV receptor (AT4 receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.     

Efficient methodology for the cyclization of linear peptide libraries via intramolecular S-alkylation using Multipin solid phase peptide synthesis.

Methodology is described here for the efficient parallel synthesis and cyclization of linear peptide libraries using intramolecular S-alkylation chemistry in combination with Multipin solid phase peptide synthesis (Multipin SPPS). The effective use of this methodology was demonstrated with the synthesis of a 72-member combinatorial library of cyclic thioether peptide derivatives of the conserved four-residue structural motif DD/EXK found in the active sites of the five crystallographically defined orthodox type II restriction endonucleases, EcoRV, EcoRI, PvuII, BamHI and BglI.