Xuyuan Gu

Stereoselective synthesis of conformationally constrained reverse turn dipeptide mimetics

Abstract Peptide side chains play critical roles in the event of molecular recognition. In order to study the bioactive conformation of parent peptides, a concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i +1 and i +2 positions has been developed. In the bicyclic structure, two dihedral angles ( ψ 2 and φ 3 ) are greatly restricted.

Enantioselective Synthesis of anti-β-Substituted γ,δ-Unsaturated Amino Acids: A Highly Selective Asymmetric Thio-Claisen Rearrangement

A novel synthesis of optically active anti-beta-substituted gamma,delta-unsaturated amino acids via a thio-Claisen rearrangement has been achieved. A 2,5-diphenylpyrrolidine was used as a C2-symmetric chiral auxiliary to control the stereochemistry, giving good yields and excellent diastereoselectivities and enantioselectivities.

A novel strategy toward [6,5]-bicyclic β-turn dipeptide

Abstract A novel strategy toward the syntheses of [6,5]-bicyclic β-turn dipeptides has been developed starting from δ,e-unsaturated amino acids. This is the first example showing that this scaffold can be synthesized from a terminal alkene using a trifluoroacetyl protected amino acid. Both enantiomers of the δ,e-unsaturated amino acid were synthesized by a modified method using Ni(II)-complexes.

Thio-Claisen Rearrangement Used in Preparing Anti-β-Functionalized γ,δ-Unsaturated Amino Acids: Scope and Limitations

Multifunctionalized amino acids, especially amino acids with unsaturation, are important, demanding building blocks in peptide chemistry. Here we present a summary of our most recent study using the thio-Claisen rearrangement for the synthesis of anti-β-functionalized γ,δ-unsaturated amino acids. Investigations on scope, limitations, chemoselectivities and stereoselectivities regarding an FeBr(3)-catalyzed allylation strategy and a thio-enolate dianion formation strategy for asymmetric thio-Claisen rearrangement are documented. An explanation of the chirality crossover observed between the Eschenmoser-Claisen rearrangement and the thio-Claisen rearrangement is proposed. Novel optically active N(α)-protected amino acids with biologically interesting functional groups were prepared for the first time.

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r and Mc4r). PG946 is a derivative of a hybrid of alpha- and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.

Synthesis of β-phenyl-δ,ε-unsaturated amino acids and stereoselective introduction of side chain groups into [4,3,0]-bicyclic β-turn dipeptides ☆

(2S,3S)- and (2R,3R)-2-amino-3-phenyl-5-hexenoic acids have been synthesized in large scale by using Ni(II)-complexes as a template. The amino acids were used in the synthesis of [4,3,0]-bicyclic β-turn mimetics by a convergent methodology. The unique advantage of this strategy is the convenience of introducing side chain groups with predetermined chiralities on both the five- and six-membered heterocyclic rings.

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]-Leu-enkephalin analogues†‡

Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid‐phase supports. By taking advantage of the enantioselective synthesis of ω‐unsaturated amino acids and their N‐methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid‐phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2–3 was favored when an L‐ and L‐bicyclic scaffold was used, and that an extended conformation at the N‐terminal was favored when a D‐ and L‐bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]‐ and [7,5]‐bicyclo‐Leu‐enkephalin analogues.

Intelligent Design in Combinatorial Chemistry: Use of Designed Peptide Libraries to Explore Secondary and Tertiary Structures in Peptides and Proteins

Publisher Summary The origins of combinatorial chemistry were in the area of peptide design. Peptide synthesis in combinatorial chemistry is a viable field in finding lead compounds and in the evaluation of the other aspects of protein research. This chapter discusses the evolution of intelligent design in combinatorial peptide synthesis, and its use in the evaluation of secondary and tertiary structures in proteins. The secondary structures of the amphipathic peptides have been studied using peptide libraries, in which it was observed that smaller the amphipathicity, greater would be the antimicrobial activity. Combinatorial libraries have been used to design a four-helix bundle. The libraries were designed to cover the packing of the ligand in the libraries around a heme group after being bound to a template attached to a cellulose backbone. The library was varied to determine the affects of different core amino acids on the packing of the heme in the bundle. This work demonstrates the use of peptide libraries to design tertiary structures, such as a heme bundle.

[N-({(R)-2-[(N-Benzylprolyl)amino]phenyl}-phenylmethylene)-2(S)-(pent-4-enyl)-glycinato]nickel(II)

The title compound, [Ni(C(32)H(33)N(3)O(3))], crystallized as a minor product during the purification of its 2(R)-pent-4-enyl diastereomer. Mixtures of the title compound and its enantiomer self-resolve.

Synthesis of β-Turn Mimetics: [5,5]-Fused Bicyclic γ-Lactam Dipeptide Analogues

The “secondary structure approach” to the de novo design of peptide rnimetics is guided by the simple elegance which nature has employed in the molecular architecture of peptide and protein species [1]. s-Turns offer the significant synthetic advantage that they are relatively compact and in principle can be more readily mimicked by conformationally constrained or rigidified small organic molecules. To truly mimic different types of s-turns requires stereo- and enantiocontrolled introduction of a minimum of four asymmetric centers, with different backbone geometry and side chain topography. Among the interesting approaches toward s-turn rnimetics, the design of azabicycloalkane amino acids have been shown to have unique potential advantages, and numerous bicyclic derivatives of this general class have been synthesized [2]. Although s-lactam bicyclic analogues have well-known antibacterial activities, most γ-lactams without appropriate side chain moieties have not shown significant biological activities. Obviously, side chains play important roles in s-turns and we have proposed [3], that introduction of side-chains on the bicyclic scaffold would generate expected biological activities. Here we report a simple but potentially general method to generate in 5 steps [5,5]-bicyclic dipeptide, which not only have both C- and N-terminals but also have side chain groups on both rings.