Hongchang Qu

Peptidomimetics, a synthetic tool of drug discovery

The demand for modified peptides with improved stability profiles and pharmacokinetic properties is driving extensive research effort in this field. Many structural modifications of peptides guided by rational design and molecular modeling have been established to develop novel synthetic approaches. Recent advances in the synthesis of conformationally restricted building blocks and peptide bond isosteres are discussed.

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.

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.

Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling.

Melanocortin 4 receptor (MC4R) plays an important role in the regulation of food intake and glucose homeostasis. Synthetic nonpeptide compound N- (3R)-1 4-tetrahydroisoquinolinium-3-ylcarbonyl-(1R)-1-(4-chlorobenzyl)-2-4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl-2-oxoethylamine (THIQ) is a potent agonist at MC4R but not at hMC2R. In this study, we utilized two approaches (chimeric receptor and site-directed mutagenesis) to narrow down the key amino acid residues of MC4R responsible for THIQ binding and signaling. Cassette substitutions of the second, third, fourth, fifth, and sixth transmembrane regions (TMs) of the human MC4R (hMC4R) with the homologous regions of hMC2R were constructed. Our results indicate that the cassette substitutions of these TMs of the hMC4R with homologous regions of the hMC2R did not significantly alter THIQ binding affinity and potency except the substitution of the hMC4R TM3, suggesting that the conserved amino acid residues in these TMs of the hMC4R are main potential candidates for THIQ binding and signaling while non conserved residues in TM3 of MC4R may also be involved. Nineteen MC4R mutants were then created, including 13 conserved amino acid residues and 6 non-conserved amino acid residues. Our results indicate that seven conserved residue [E100 (TM2), D122 (TM3), D126 (TM3), F254 (TM6), W258 (TM6), F261 (TM6), H264 (TM6)] are important for THIQ binding and three non-conserved residues [N123 (TM3), I129 (TM3) and S131 (TM3)] are involved in THIQ selectivity. In conclusion, our results suggest that THIQ utilize both conserved and non-conserved amino acid residues for binding and signaling at hMC4R and non conserved residues may be responsible for MC4R selectivity.

Substitution of Arginine with Proline and Proline Derivatives in Melanocyte-Stimulating Hormones Leads to Selectivity for Human Melanocortin 4 Receptor

A new series of melanotropin analogues with His or Arg residues in the core pharmacophores of MTII, SHU9119, and Ac-NDP-gamma-MSH-NH(2) replaced by Pro or trans-/cis-4-guanidinyl-Pro derivatives were designed and synthesized to introduce selectivity toward the human melanocortin 4 receptor (hMC4R). Analogues 1, 2, 3, 6, 7, 8 were found to be hMC4R selective. Second messenger studies have demonstrated that analogues 1 and 2 are insurmountable inhibitors of MTII agonist activity at the hMC4R. Molecular modeling studies suggest that the hMC4R selectivity is due to a beta-turn shift induced by the Pro ring that makes the global minimum structures of these analogues resemble the NMR solution structure of the hASIP melanocortin receptor binding motif. Substitution of His in MTII also provided functional selectivity for the hMC3R or the hMC4R. These findings are important for a better understanding of the selectivity mechanism at the hMC3R/hMC4R and the development of therapeutic ligands selectively targeting the hMC4R.

Peptide and Non-Peptide Mimetics Utilize Different Pathways for Signal Transduction

Introduction Despite the central importance of peptides as drugs such as insulin, oxytocin, calcitonin, ace inhibitors, etc., there has been a prejudice against developing peptide drugs. Instead large efforts are made to develop non-peptide small molecules (“peptide mimetics”) to replace peptides. But are they true mimetics (same SAR, same bioactivity, same toxicity profile, etc.)? This issue generally has not been addressed directly. This is especially the case when the targets for the ligands are GPCRs. When the ligands are antagonists (for receptors, enzymes, etc.) this issue is not as critical as when the ligand is an agonist for a GPCR (or growth factors, or cytokines, etc.). The issue is highly relevant because biological function will depend on activation of a particular signaling pathway, and to obtain the same bioactivity will require the same SARs. To examine this conundrum we have begun to carefully evaluate whether peptide and non-peptide mimetics utilize the same signaling pathways. We find that often they do not, which raises questions regarding drug design. Here we examine the signaling of two agonist (a peptide and a nonpeptide) ligands for the human melanocortin 4 receptor (hMC4R) utilizing molecular biological, pharmacological, biophysical, and biochemical methods and demonstrate that though both are agonists they utilize quite different signaling pathways. The implications for drug design are briefly discussed.

(1R,2S)-Benzyl N-[3-(diisopropylaminocarbonyl)-2-phenylprop-3-enyl]carbamate

The title compound, C(25)H(32)N(2)O(3), was synthesized as part of a series of related compounds using a modified Eschenmoser-Claisen rearrangement reaction. The compound is racemic and the structure features a centrosymmetric hydrogen-bonded dimerization along with some aromatic stacking stabilization.