Hiromu Habashita

Unprecedented rearrangement reaction of 2-aziridinemethanols with lower order lithium methylcyanocuprate

Abstract Complementary selectivity can be achieved in ring opening reactions of 2-aziridinemethanols by using either the Gilman reagent or lower order cyanocuprate. In the former case, the usual attack of the Gilman reagent to the substrates 1 and 2 results in the formation of the expected ring opening products ( 3 and 4 ) and ( 7 and 8 ), respectively. In contrast, exposure of both 1 and 2 to the lower order cyanocuprate proceeds in an unprecedented fashion, presumably via epoxides D and G , to yield unexpected secondary alcohols ( 11 and 12 ) as the major products.

Certification of the Critical Importance of l-3-(2-Naphthyl)alanine at Position 3 of a Specific CXCR4 Inhibitor, T140, Leads to an Exploratory Performance of Its Downsizing Study

We have previously found that a 14-amino acid residue-peptide, T140, inhibits infection of target cells by T cell line-tropic HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. Here, the importance of an L-3-(2-naphthyl)alanine (Nal) residue at position 3 in T140 for high anti-HIV activity and inhibitory activity against Ca(2+) mobilization induced by stromal cell-derived factor (SDF)-1alpha-stimulation through CXCR4 has initially been shown by the synthesis and biological evaluation of several analogues, where Nal(3) is substituted by diverse aromatic amino acids. Next, the order of the N-terminal 3 residues (Arg(1)-Arg(2)-Nal(3)) has been proved to be important from the structure--activity relationship (SAR) study shuffling these residues. Based on these results, we have found 10-residue peptides possessing modest anti-HIV activity by systematic antiviral evaluation of a series of synthetic, shortened analogues of T140.

A simple synthesis of Ω[(E)CHCH]gly dipeptide isosteres via reductive elimination of γ-oxygenated α,β-enoates with alkenylcopper reagents

Abstract Readily available protected forms of δ-amino-γ-msyloxy-α,β-enoates can be converted to protected dipeptide isosteres, Ω[(E)CHCH]Gly, in high yields by reduction with alkenylcopper reagents.

Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic acini

The short-chain pseudopeptide, [d-Phe6, Leu13Φ(CH2NH)Leu14]bombesin(6–14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [d-Phe6, Leu13Φ[(E)CH = CH]Leu14] bombesin(6–14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 μM, and RBI showed slight agonistic activity at concentrations >10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC150 of 6.7 ± 1.7 nM, and induced almost-complete inhibition at 0.3 μM. RDI caused a dosedependent inhibition of amylase release, with an IC50 of 68.7 ± 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 μM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist. EABI was 10 times more potent than RDI in terms of inhibition of bombesin-stimulated amylase release. Thus, EABI can be a useful probe for studying the biological roles of bombesin and related peptides in a basic and clinical sense.

SN2′ selective alkylation of allylic chlorides and mesylates with RZnX reagents generated from Grignard reagents, zinc chloride, lithium chloride, and Cu(II)-salts

Abstract Treatment of RMgX (1 equiv. R = alkyl; X = Cl, Br) with ZnCl 2 (1 equiv.) in a mixed solvent of THF and Et 2 O leads to a highly turbid white suspension. Addition of LiCl (1∼2 equiv.) solubilizes the insoluble species to yield a colorless clear solution. Addition of a catalytic amount of a Cu(II)-salt followed by allylic halides or mesylates at 0 °C ∼ room temperature yielded S N 2′products in high yields. Application for the synthesis of ( E )-alkene dipeptide isosteres is also reported.

Effects of structural modulation on biological activity of bombesin analogues with (E)-alkene bond

The specific bombesin receptor antagonist, (E)-alkene bombesin isostere (EABI-1), [D-Phe6,Leu13psi[(E)CH=CH]Leu14]bombesin(6-14) is a potent antagonist in terms of inhibition of bombesin-stimulated amylase release from rat pancreatic acini. This study examined the effects of EABI-1 (L-L diastereomer) and three novel bombesin analogues on amylase release in rat pancreatic acini. EABI-2 is a L-D diastereomer of EABI-1. EABI-3 is an analogue, of which leucine at position 13 of EABI-1 was replaced with valine. EABI-4 is a L-D diastereomer of EABI-3 (L-L). The order of agonist potency was EABI-2>EABI-3>EABI-4. EABI-1 showed no agonist activity at concentrations up to 100nM. On the other hand, all of four analogues had antagonist activity. The order of antagonist potency was EABI-1>EABI-3>EABI-4>EABI-2. EABI-1 was a complete antagonist, EABI-2 and EABI-3 were partial agonists, and EABI-4 had a weak agonist effect. The present study provides a useful information on the future development of peptide analogues for anticancer agents and biological tools for investigating actions of bombesin family peptides.

Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold.

Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice.

“Higher order” zinc cuprates involving lithium chloride: Synthesis of (E)-alkene dipeptide isosteres free from reductive elimination products

Abstract The “higher order” organozinc cuprates, R 2 Cu(CN)(ZnCl) 2 ·2Mg(X)Cl·nLiCl, derived from admixture of LiCl (1∼2 equiv.), ZnCl 2 (1 equiv.), RMgX (1 equiv.), and CuCN (0.5 equiv.) in a mixed solvent of THF and Et 2 O exhibit high diastereoselection of up to > 99: 1 in the synthesis of (E)-alkene dipeptide isosteres from γ-mesyloxy-α,β-unsaturated esters. Addition of lithium chloride is essential for the preparation of clear solutions of reagents.

Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles.

Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.

Discovery of orally available spirodiketopiperazine-based CCR5 antagonists

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.