Remote Stereoinduction in the Organocuprate-Mediated Allylic Alkylation of Allylic <i>gem</i>-Dichlorides: Highly Diastereoselective Synthesis of (<i>Z</i>)‑Chloroalkene Dipeptide Isosteres

Highly diastereoselective synthesis of (<i>Z</i>)-chloroalkene dipeptide isosteres has been achieved by 1,4-asymmetric induction in the organocuprate-mediated allylic alkylation adjacent to the chiral center of allylic <i>gem</i>-dichlorides. The reaction proceeds with a variety of heterocuprates prepared from CuCN and various organometallic reagents. It allows rapid construction of valuable architectures of l,d-type and l,l-type (<i>Z</i>)-chloroalkene dipeptide isosteres from the corresponding (<i>E</i>)- and (<i>Z</i>)-allylic <i>gem</i>-dichlorides in high yields, with excellent (<i>Z</i>)-selectivity and diastereoselectivity

Delivery of a Proapoptotic Peptide to EGFR-Positive Cancer Cells by a Cyclic Peptide Mimicking the Dimerization Arm Structure of EGFR

A cyclic decapeptide, CQTPYYMNTC (<b>1</b>), which mimics the dimerization arm of the EGF receptor (EGFR), was previously found to be captured into cells. We have sought to investigate the promising potential of this peptide as an intracellular delivery vehicle directed to EGFR-positive cells. The selectivity of peptide <b>1</b> to the EGFR was confirmed by a positive correlation between the expression level of the receptor and the cellular uptake of peptide <b>1</b> as shown by siRNA knockdown of the EGFR. The proapoptotic domain (PAD) peptide ([KLAKLAK]₂) has limited use due to a deficiency of cell membrane permeability resulting from cationic sequences and lack of specificity for cancer cells. As a proof-of-concept study, the cellular delivery of the PAD peptide was challenged by conjugation with peptide <b>1</b>. The cellular uptake of a conjugated peptide <b>2</b>, which was composed of peptide <b>1</b>, the PAD peptide, and a linker cleavable with a protease, was evaluated by treatment of an EGFR-positive lung carcinoma cell line, A549. Significant suppression of proliferation by peptide <b>2</b> was shown in the results of a cell viability assay. The PAD peptide alone had no effect on the cells. The results suggest that peptide <b>1</b> is a promising lead compound as a new intracellular delivery vehicle for therapeutically effective peptides

Stereoselective Formation of Trisubstituted (<i>Z</i>)‑Chloroalkenes Adjacent to a Tertiary Carbon Stereogenic Center by Organocuprate-Mediated Reduction/Alkylation

A robust and efficient method for the synthesis of trisubstituted (<i>Z</i>)-chloroalkenes is described. A one-pot reaction of γ,γ-dichloro-α,β-enoyl sultams involving organocuprate-mediated reduction/asymmetric alkylation affords α-chiral (<i>Z</i>)-chloroalkene derivatives in moderate to high yields with excellent diastereoselectivity, and allylic alkylation of internal allylic <i>gem</i>-dichlorides is also demonstrated. This study provides the first examples of the use of allylic <i>gem</i>-dichlorides adjacent to the chiral center for novel 1,4-asymmetric induction

Synthesis of a Chloroalkene Dipeptide Isostere-Containing Peptidomimetic and Its Biological Application

The first rapid and efficient chemical synthesis of a cyclic Arg-Gly-Asp (RGD) peptide containing a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an <i>N</i>-<i>tert</i>-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an <i>N</i>-Fmoc protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-containing cyclic RGD peptide was successful, and the synthesized CADI-containing peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide