Small peptide inhibitors of smooth muscle myosin light chain kinase

Abstract

The pentapeptide Ser-Asn-Val-Phe-Ala-OBzl has been identified as the smallest inhibitory peptide of myosin light chain kinase (MLCK) derived from the primary sequence of the light chain phosphorylation site. The specific contributions of individual amino acid side chains and backbone elements of this pentapeptide toward the stabilization of the enzyme-inhibitor (E-I) complex have been evaluated. The potency of these peptides as inhibitors of MLCK has been enhanced by the incorporation of synthetic nonnatural amino acids into the sequence. Finally, it has been demonstrated that these peptide sequences could be converted into pseudopeptides with synthetic nonpeptide subunits designed to mimic peptide bonds, and that certain pseudopeptides retained the high-affinity inhibition of the parent pentapeptides.

Synthesis of a 35-Member Stereoisomer Library of Bistramide A: Evaluation of Effects on actin State, Cell Cycle and Tumor Cell Growth

“…Construction of the C29−C40 segment of the spiroketal subunit utilized starting materials obtained from a chiral pool source (Scheme ). Subjection of the commercially available ( S )-1,2,4-butanetriol derivative 37 to a Wittig olefination reaction with phosphonium salt 38 provided olefin 39 as a mixture of geometric isomers in 70% yield ( Z : E = 10:1). The exocyclic olefin was reduced and concomitant deprotection of the benzyl ether with Raney nickel yielded a primary alcohol in 78% yield.…”

In Pursuit of a Competitive Target: Total Synthesis of the Antibiotic Kendomycin

“…Conversion into the fully substituted arene 111 was achieved in four steps including a Stille coupling at C20a. After reduction of the C10 ester into the aldehyde, a Wittig reaction with phosphonium bromide 112, [46] with subsequent hydrogenation/debenzylation and oxidation gave aldehyde 113, which was converted into E-vinyl iodide 103 in a standard reaction sequence. The preparation of the ansa chain was completed by a Negishi coupling of iodide 104 with vinyl iodide 103 to give intermediate 114 which was converted into seco-compound 102 in four steps (Scheme 23).…”

Einem kompetitiven Zielmolekül auf den Fersen: Totalsynthese des Antibiotikums Kendomycin

“…Die Komplettierung des Arens erfolgte in vier weiteren Stufen, wobei eine Stille‐Kupplung an C20a zum Einsatz kam. Nach der Reduktion des C10‐Esters zum Aldehyd wurde dieser in einer Wittig‐Reaktion mit dem Phosphoniumbromid 112 46 kettenverlängert und anschließend über eine Hydrierung/Debenzylierung mit nachfolgender Oxidation in den Aldehyd 113 überführt. Vier weitere Standardschritte lieferten das Vinyliodid 103 .…”