Synthesis of a 2, 4, 8-trisubstituted pyrimidino[5, 4-d]pyrimidine library via sequential SNAr reactions on solid-phase.

A solid-phase synthesis of 2, 4, 8-substituted pyrimidino[5, 4-d]pyrimidines involving three controlled S(N)Ar reactions has been developed. Exploration of different heterocyclic starting materials and resin-bound intermediates is highlighted. The preferred method starts with the treatment of resin-bound anilines with 2, 4, 8-trichloropyrimidino[5, 4-d]pyrimidine. This intermediate is subsequently treated with various amines in two steps to yield the final products. The scope of each diversity step was determined and a library of 16, 000 compounds was synthesized.

UPS on Weinreb resin: a facile solid-phase route to aldehyde and ketone derivatives of "unnatural" amino acids and peptides.

The solid-phase synthesis of "unnatural" amino aldehydes, amino ketones, peptide aldehydes, and peptide ketones was accomplished from commercially available resin in a series of room temperature reactions. The initial step involved addition of an "unnatural" side chain to the N-terminus of a benzophenone imine-activated Weinreb resin-bound amino acid or peptide derivative. The alkylated imine was hydrolyzed, and the amine was converted to the Boc-, Cbz-, or naphthoyl derivative. The resin-bound substrate was then cleaved with DIBAL-H or a Grignard reagent to give the amino aldehyde, amino ketone, peptide aldehyde, or peptide ketone products. Twenty-four reactions were carried out simultaneously using a "Billboard" reaction apparatus to give products in 27-87% (59% average) isolated yield.

Synthesis and channel properties of [Tau 16]gramicidin A.

Des(ethanolamine)-taurine16-gramicidin A ([Tau 16]gramicidin A) was synthesized by the solid phase method and its channel-forming behavior in planar lipid bilayers was examined. The purified monovalent anionic peptide formed channels when applied to the aqueous compartments on both sides of the bilayer, but not when applied to one side only. The single-channel conductance was measured for KCl concentrations between 0.1 and 1.0 M and was found to be higher than that of gramicidin A in each case. Single-channel lifetimes were similar to those of gramicidin A suggesting that the channels have the beta 6.3 helix structure.

Synthetic bovine prothrombin precursor 13-29 for studies of vitamin K dependent carboxylase.

The synthesis of the amino acid sequence found in bovine prothrombin precursor 13-29 (PTP 13-29) has been achieved by solid-phase synthesis of the bis(acetamidomethyl)-protected linear peptide followed by cyclization to the monomeric disulfide. Synthesis of the disulfide bond was achieved by deprotection with mercuric acetate in acetic acid followed by oxidation with potassium ferricyanide. Experimental conditions for closure of the disulfide bond were identified by obtaining the circular dichroism spectra of the linear precursor in a variety of solvent systems. Cyclization in organic solvent systems was not successful but led to the formation of insoluble polymers. Synthetic PTP 13-29 was tested as a substrate for the vitamin K dependent carboxylase. Neither the linear nor cyclic synthetic 17 amino acid peptides were carboxylated as well as the standard, Boc-Glu-Glu-Leu-OMe, at mM concentrations. The estimated Km of synthetic PTP 13-29 is greater than 1 mM. Thus, bovine prothrombin precursor 13-29 is not an unusually effective substrate for the carboxylase as reported by Soute et al.

Structure and solution conformation of the cytostatic cyclic tetrapeptide WF-3161, cyclo[L-leucyl-L-pipecolyl-L-(2-amino-8-oxo-9, 10-epoxydecanoyl)-D-phenylalanyl].

The sequence and configuration of amino acids in the cytostatic cyclic tetrapeptide WF-3161 are established as cyclo(L-Leu-L-Pip-L-Aoe-D-Phe) where Pip = pipecolic acid and Aoe = 2-amino-8-oxo-9,10-epoxydecanoic acid. In chloroform, WF-3161 adopts a conformation with a possible gamma-turn between Leu NH and Aoe C = O and a cis amide bond between Leu and Pip. The torsion angles for this conformation are L-Aoe, phi, -95 degrees, psi, +85 degrees, omega, -155 degrees; D-Phe, phi, +120 degrees, psi, -80 degrees, omega, -175 degrees; L-Leu, phi, -145 degrees, psi, +35 degrees, omega, -10 degrees; L-Pip, phi, +20 degrees, psi, -135 degrees, omega, -170 degrees. The cis,trans,trans,trans amide bond sequence is related to the dimethyl sulfoxide conformation of chlamydocin, another cytostatic cyclic tetrapeptide.