The synthesis of five amino phosphorus derivatives, 1a-e, is described. The derivatives were incorporated into a series (18) of analogues of the 5-14 portion of angiotensinogen, in most cases at the scissile Leu-Val bond. The resultant compounds were tested in vitro for their ability to inhibit human plasma renin. Replacement of the scissile bond with the phosphinic analogue of Leu10-Val11 (1b) gave the most potent inhibitors, having IC50 = 7.5 x 10(-8) M for H-Pro-His-Pro-Phe-His-(1b)-Ile-His-Lys-OH and IC50 = 1.0 x 10(-7) M for Z-Arg-Arg-Pro-Phe-His-(1b)-Ile-His-NH2. The shorter phosphonic acid sequence Z-Pro-Phe-His-(1d) retained biological activity with an IC50 = 6.4 x 10(-6) M.
X-ray crystallography and computer-assisted molecular modeling (CAMM) studies aided in the design of a potent series of mammalian purine nucleoside phosphorylase (PNP) inhibitors. Enhanced potency was achieved by designing substituted 9-(arylmethyl)-9-deazaguanine analogs that interact favorably with all three of the binding subsites of the PNP active site, namely the purine binding site, the hydrophobic pocket, and the phosphate binding site. The most potent PNP inhibitor prepared during our investigation, (S)-9-[1-(3-chlorophenyl)-2-carboxyethyl]-9-deazaguanine (18b), was shown to have an IC50 of 6 nM, whereas the corresponding (R)-isomer was 30-fold less potent.
Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.
The synthesis is described of fLcorticotrophin-(1 -24) -tetracosapeptide t labelled with tritium in the histidine residue at position 6 at a specific radioactivity of 30 Ci mmol-l by reductive dehalogenation of a protected precursor. Evidence for the integrity of the final product is provided by amino-acid analysis, column chromatography, and bioassay, supported by chemical and enzymic analytical data on the protected precursor and the derived free peptide containing di-iodohistidine.FOLLOWING the syntheses of p-corticotrophin-( 1-24)-and implicated for the 61-residue a-neurotoxin of Naja tetracosapeptide labelled with tritium in the tyrosine 2*3 nigricoZZis,6 and we were confident that protected synand phenylalanine residues, we wished to extend our thetic peptides containing di-iodohistidine could be investigations to ascertain whether the labelling method, similarly labelled by reductive de-iodination. catalytic dehalogenation, could be used to label specific-Of the various possibilities (Scheme l), the most ally the aromatic side-chain of the amino-acid histidine, attractive synthetic approach to the key intermediate, which is also present in Synacthen.the N-terminal decapeptide, seemed to be by a 5 + 5
Boc-Ser-Tyr-Ser-Met-Glu (OBut 1-N3 ( f r o m 4 1 + His ( I2 I-Phe-Arg-lip-Gly Boc-Ser-Tyr-Ser-Met-Glu (OBut )--His ( IzI-N~ tetracosactrin, SynacthenQ (trade name of CIBA-GEIGY, Basle) ,. Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro. t P-Corticotrophin-( 1-24) -tetracosapeptide : $ In this paper, all amino-acid residues are L.coupling at the glutamic acid residue as this allowed fewest synthetic steps from the scarce unnatural aminoacid di-iodohistidine to the final product. We prepared the hydrazide (4) and carboxylic acid (5) of the Nterminal pentapeptide by conventional procedures (Scheme 2). Coupling of the free acid to the C-terminal pentapeptide (12) by hydroxybenzotriazole-assisted carbodi-imide condensation (DCC-HOBt) was completely unsuccessful and is not detailed here. This was surprising since successful couplings in high yield at this bond have been reported. Biossonnas and his coworkers synthesised a-MSH and the N-terminal eicosapeptide sequence of ACTH by DCC condensation at the Glu-His bond. The y-carboxy-function of the glutamic
Durch schrittweisen Aufbau nach klassischen Fragmentkondensationsmethoden wird ausgehend vom Tripeptid (I) über die Fragmente (II) und (III) das geschützte lineare Tetradecapeptid (IV) synthetisiert, das a) durch reduktive Deiodierung des Phe(I)‐Bausteins mit T2, Disulfidbrückenbildung der Cysteinreste mittels Iodoxidation und Deblockierung das im Baustein 6 tritiierte Somatostatin (Va) bzw. b) durch Iodoxidation und Deblockierung das iodierte Somatostatin (Vb) liefert.
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