Solid phase synthesis and some pharmacological properties of 8-D-homolysine-vasopressin and 1-deamino-8-D-homolysine-vasopressin.

8-DL-Homolysine-vasopressin and its 1-deamino derivative were synthesized by the solid phase method. The desired D-homolysine analogues were obtained by digestion of the mixtures with trypsin and isolation of the peptide components by ion-exchange chromatography. In agreement with earlier observations on vasopressins containing alpha, omega-diamino acids of D configuration the new analogues show very low pressor activities. However, the antidiuretic effects are surprisingly high, thus reversing the known activity trend and making the D-homolysine analogues highly selective antidiuretic agents.     

The synthesis and some pharmacological properties of (2-L-DOPA)-oxytocin.

The first reported synthetic analogue of a naturally occurring peptide with a residue of L-3,4-dihydroxyphenylalanine (L-DOPA) was prepared by coupling N-carbobenzoxy-S-benzylcysteinyl-L-DOPA azide with isoleucylglutaminylasparaginyl-S-benzylcysteinylprolylleuclglycinamide. The protecting groups were removed from the resultant nonapeptide derivative by sodium in liquid ammonia and the peptide analogue was formed by short term oxidation of the dithiol-containing compound. It was isolated by sequential partition chromatography and exclusion chromatography on Sephadex G-25. It was unstable at neutral or alkaline pH. [2-L-DOPA]-oxytocin was found to possess a minimum milk-ejection-like activity of 54 +/- 9 U/mg and uterotonic activity of 26 +/- 4 U/mg. These potencies are approximately 12% and 5% of the corresponding potencies of oxytocin.     

Solid phase synthesis of peptide-selenoesters

The synthesis of proteins by native chemical ligation greatly enhances the application of chemistry to complex molecules such as proteins. The essential building blocks for this approach traditionally have been peptide-thioester segments that are linked chemoselectively in consecutive reactions. By using peptide selenoesters instead of thioesters, the ligation rate can be significantly accelerated permitting couplings at difficult sites and potentially enabling new ligation strategies. To facilitate the routine synthesis of selenoester peptides, a general and straightforward procedure has been developed that generates a suitably functionalized resin from which the desired selenoester peptide can be readily synthesized. This simple approach utilizes readily available and cheap chemical agents and enables production of peptide selenoesters of excellent quality in short time and with high recovery. In addition, the stability of peptide selenoesters was examined under different native chemical ligation conditions and compared to thioesters. Selenoesters are slightly more reactive and more susceptible to hydrolysis and aminolysis than thioesters but sufficiently stable under mildly acidic conditions (pH 6.5). Under these conditions, rapid selenoester-mediated ligation is kinetically favoured.     

Solid phase synthesis of oligodeoxyribonucleoside phosphorodithioates from thiophosphoramidites.

Oligonucleoside phosphorodithioates 1 are modified DNA sequences with potential use as antisense oligonucleotides. The preparation of up to 20-mers containing all four bases by solid phase synthesis is described, with details on the preparation of the four monomer units (protected nucleoside thiophosphoramidites 2), the conditions used for the assembly of the strands with up to 19 phosphorodithioate linkages, and the purification and characterisation of the products. Full-length homogeneity of HPLC-purified all-phosphorodithioate products is demonstrated by PAGE, but 31P NMR discloses the presence of phosphorothioate impurities (typically 8-9%), the origin of which is discussed. Oligonucleoside phosphorodithioates are freely soluble in water at neutral or basic pH, and are very stable towards oxidation, hydrolysis, and nuclease cleavage. Their ability to hybridize to complementary DNA has been studied by UV melting point (Tm) measurements. The observed depression of Tm, 0.5-2 degrees C per phosphorodithioate linkage, is higher that the 0.4-0.6 degrees C found for phosphorothioates.     

Solid phase synthesis of somatostatin-28

The synthesis of ovine hypothalamic somatostatin-28 (Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-$\text{Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys}$-OH) has been accomplished by solid phase methodology. The structure of the synthetic material was verified by: (1) direct sequence analysis with a Beckman 89°C sequencer, (2) correlation of the amino acid analyses of the isolated tryptic peptide fragments with their theoretical compositions, and (3) comparison, using high performance liquid chromatography, of the synthetic methionine-sulfoxide and methionine-sulfone modified NH₂-terminal peptides (residues 1–11) with the corresponding tryptic fragment from somatostatin-28.     

Solid phase synthesis of 2-aminobenzothiazoles

A traceless solid supported protocol for the synthesis of 2-aminobenzothiazoles is described, employing resin-bound acyl-isothiocyanate and a series of anilines. Cyclization of the resulting N-acyl, N′-phenyl-thioureas generates the 2-aminobenzothiazole scaffold, which can be further elaborated prior to hydrazine-mediated cleavage of the final products from the carboxy-polystyrene resin. A small, focused library of 2-aminobenzothiazoles was prepared.     

alpha-DNA. VII. Solid phase synthesis of alpha-anomeric oligodeoxyribonucleotides.

An efficient procedure for the synthesis of unnatural alpha-anomeric oligodeoxyribonucleotides is described. This solid-phase procedure is based on the use of alpha-nucleoside phosphoramidites and alpha-nucleoside derivatized solid supports corresponding to the four natural bases and allow rapid synthesis of oligonucleotides up to 20 alpha-deoxynucleotide units in length. After HPLC purification, a 15-mer: alpha-d(CCTCTCGTTCTTTAC) and a 20-mer: alpha-d(ATACTTGAGGAAGAGGTGTT) were obtained respectively in 27 and 29% overall yields. Their purity, nucleoside composition and primary structure were ascertained by HPLC and Maxam-Gilbert sequence analyses.     

Solid phase synthesis of complex natural products and libraries thereof.

Natural products have served as an important source of medicinal compounds and pharmaceutical leads over the last century. Within the last 10 years, significant interest has developed in applying combinatorial chemistry techniques to the study of natural products and their biological activities. In this review, we examine several representative efforts wherein natural product skeletons have been constructed or immobilized on solid support and subsequently derivatized, giving rise to analog libraries useful in understanding the structure-activity relationships of the parent natural product. Issues such as target selection, library design, linker development, automation, and library characterization are addressed.     

Synthesis and some pharmacological properties of (2-tryptophan)-oxytocin.

Previous studies have suggested that an aromatic amino acid residue at position 2 in oxytocin facilitates the expression of the hormone's biolgocial activities. [2-Tryptophan]-oxytocin, in which a residue of tryptophan has replaced that of tyrosine in oxytocin, has been synthesized by the method of azide coupling of the N-terminal dipeptide and C-terminal heptapeptide amide. It was found to have approximately 0.1% of the potency of oxytocin in milk ejection and uterotonic biological activities.     

Solid phase synthesis of thymosin beta 9

Thymosin beta 9, a 41 residue thymic polypeptide, has been synthesized by a solid phase method. A modification of the low HF method was used to deprotect and cleave the peptide from the resin. Thymosin beta 9 was then obtained in analytically pure form by a one-step purification procedure in 32% yield. The activity of thymosin beta 9 in the terminal deoxynucleotidyl transferase assay was greater than calf thymus fraction 5, but comparable to thymosin beta 4. In contrast to thymosin alpha 1, neither beta 4 nor beta 9 was active in the rosette inhibition assay.     

Solid phase synthesis of acylglycine human metabolites

Acylglycines represents a large and important class of human metabolites. They are often used in medicine to identify fatty acid oxidation disorders. A highly efficient solid phase synthesis approach to obtain these clinically important compounds is developed via coupling reaction between glycine-preloaded Wang resin and a set of carboxylic acids. The developed methodology facilitates the preparation of several structurally-diverse acylglycines with high yields and purity.     

Nucleoside 5''-phosphordiamidates, synthesis and some properties.

A simple way of preparing nucleoside 5'-phosphordiamidate is described. The procedure is based on the ammonolysis of nucleoside 5'-phosphordichloridates by dilute aqueous ammonium hydroxide. The behaviour of nucleoside phosphordiamidates under acidic and alkaline conditions is also reported. Alkaline hydrolysis results in the formation of the parent nucleoside, whereas one amide group can be removed selectively by mild acid hydrolysis. This property of nucleoside phosphordiamidates served as a basis for the elaboration of a simple synthesis of nucleoside phosphoramidates starting from nucleosides.     

Solid phase synthesis of ovine corticotropin releasing factor

Ovine corticotropin releasing factor was synthesized by the stepwise solid phase method under conditions anticipated to maximize yield. Final yields of fully active hormone were 34% based on peptide which could be removed from the resin and 24% on initial resin substitution.     

Solid phase synthesis of growth hormone-release inhibiting factor

The growth hormone-release inhibiting factor (GH-RIF) tetradecapeptide

, was prepared by the cyclization of a linear, disulfhydryl peptide intermediate by treatment with potassium ferricyanide. The linear peptide was synthesized by an automated solid-phase technique. The cyclic material inhibited the secretion of radioimmunoassayable growth hormone $\text{in vitro}$ at doses as low as 0.1 μg. A high molecular weight compound formed during the cyclization reaction and believed to be predominantly dimer also possessed considerable inhibitory activity.     

Preliminary evaluation of pharmacological properties of some xanthone derivatives

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for α₁- and β₁-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.