Dimitrios Theodoropoulos

Convenient synthesis of n-trityl-o-alkyl-l-hydroxyamino acids and derivatives : Application to the synthesis of related peptides

Abstract The disodium salts of N-trityl-hydroxyamino acids 2 prepared in situ with NaH, in the presence of imidazole, were selectively alkylated with alkyl iodides to give N-trityl-O-alkyl-hydroxyamino acids 3 . Compounds 3 were readily converted to O-alkyl-hydroxyamino acids 5 or other intermediates useful for incorporation into a peptide chain. The applicability of these derivatives in the preparation of related peptides is illustrated by the synthesis of the protected analogues of enkephalin N-carbobenzoxy-tyrosyl-glycyl-glycyl-phenylalanyl-(O-ethyl) serine benzyl ester and N-carbobenzoxy-tyrosyl-glycyl-glycyl-phenylalanyl-(O-methyl) homoserine benzyl ester.

Fast atom bombardment, field desorption, and desorption chemical ionization mass spectrometry of cis-dichloroplatinum amino acid and dipeptide complexes

Abstract The ionic cis -dichloroplatinum(II) complexes of glycine, phenylalanine, and tyrosine; and the non-ionic complexes with methyl methionate, methyl leucylmethionate, and leucylmethionamide were analyzed by fast atom bombardment, field desorption, and desorption chemical ionization mass spectrometry. Negative ion fast atom bombardment spectra of the ionic complexes contained (M-K) and (M-H) ions, considerable fragmentation, and adduct ions with water and the glycerol matrix. No useful results were obtained for the non-ionic complexes. While technically more difficult, field desorption analyses were successful for both ionic and non-ionic complexes. Information was limited to a determination of the molecular weight due to the absence of fragment ions. Desorption chemical ionization spectra were successful only with the non-ionic complexes. Spectra contained protonated molecular ions and structurally significant fragments.

Synthesis of enantiomeric pureCis-dichloroplatinum(II) amino acid complexes

The reaction of potassium tetrachloroplatinate(II) with six representative sulfurcontaining amino acids, namely,d- andl-cysteine,d- andl-methionine and its methyl ester hydrochloride gives the corresponding enantiomerically purecis-dichloroplatinum(II) complexes. This represents the first reported series of well-characterized enantiomerically pure platinum(II) complexes for bothd- andl-amino acids.The spectroscopic properties, including IR,1H-NMR, and13C NMR, of these complexes and their configuration are discussed.

Structural studies with weak oxytocin antagonists

[Aib3,Thr5]OT, [Aib3,Thr(OMe)5]OT, [Aib3,Orn8]OT, [Thr(OMe)5,Orn8]OT and [Phe2,Thr(OMe)5,Orn8]OT were synthesized by solid-phase techniques. From the biological properties of these peptides, it seems that the simultaneous replacement of positions 3 and 5 of oxytocin with Aib and Thr(OMe) results in an analogue devoid of antagonistic activity in comparison with the singly substituted compounds. Simultaneous Orn8 substitution does the same in the case of the Aib3 analogue and even leads to agonistic activity in the case of the Thr(OMe)5 analogue. Replacement of Tyr2 by Phe2, e.g. [Phe2,Thr(OMe)5,Orn8]OT, again favors the appearance of minor antagonistic potency.

Synthesis and conformation of n-trityl dipeptide derivatives

Abstract N-Tritylamino acids activated with DCC/HOBt, were coupled with various amino acid derivatives without racemization. The trityl group was split off quantitatively in 10% CCl3COOH monohydrate or CH2ClCOOH in CH2Cl2. Under these conditions detritylation of N-Trt-Trp-Gly-NH2 proceeds without formation of an oxindole derivative and side alkylation products, even in the absence of a scavenger. Dipeptide derivatives 1 and 2 exhibited magnetic asymmetry, attributed to steric factors.

Synthesis and proposed conformations of l-prolyl-l-leucyl-β-alanine alkylamides

Abstract The synthesis of H-Pro-Leu-β-Ala-NH 2 , H-Pro-Leu-β-Ala-NHCH 3 and H-Pro-Leu-β-Ala-N(CH 3 ) 2 is described. On the basis of IR and 1 H NMR spectral data, a 7-membered ring including the NH of β-alanine with the CO of proline should be assigned for the H-Pro-Leu-β-Ala-N(CH 3 ) 2 . Consequently, the plausible conformations for H-Pro-Leu-β-Ala-NH 2 and H-Pro-Leu-β-Ala-NHCH 3 derive from the formation of an 11-membered ring, between the trans amide proton and the CO of Pro, or from the formation of an 8-membered ring, between this carboxamide proton and the CO of Leu, plus the aforementioned 7-membered ring.

Synthesis of N-Trityl-L-homoserine

Abstract L-Homoserine was tritylated via its silylated product with Me2SiCl2 or Ph2SiCl2 in 65-68% yield. Also N-Trt-L-methionine upon treatment with Mel and degradation of the resulting sulfonium salt with KOH yielded N-Trt-L-homoserine in 75% yield. Both routes provided N-Trityl-L-homoserine with identical physical data. In contrast to N-alkyloxycarbonyl-L-homoserine derivatives, N-Trt-L-homoserine shows no tendency to spontaneous lactonization.

Synthesis and contractile activity of the C-terminal heptapeptide of substance P with N5-dimethyl glutamine in the 6-position. Active site studies

The synthesis and testing of [N5-dimethyl-Gln6]-SP5–11 showed 37±12% contractile activity relative to SP, and intrinsic efficacy 98±4%. This finding indicates that the carboxamide groups of the dual Gln5-Gln6 moiety are not equally related with the contractile response of the C-terminal heptapeptide of SP.

Synthesis and biological properties of the [5-(N5-dimethyl)-glutamine]-analogue of the C-terminal heptapeptide of substance P: active-site studies.

Substance P (SP), an undecapeptide amide, is the hypotensive, spasmogenic agent detected [l], the sialogogic peptide noticed in [2], and the motoneuron-depolarizing peptide studied [3]. Complete amino acid sequence of SP was determined [4,S] . (fig.la). Its primary structure was confirmed by synthesis either by the solid-phase method [4,6,7] or conventional solution techniques [8-lo]. Studies on the relationship between chainlength and activity revealed that the C-terminal heptapeptide of SP exhibited higher contractile activity on the isolated guinea pig ileum than that of synthetic SP [7,9]:Thus, in an effort to identify sites involved in the receptor recognition and activation of SP, the Nglutamine residue of the C-terminal heptapeptide of this hormone has been modified by replacing its carboxamide hydrogen atoms by methyl groups (fig.1 b). This modification of the -NH2 portion of the carboxamide group renders it less hydrophilic and possibly less available to the receptor due to steric hindrance.

Synthesis and biological activities of [β-malyl1]- and [β-Malyl1, Leu8]-angiotensin II analogues

The synthesis of [β-Malyl1]- and [β-Malyl1, Leu8]-angiotensin II using a solid phase procedure is reported. The replacement of the N-terminal amino group of aspartic acid by a hydroxyl group gives analogues with lower affinity than [Asn1]- and [Asn1, Leu8]-AII. However, the isoster [β-Malyl1]-AII shows higher potency than [Asn1]-AII and this may be due to metabolic or enzymatic resistance.