Summary. The synthesis of a new, boron-containing analogue of phenylalanine is described. Carboranylala.nine (Car) carries a 1,2-carborane cage in place of the benzene ring of phenylalanine. It is obtained by the reaction of derivatives of propargylglycine with decaborane. Possibilities of practical application derive from the facile neutron activation of boron nuclei with mass number 10.o-Carborane (1, 2-C~BloH12) and its C-derivatives [ 21 display icosahedral geometry. The dimensions of the cage are only slightly larger than the space occupied by a benzene ring rotating about its C(l)-C(4) axis, and the two carbon atoms participate in the delocalized bonding. It thus appears that o-carboranylalanine (1; Car) would be sufficiently similar to phenylalanitie in order to be an interesting analogue for probing the role of this amino acid in certain biologically active peptides. The likeness becomes apparent from the Figure.The possible role of 1 as a probe becomes even more intriguing if one considers the interaction of boron with thermal neutrons, having v N 2,220 m/s at 0.025 eV '31 : Natural boron is composed of 18.45% 1% and 81.5Sy0 IlB; the former has a large capture cross section for thermal neutrons of 3,900 barns (= 10--2* 1112). Very pure [loB]-decaborane, the starting material for [10B]-o-carboranylalariine, has been prepared in this laboratory (E. Escher). From the above data it would appear that o-carboranylalanine with -on the average -two or more 10R nuclei would be an excellent molecule for producing ionizing radiation in biological materials.Boron, introduced into certain parts of the animal or plant body, has been used for auto-radiographic purposes [3], and for the treatment of neoplastic diseases (cancer) [4]. o-Carboranylalanine, as a component of peptides such as peptide hormones, might offer an especially attractive means of transporting via the blood )This work was supported by the Schweizerischer Nationalfonds zur Forderung der wissenschaftlichen Fovschung, and is part of the doctoral thesis of 0. L. Abbreviations according to [l] and [Z]. For the new amino acid, o-carboranylalanine, the abbreviation Car is proposed.HELVETICA CHIMICA ACTA -Vol. 59, Fasc. 6 (1976) -Nr. 225 2185 CarFhe stream rather high concentrations of boron to specifically defined areas (target cells and target organs). Starting materials for the synthesis of 1 (Scheme) were the bis(acetonitri1e)-decaborane complex [5], and L-phthalyl-propargylglycine methyl ester [6] : (4Condensation (c) was carried out according to the general procedure of Heying [7], and immediately and stereospecifically gave pure, crystalline 2 in a moderate yield (50-60%). Concentrated boiling HC1 solution removed both protecting groups (reaction (d)) ; the free amino acid 1 was readily obtained, although in a small yield (22%). More diluted HC1-solution in acetic acid, according to the general procedure of Sheehan et al. [8], selectively hydrolysed the methoxycarbonyl group to give the N-phthalyl-L-amino-acid 3 (Ieaction (e)) . 86HELVETICA CHIMI...

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Summary2-Pyridine sulfenyl chloride (PS-Cl) is a useful reagent for simultaneously deprotecting and activating the mercapto-group of cysteine and of cysteine-peptides preliminary to disulfide-bond formation. The S-protecting groups that are amenable to this reaction include trityl, diphenylmethyl, acetamidomethyl, t-butyl, and t-butylsulfenyl.In order to produce a peptide cysteine bridge, two S-protected cysteine residues are usually introduced during the synthesis. They are then deprotected and finally oxidized to the required disulfide bond. A wide variety of S-protecting groups have been described in the literature. The conditions for their removal are sometimes quite strong, For example, the cleavage of S-trityl cysteine with HBr or trifluoroacetic acid (TFA) affords only 60% of free cysteine because the removal of the S-trityl group in acid is in equilibrium with its attachment [I]; S-Diphenylmethyl (S-Dpm) requires 15-30 min of boiling in TFA and phenol [l]; HBr affords only a 50% yield at 50". However, S-trityl and S-Dpm-cysteine can be deblocked with Ag+-or Hg2+-ions [2]. S-t-butyl-cysteine can be cleaved either by sulfitolysis [3] or with o-nitrophenyl-sulfenyl chloride [4]. The S-acetamidomethyl group [5] has also been widely used, the conditions for deprotection with Ag+ or Hg2+ are very mild, The oxidation step is also critical. While many procedures offer high yields for cysteine or cysteine derivatives [6] they sometimes fail in more complicated situations.We wish to report here a rather general and mild method for deprotecting S-protected cysteine-residues which affords, after reaction, a reactive mixed disulfide which can react further with free SH-groups to provide an other disulfide.Scheme1 shows an outline of this S-deprotection by means of 2-pyridine sulfenyl chloride (PS-Cl, compound I).PS-C1 is extremely reactive and decomposes immediately with moisture. However it is a solid and can be easily handled in water-free glacial acetic acid. The i)Abbreviations are according to the IUPAC-IUB Commission on Biochemical Nomenclature.

Chemical synthesis and biological activities of a new a-melanotropin derivative are described. Nu-(5-Bro-movalery1)-Na-deacetyl-a-melanotropin contains the 5-bromopentanoyl group as a chemical 'handle' in place of the acetyl group of the natural hormone. The synthesis involved a new protected intermediate which allowed the selective deprotection of either the N" or N' amino group. The title compound reacted with sodium thiosulfate to give N"-deacetyl-Na-(5-(sulfothio)valeryl)-a-melanotropin, a key intermediate for the preparation of tobaccomosaic virus/a-melanotropin disulfide conjugates. As a basis for the study of the conjugates, biological activities of the title compound on Cloudman S-YI mouse melanoma cell cultures (tyrosinase stimulation, binding, and cyclic AMP accumulation) were determined. They proved to be quite similar to the corresponding a-melanotropin activities. Differences in bindings may be explained by stronger hydrophobic interaction of the new derivative with the lipid phase of the target cell membranes. ') Parts of this report have appeared as a thesis [I]. Nomenclature and abbreviations [2]. Additional abbreviations: MSH = rnelanophore stimulating hormone (melanotropin), DCC = N,N-dicyclohexylcarbodiimide, DCU = N,N'-dicyclohexylurea, DMF = dimethylformamide, HOBt = 1-hydroxybenzotriazole, Boc = tert-butoxycarbonyl, OBu' = tert-butoxy, Msoc = 2-(methylsulfonyl)ethoxycarbonyl, Np = 4-nitrophenyl, Z = benzyloxycarbonyl, TFA = trifluoroacetic acid. Chiral amino acids are in their L-configuration. Culture media see E.xperimentu1. Synthesis of N"-(5-Bromovaleryl)-N"-deacetyl-a-melanotropin (10).-Two approaches are illustrated in the Scheme. One (steps 11+12-+10) was based on an earlier synthesis of a-MSH [7] wherein the Lys (Msoc)-11 protection is removed by alcaline /I-elimination in the last step. This worked here for the relatively stable 5-bromovaleryl derivative. However, for more reactive handles, such as bromoacetyl or maleimido groups [5] [8], deblocking in the final stage must be effected by mild acid treatment. We, therefore, reversed the type of protection, using Msoc for the IT-atom and protecting groups derived from t-butyl alcohol for the side chains [9]. The key intermediates 7 and 8 can serve a wider range of handles than 11.Suitable educts for the second approach (steps l+lO) were the Boc-tetrapeptide methyl ester 1 [lo] and the Z-protected nonapeptide 5 [ll]. The former was saponified to the free acid 2 which was treated with TFA to remove the N-terminal protection. The crystalline tetrapeptide salt 3. TFA was reacted with 4-nitrophenyl 2-(methyl-sulfony1)ethyl carbonate [7] [ 121 to yield crystalline, analytically pure Msoc-tetrapeptide 4. Its isolation was rather difficult because of a pronounced solubility in H,O and organic solvents.Compound 4 was condensed with the mixed HOBt.HC1 salt 6 of partially protected nonapeptide amide (produced from 5 by catalytic hydrogenation in the presence of HOBt), using the DCC/HOBt method without base. This procedure is known to minimize sid...

Thc IH-and W-NMR. spcctra of cyclo-tetrirglycyl show that thc four pcptido groups are magnetically cquivalcnt, and different from either a standard trans or a standard cia peptide group. It is suggested that the observed NMR. features corrcspond to a non-planar form of the peptide groups. On the one hand these data confirm thc carlicr conclusions from theoretical investigations of the molecular geometry, that cyclic tetrapeptides could not contain four stanclan1 trans peptidc groups. O n the other hand they are not consistent with a prevjously suggcstd alternative molccular conformation according to which cyclo-tetraglycyl would adopt a conformation similar to cyclo-tetrasarcosyl. with two cis and two trans peptide bonds. The diffcrcnt