The all-light-atom X-ray crystal-structure analysis of cyclosporin A (l), a cyclic undecapeptide containing seven N-methylated amino acids, reveals a conformation very similar to that of the previously analysed iodo derivative which is characterised by a twisted P-pleated sheet involving the residues Me-Val-1 1, MeBmt-1, Abu-2, Sar-3, MeLeu-4, Val-5, MeLeu-6, and Ala-7. The@-bend at Sar-MeLeu-4 is of type II', and the loop of the residual amino acids involves a cis-peptide bond between MeLeu-9 and MeLeu-10. The NH proton of D-Ala-8 closes a $-bend with a H-bond to the MeLeu-6 CO group. The crystal was grown from acetone. A closely similar backbone conformation in apolar solvents such as CDCl, or C6D6 has been derived from the interpretation of the NMR spectral parameters (homo-and heteronuclear NOE effects, coupling constants, chemical-shift values of the C-, H-, and N-atoms). A minor variation in the backbone conformation between crystal and solution is observed in the region of o-Ala-8, where in solution a 3-center H-bond is established between the NH of D-Ala-8 und the carbonyl 0-atoms of both MeLeu-6 ($-turn) and o-Ala-8 (C5-bend). A recently proposed technique to identify intramolecular H-bond via heteronuclear NOE from NH proton to carbonyl C-atoms is critically analysed. The main difference between crystal and solution conformations lies in the orientation of the side chains of the unusual amino acid MeBmt kl = f60" in solution, -168" in the crystal) and of MeLeu-10 k1 = -60" in solution, +60' in the crystal). The differences in crystal and solution are caused by the break ofthe intermolecular H-bond of the OH group of MeBmt on dissolution of the crystal. The bifurcated H-bond ofo-Ala-8 twists the backbone in this region. Molecular modeling demonstrates that this is the origin of the change in the side chain conformation of MeLeu-10. The intramolecular flexibility in the crystal indicated by the thermal parameters obtained from the X-ray refinement, and in solution by an analysis of spin-lattice relaxation times in the NMR experiments, indicate a fairly rigid backbone and fixed conformations for all the side chains except for that of Abu-2 and the distal atoms of MeBmt.
Sunzmary. The crystal structure of an iodo-derivative of cyclosporin .I has bccn dctcrniined in order to elucidate the constitution of this cyclic undecapept ide. Crystals of iodocyclosporin A are monoclinic, a = 10.475(5), b = 19.60(1), c = 21.04(1) is, ,!j =: 99.35(2)", space group P21 (Cz, No. 4). The structure was solved by the heavy atom nicthod and refined by blockdiagonal least-squares analysis to a final 12-€actor of 0.135 with hydrogen atonis in calcuhtcd positions. The cyclic peptide h a s a conformation which is partly P-pleated sheet and partly open loop. The structure analysis demonstrates for the first time the rcality of a new type of dipcptide hydrogen-bonding, predicted by Pullman from MO calculations and leading to a conforination described by him as C;cl.Cyclosporin A is a cyclic undecapeptide CszHlllNllOlz wliicli niiiy IIC isolated frtm Trichoderma poZys$orurn (Link ex Pers.) Rifai 111. The compound is neutral, rich in hydrophobic amino-acids, insoluble in water and 9%-liexane, but very soluble in all other organic solvents, and exceedingly difficult to crystallise. (In fact, it was not until some three months after the completion of this structure analysis, that excellent crystals were serendipitously obtained from acetone solutioi I at -1.5O.) \Ye were, Iiowever, able to obtain a crystalline derivative from the rcac-tion of cyclosporin and iodine in the presence of tliallium acetate.The analysis of iodocyclosporin was undertaken to deterinine the constitution of the natural product. *4t the beginning of the analysis the amino-acid cornpusition and part of the sequence was known froin chemical and spectroscopic studies 121, as was the presence of a hitherto unknown P-hydroxy, singly unsaturated Cg amino acid, the site of iodine addition. (We abbreviate this amino-acid as Cg-ene.) The structure analysis showed the constitution of cyclosporin A to be 1, where a11 optically active amino-acids are L with the exception of Ala (8) which is D.
The structure and absolute configuration of pseurotin (1), a new metabolite, isolated from culture filtrates of Pseudeurotium ovalis STOLK (Ascomycetes), has been shown to be 2‐[1′(S), 2′ (S)‐dihydroxhex‐3′‐ene‐yl]‐3‐methyl‐8(S)‐methoxy‐8‐benzoyl‐9(R)‐hydroxy‐(5S)‐1‐oxa‐7‐aza‐spiro[4.4]non‐2‐ene‐4, 6‐dione (1), by spectral data and chemical transformations, and by X‐ray analysis of its dibromo derivative 2 [1].
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.