Serine-containing 10-membered cyclodepsipeptides. Synthesis and molecular structure of PhCH2CO-DSer-Pro-Pro- and PhCH2CO-DSer-Pro-DPro-.

As a part of a research program aimed at studying synthesis and conformation of small ring peptides, the cyclization of diastereoisomeric N-phenylacetyl-seryl-propyl-proline tripeptides has been examined. Two 10-membered peptide lactones, PhCH2CO-DSer-Pro-Pro- 5a and PhCH2CO-DSer-Pro-DPro- 5b, have been isolated by treating the corresponding linear p-nitrophenyl esters with DBU in dry benzene. In these two compounds the serine lactone fragment (a common structural feature of several bioactive cyclodepsipeptides) is inserted into a highly strained small ring system. The conformation in the crystal of 5a and 5b has been studied by X-ray analysis. Both the 10-membered rings of 5a and 5b adopt an overall cis-cis-trans conformation in which the lactone junction is trans. The deviations from planarity of the peptide units vary from delta omega = 30 degrees for the DSer-Pro bond in 5b to delta omega = 5-6 degrees for the DSer-Pro bond in 5a and Pro-DPro bond in 5b. The skeletal atoms of 5b, containing the Pro-DPro sequence, are related by a pseudo-symmetry mirror plane passing through the Pro carbonyl and the opposite DSer C beta H2 group. In both the molecules the exocyclic amide bond adopts an extended conformation with respect to the DSer-Pro ring junction; this arrangement gives rise to a C5-type ring structure which is well evidenced in the case of 5a.

Ten-membered cyclotripeptides. III. Synthesis and conformation of cyclo(-Me beta Ala-Phe-Pro-) and cyclo(-Me beta Ala-Phe-DPro-).

The 10-membered cyclotripeptide cyclo(-Me beta Ala-Phe-Pro) 3 and its diastereoisomer cyclo(-Me beta Ala-Phe-DPro-) 4 have been synthesized under mild cyclization conditions starting from linear precursors containing C-terminal proline. The crystal and molecular structure of the two models has been determined by X-ray crystallography. Analysis of the NMR spectra supported by NOE data clearly indicates that the conformations found in the crystals are retained in solution. Both cyclotripeptides exhibit a cis-cis-trans backbone conformation. The two tertiary peptide bonds, at the proline and Me beta Ala nitrogen atoms, adopt a cis conformation whereas the CO-NH junctions are trans in both the models. The deviations from planarity of the peptide units vary from delta omega values of ca. 18 degrees for the Pro-Me beta Ala and DPro-Me beta Ala bonds to ca. 7 degrees for Phe-Pro and Phe-DPro bonds. Relevant conformational details of 3 and 4, as revealed by X-ray and NMR analysis, are reported. Crystals of 3 are monoclinic: P2(1), a = 5.317(2), b = 17.059(6), c = 9.514(3) A, beta = 99.18(3), Z = 2. The final R and Rw are 0.054 and 0.071 respectively. Crystals of 4 are orthorhombic: P2(1)2(1)2(1), a = 8.797(2), b = 19.440(9), c = 21.605(10) A, Z = 8. The final R and Rw are 0.069 and 0.104 respectively.

N-benzhydryl-tryptamines and 1,1-diphenyl-tetrahydro-beta-carbolines: synthesis, X-ray crystal structure and benzodiazepine receptor affinity.

Several N-benzhydryl-tryptamines and 1,1-diphenyl-tetrahydro-beta-carbolines were synthetized and the requisites for their formation were established. Crystallographic and conformational analyses were carried out on selected compounds and the affinity for the central benzodiazepine receptors was measured.

Structure-activity relationships in 4-deoxypyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV derivatives.

New 4-deoxyhalogenopyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV derivatives (V-VIII) have been prepared as an extention of a program which led to the synthesis of analogous pyrido- and alkylpyrido compounds (I-IV) displaying a low level of g.i. absorption. The new compounds give comparatively much lower ED50 p.o./s.c. ratios showing a recovery in the extent of oral absorption. XPS, N.M.R., and HPLC data rationalize this activity in hydrophilicity due to the electron-withdrawing inductive effect of the halogen atoms bound to the pyridoimidazo system. This effect is exerted in particular on the negatively charged N(2'), and is the opposite as that exerted by the alkyl groups present in (I-III).

The crystal and molecular structure of the alpha-helical nonapeptide antibiotic leucinostatin A.

The crystal and molecular structure of the nonapeptide antibiotic leucinostatin A, containing some uncommon amino acids and three Aib residues, has been determined by x-ray diffraction analysis. The molecule crystallizes in the orthorhombic space group P2(1)2(1)2(1), a = 10.924, b = 17.810, c = 40.50 A, C62H111N11O13, HCl.H2O, Z = 4. The peptide backbone folds in a regular right-handed alpha-helix conformation, with six intramolecular i----(i + 4) hydrogen bonds, forming C13 rings. The nonapeptide chain includes at the C end an unusual beta-Ala residue, which also adopts the helical structure of the other eight residues. In the crystal the helices are linked head to tail by electrostatic and hydrogen-bond interactions, forming continuous helical rods. The crystal packing is formed by adjacent parallel and antiparallel helical rods. Between adjacent parallel helical columns there are only van der Waals contacts, while between adjacent antiparallel helical columns hydrogen-bond interactions are formed.

A study of structure-activity relationships in 4-deoxypyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV derivatives by electron spectroscopy for chemical analysis and 1H NMR.

A new class of rifamycins, 4-deoxypyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV derivatives, has been synthesized. They are potent antibacterial agents and are not absorbed at the gastrointestinal level and can therefore probably be used as antibacterial intestinal disinfectants. From the present X-ray, electron spectroscopy for chemical analysis, and 1H NMR study, it appears that this peculiar pharmacokinetic behavior is mainly to be attributed to the fact that the pyridoimidazo system exists in these compounds in a mesomeric betaine form, bearing one positively and one negatively charged nitrogen. If it is assumed that rifamycins are generally absorbed by passive diffusion, the presence of the two oppositely charged nitrogens, together with the presence of the phenolic hydroxyls, means that these molecules are ionized at all pH values encountered along the gastrointestinal tract, which thus prevents their absorption. These molecules also display a strong tendency to self-associate both in solution and in the solid state, and the increase in molecular size may also play a role in preventing their absorption.

X-ray crystal structure of 4-deoxy-3'-bromopyrido[1',2'-1,2]imidazo[5,4-c]rifamycin S.

This paper reports the determination of the X-ray molecular structure of 4-deoxy-3'-bromopyrido[1',2'-1,2]imidazo[5,4-c]rifamycin S, carried out in order to unequivocally define the general structure of a new series of rifamycin SV derivatives, which are potent antibacterial agents, and are not absorbed at the gastroenteric level. They have been prepared by Alfa Farmaceutici, Bologna, by condensing 2-aminopyridine derivatives to 3-bromorifamycin S. The solid state X-ray study has confirmed the structure proposed on the basis of 1H NMR studies in solution. It has also shown that the newly formed pyridoimidazo system is in a mesomeric betaine form, the pyrido nitrogen being positively charged and the imidazo nitrogen being negatively charged. This feature is believed responsible for the pharmacokinetic behavior of these new drugs, one of which, denoted either as rifamycin L 105 or rifaximin, is actually under clinical trial as a topical intestinal disinfectant.

Metabolites of microorganisms. 229. Absolute configuration of naphthomycin A determined by X-ray analysis and chemical degradation.

The relative and absolute configurations of naphthomycin A were elucidated by an X-ray structural analysis of a methylation product, 25-O-methylnaphthomycin A iminomethyl ether. The absolute configuration was confirmed by degradation (O3, NaBH4) to (S)-butane-1,2,4-triol.

Cyclols, cyclodepsipeptides, and N-acyl-diketopiperazines from linear precursors. Synthesis and crystal structure of 10-membered cyclodepsipeptides.

In order to investigate the relative formation tendency of different tautomeric ring systems (cyclols, cyclodepsipeptides and corresponding N-acyl-diketopiperazines), two linear peptide precursors containing proline as C-terminal residue, have been synthesized and subjected to cyclizing conditions. Boc-Ser-Phe-Pro-ONp (I) gave three isomeric cyclic compounds: Boc-Ser-Phe-Pro- (IV), N-(Boc-Ser)-cyclo-(Phe-D-Pro) (III) and the corresponding aza-cyclol (II). Starting from Hyb-Phe-Pro-ONp (V) two epimeric N(3-hydroxybutyryl)diketopiperazines (VI) and (VII) and the corresponding 10-membered cyclodepsipeptide (VIII) could be isolated. Crystal and molecular structure of VIII is reported. Crystals of VIII are orthorhombic, P212121 with a = 9.684, b = 22.985, c = 7.841, z = 4. The two peptidic bonds are cis with omega values of 6.6 degrees and - 18.1 degrees, whereas the lactonic bond is of transoid type. The pyrrolidine ring has C2-C gamma-exo conformation.

Structure-activity relationships in the ansamycins. Molecular structure and activity of 3-carbomethoxy rifamycin S.

The X-ray and NMR structural study of 3-carbomethoxy rifamycin S5 was undertaken in order to determine whether its low antimicrobial activity was related to a conformation of the molecule which was unfavorable for interaction with bacterial DNA-dependent RNA polymerase. However, the molecule assumes a conformation similar to that of the active rifamycins. Indeed the compound was found to be active on the isolated enzyme, so that its low activity on whole bacteria has to be attributed to factors affecting its penetration through the bacterial cell wall.