The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis

The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with anti-metastatic properties, has been accomplished. Our concise and flexible approach utilized a Lewis acid-catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin (2 + 3 --> 21). Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain was achieved by an anti-selective aldol addition of propionyl oxazolidinone 28 to angelic aldehyde 27, followed by a Horner-Wadsworth-Emmons (HWE) coupling of 32 with glutarimide aldehyde 5. Finally, the assembly of the macrocycle was realized by a highly (E)-selective ring-closing metathesis (35 --> 37). Utilizing the power of diverted total synthesis (DTS), a series of otherwise inaccessible analogues was prepared and evaluated for their potential as tumor cell migration inhibitors in several in vitro assays. These studies revealed a dramatic increase in activity when the natural motif was considerably simplified, presenting macrolactones 45 and 48, as well as macrolactam 55, macroketone 60, and CF(3)-alcohol 71 as promising anti-metastatic agents.     

A biocompatible stapling reaction for in situ generation of constrained peptides

Constrained peptides are promising next-generation therapeutics. Peptide stapling is a particularly attractive technique to generate constrained macrocycles with improved biological activity and metabolic stability. We introduce a biocompatible two-component stapling approach based on the reagent 2,6-dicyanopyridine and a pseudo-cysteine amino acid. Stapling can proceed either directly on-resin during solid-phase synthesis or following isolation of the linear peptide. The stapling reaction is orthogonal to natural amino acid side chains and completes in aqueous solution at physiological pH, enabling its direct use in biochemical assays. We performed a small screening campaign of short peptides targeting the Zika virus protease NS2B-NS3, allowing the direct comparison of linear with in situ stapled peptides. A stapled screening hit showed over 28-fold stronger inhibition than its linear analogue, demonstrating the successful identification of constrained peptide inhibitors.

A synthetically straightforward and biocompatible peptide-stapling strategy that can be used directly in biochemical assays to identify constrained enzyme inhibitors.     

Nucleosides and nucleotides. Part 25.. Synthesis of a protected 1-(2′-deoxy-β-D-ribofuranosyl)-1 H-benzimidazole 3′-phosphate

1-(2′-Deoxy-5′-O-dimethoxytrityl-′-D -ribofuranosyl)-1 H-benzimidazole 3′-[(p-chlorophenyl)(2-cyanoethyl) phosphate] ( 6 ) has been synthesized from 1-(β-D -ribofuranosyl)-1H-benzimidazole ( 3b ) using regiospecific 2′-deoxygenation. The latter compound was obtained by glycosylation of benzimidazole with the D -ribose derivative 2 leading exclusively of the β-D -anomer.     

Aromatic Radical Anions with Parallel or Crossed Triple Bonds

Proton hyperfine data are reported for the radical anions of 1,8-di (propyn-1-yl)-naphthalene (I), 7,8,12,13-tetradehydro-10,11-dihydro-9H-cyclodeca[d,e]naphthalene (II) and 2,2′-di(propyn-1-yl)-biphenyl (III), as well as of 5,6,11,12-tetradehydro-7,8,9,10-tetrahydro-dibenzo[a,c]cyclodecene (IV) and its 8,8,9,9-tetradeuterio-derivative (IV-d₄). The triple bonds in I and II can be regarded as roughly parallel, while those in IV (and IV-d₄) may be considered as crossed. The π-spin distributions in I? to IV? are discussed in terms of simple MO models which suggest a weekly bonding interaction between the acetylenic fragments in IV?, in contrast to III? where such an effect appears to be negligible. The importance of an analogous interaction in I? and II? is difficult to deduce, since its inclusion into a MO model does not substantially affect the π-spin distribution in these radical anions.     

Röntgenkleinwinkeluntersuchungen an Lösungen von Schweineserum-Albumin bei verschiedenen pH-Werten

Zusammenfassung Schweineserum-Albumin wurde nach sorgfältiger Reinigung bei den pH-Werten 7,0, 5,1 und 3,7 mit Hilfe der Röntgenkleinwinkelstreuung untersucht. Es wurde bei allen Messungen praktisch dasselbe Molekulargewicht gefunden: der Mittelwert liegt bei 70 300±2 500. Die Ermittlung der Streumassenradien ergab bei pH 7,0 und pH 5,1 ähnliche Werte (33,0 Å bzw. 31,1 Å), bei pH 3,7 dagegen einen Wert von 37,8 Å. Die Formbestimmung ergab bei pH 7,0 und pH 5,1 identische Achsenverhältnisse (0,75 : 1 : 2), während bei pH 3,7 ein solches von 0,2 : 1 : 1 gefunden wurde.

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X-ray small-angle scattering investigations on solutions of porcine serum albumin at differentpH-values

Higly purified samples of porcine serum albumin were measured by the X-ray small-angle scattering method at pH 7.0, 5.1, and 3.7. The molecular weight is found to be the same in all three cases: the mean value is 70 300±2 500. The radius of gyration is 31.1 Å and 33.0 Å at pH 5.1 and 7.0 resp., whereas at pH 3.7 a value of 37.8 Å is found. The determination of the molecular conformation yields a similar axial ratio at pH 5.1 and pH 7.0 of 0.75 : 1 : 2; at pH 3,7 we find an axial ratio of 0.2 : 1 : 1 to be consistent with the scattering curves.

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Herrn Prof. Dr.H. Nowotny gewidmet.     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

High-resolution small-angle x-ray investigations on poly-o-bromostyrene in benzene solutions

Small-angle x-ray investigations on poly-o-bromostyrene in benzene solution at extremely high resolution (corresponding to a Bragg's value of 3200 Å) proved to be able to link together the ranges covered by small-angle x-ray scattering and light scattering. On the other hand, there are problems encountered in molecular weight determination of chain molecules, since both methods at extremely small angles and at finite concentrations reach the limits of particle scattering. The differing results obtained by means of the two methods for the molecular weight of a rather high molecular weight sample of poly-o-bromostyrene are ascribed to entangelements stabilized by dipole–dipole interactions. These, due to the differing Bragg's angles and concentration ranges in the two methods, affect the experimental results to a different degree.     

Zerlegungen der Grenzgruppe des einfach-isotropen Raumes Jn

According to Strubecker an affine metric n-space (J_n,g) over a field F of char. 2 (n2) is called simply-isotropic if Radg is one-dimensional; let Fu be the totally isotropic direction w.r. to g. The group B_g of motions of (J_n,g) contains an invariant (2n–1)-dimensional subgroup G, called thelimit group (Grenzgruppe) which maps planes parallel to Fu into parallel ones. In case n=3, n=5, F= Strubecker [12], [13], [14] gave several factorizations G=G_L oG_R of G into a commutative product of subgroups acting 1-transitively (=regularly) on J_n.This note deals with all factorizations of this kind; it followes that n must be odd. A factorization is invariant under B_g iff n=3. Finally it is shown for each factorization of G how the space J_n can be made into a two sided incidence group and into a kinematic space in the sense of Karzel [5], and how the two structures are related to each other.

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Herrn Professor Dr. Karl Strubecker zum 75. Geburtstag gewidmet     

Highly substituted azulene dyes as multifunctional NLO and electron-transfer compounds

Two highly substituted azulene derivatives were synthesised by Pd-mediated dimerisation from the corresponding tolan species. One azulene derivative (2) has donor functionalities (dianisylaminophenyl and dianisylamino) in the 1-, 2-, 3- and 6-positions, while the other (1) has donors (dianisylaminophenyl) in the 2- and 6-positions and acceptors (nitrophenyl) in the 1- and 3-positions. Each azulene derivative shows strong bond length alternation in the solid state, determined by X-ray crystal analysis, and an intense CT band around 450-500 nm in its UV/Vis spectrum. The first-order hyperpolarisability of 1 and of 2 was measured by hyper-Rayleigh scattering and is about that of disperse red DR1. Both azulene derivatives show multiple oxidation processes. The intramolecular adiabatic ET behaviour of the mixed valence radical cations of 1 and of 2 was investigated by UV/Vis/NIR spectroelectrochemistry. The intervalence-CT band of 1(+) could be analysed by the Generalised Mulliken-Hush theory, which yields an electronic coupling V=1140 cm(-1) for the optically induced adiabatic hole transfer.     

Analysis of human brain tissue, brain tumors and tumor cells by infrared spectroscopic mapping

This study uses infrared (IR) spectroscopic, point detection, mapping procedures to examine tissue samples from normal brain specimens and from astrocytic gliomas, the most frequent human brain tumors. Model systems were derived from cultured glioma cell lines. IR spectra of normal tissue sections distinguished white matter from gray matter by increased spectral contributions from lipids and cholesterol. Qualitatively the same differences were found in IR spectra of low and high grade glioma tissue sections pointing to a significant reduction of brain lipids with increasing malignancy. Whereas spectral contributions of proteins and lipids were similar in IR spectra of glioma cells and tissues, nucleic acid bands were more intense for cells suggesting higher proliferative activities. For statistical analyses of IR spectroscopic maps from 71 samples, a parameter for the lipid to protein ratio was introduced involving the CH(2) symmetric stretch band with lipids as main contributors and the amide I band of proteins. As this parameter correlated with the grade of gliomas obtained from standard histopathological examination, it was applied to classify brain tissue sections based on IR spectroscopic mapping.