Application of solid phase peptide synthesis to engineering PEO–peptide block copolymers for drug delivery

This work describes a simple, versatile solid-phase peptide-synthesis (SPPS) method for preparing micelle-forming poly(ethylene oxide)-block-peptide block copolymers for drug delivery. To demonstrate its utility, this SPPS method was used to construct two series of micelle-forming block copolymers (one of constant core-composition and variable length; the other of constant core length and variable composition). The block copolymers were then used to study in detail the effect of size and composition on micellization. The various block copolymers were prepared by a combination of SPPS for the peptide block, followed by solution–phase conjugation of the peptide block with a proprionic acid derivative of poly(ethylene oxide) (PEO) to form the PEO-b-peptide block copolymer. The composition of each block component was characterized by mass spectrometry (MALDI and ES-MS). Block copolymer compositions were characterized by ¹H NMR. All the block copolymers were found to form micelles as judged by transmission electron microscopy (TEM) and light scattering analysis. To demonstrate their potential as drug delivery systems, micelles prepared from one member of the PEO-b-peptide block copolymer series were physically loaded with the anticancer drug doxorubicin (DOX). Micelle static and dynamic stability were found to correlate strongly with micelle core length. In contrast, these same micellization properties appear to be a complex function of core composition, and no clear trends could be identified from among the set of compositionally varying, fixed length block copolymer micelles. We conclude that SPPS can be used to construct biocompatible block copolymers with well-defined core lengths and compositions, which in turn can be used to study and to tailor the behavior of block copolymer micelles.     

Exploiting the Potential of Meroterpenoid Cyclases to Expand the Chemical Space of Fungal Meroterpenoids

Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.     

Structural Revision and Elucidation of the Biosynthesis of Hypodoratoxide by 13C,13C COSY NMR Spectroscopy

Feeding of (2,3,4,5,6‐¹³C₅)mevalonolactone to the fungus Hypomyces odoratus resulted in a completely labeled sesquiterpene ether. The connectivity of the carbon atoms was easily deduced from a ¹³C,¹³C COSY spectrum, revealing a structure that was different from the previously reported structure of hypodoratoxide, even though the reported ¹³C NMR data matched. A structural revision of hypodoratoxide is thus presented. Its absolute configuration was tentatively assigned from its co‐metabolite cis‐dihydroagarofuran. Its biosynthesis was investigated by feeding of (3‐¹³C)‐ and (4,6‐¹³C₂)mevalonolactone, which gave insights into the complex rearrangement of the carbon skeleton during terpene cyclization by analysis of the ¹³C,¹³C couplings.     

C-H···π interactions in the CHBrF2···HCCH weakly bound dimer

The microwave spectra of four isotopologues of the CHBrF(2)···HCCH weakly bound dimer have been measured in the 6-18 GHz region using chirped-pulse and Balle-Flygare Fourier-transform microwave spectroscopy. Spectra of (13)CH(79)BrF(2) and (13)CH(81)BrF(2) monomers have also been measured, and spectroscopic constants are reported. Measurement of spectra for the (79)Br and (81)Br isotopologues of CHBrF(2) complexed with both (12)C(2)H(2) and (13)C(2)H(2) have allowed the determination of a structure with C(s) symmetry for this complex. CHBrF(2) interacts with the triple bond of acetylene via a C-H···π contact (R(H···π) = 2.670(8) ?) with the Br atom lying in the ab plane, located 3.293(40) ? from a hydrogen atom of the HCCH molecule. The structure of CHBrF(2)···HCCH has been compared with recently studied related acetylene complexes, including a comparison with (and further structural analysis of) the CHClF(2)···HCCH complex.     

Porous 3-D honeycomb architecture by self-assembly of helical H-bonded molecular tapes

Enantiopure dipeptide-derived 1,3,5-triazepan-2,6-diones and form H-bonded 3(1) helical molecular tapes with P chirality in the solid state; in the case of , these columnar tapes self-assemble through aromatic-aromatic interactions to give hollow tubular structures.     

Genetic Manipulation of the Fusarium fujikuroi Fusarin Gene Cluster Yields Insight into the Complex Regulation and Fusarin Biosynthetic Pathway

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Homochiral helices of oligonaphthalenes inducing opposite-handed cholesteric phases

The helical structure of the chiral nematic phases (cholesterics) obtained by doping nematic solvents with chiral non-racemic compounds is a macroscopic proof of the solute chirality. Oligonaphthalene (tetra-, hexa-, octa-) derivatives linked at the 1,4-positions have been used as chiral dopants: When the chirality axes are configurationally homogeneous (that is, all-S), the molecular structures correspond to right-handed helices. Yet, we have found series of derivatives with the surprising property that the handedness of the induced cholesteric phase alternates from positive to negative and to positive again, on passing from tetra- to hexa- and to octanaphthalene. A comparison with oligonapthalene derivatives, which do not exhibit this twisting ability, points to the importance of the substitution pattern. Both the possibility of inducing oppositely-handed cholesteric phases by homochiral helices of different length, and the role played of substituents, are confirmed by calculations performed with the surface chirality model.     

Unexpected Kinetics in the Polymerization of Ethene by Cp$\rm{ {_{2}^{{\ast}}}}$ZrCl2/MAO

A sterically hindered metallocene catalyst, Cp ZrCl₂ activated with methylaluminoxane (MAO), is found to polymerize ethene at temperatures up to 60° with a good propagation rate constant but low number of active sites, and with negligible β‐hydride elimination or β‐hydride transfer to monomer. Moreover, transmetalation to Al is found to be effectively irreversible for alkyl groups larger than Me. With the major mechanisms for chain transfer and termination suppressed, one might expect a living polymerization. The bulk polymerization of ethene was indeed found to be quasi‐living even when performed at well above room temperature, and furthermore provided rate constants which agreed remarkably well with those from the mass‐spectrometric study.