78 research outputs found
Diethyl trans-2,5-bisÂ(4-methoxyÂbenzylÂsulfanÂyl)-1,4-dimethyl-3,6-dioxopiperazine-2,5-carboxylÂate
The title compound, C28H34N2O8S2, was synthesized as part of a project to develop synthetic routes to analogues of sporidesmins, a class of secondary metabolite produced by the filamentous fungi Chaetomium and Pithomyces sp. The complete molecule is generated by crystallographic inversion symmetry: the methoxy group is essentially coplanar with the benzene ring to which it is bonded, a mean plane fitted through the non-H atoms of the aromatic ring and the methÂoxy group having an r.m.s. deviation of 0.0140 Å. Similarly, the ester group is also essentially planar (r.m.s. deviation of a plane fitted through all non-H atoms is 0.0101 Å). There is only one independent C—H⋯O interÂaction, which links together adjacent molÂecules into a two-dimensional sheet in the bc plane
Self-assembly of artificial microtubules
Understanding the complex self-assembly of biomacromolecules is a major
outstanding question. Microtubules are one example of a biopolymer that
possesses characteristics quite distinct from standard synthetic polymers that
are derived from its hierarchical structure. In order to understand how to
design and build artificial polymers that possess features similar to those of
microtubules, we have initially studied the self-assembly of model monomers
into a tubule geometry. Our model monomer has a wedge shape with lateral and
vertical binding sites that are designed to form tubules. We used molecular
dynamics simulations to study the assembly process for a range of binding site
interaction strengths. In addition to determining the optimal regime for
obtaining tubules, we have calculated a diagram of the structures that form
over a wide range of interaction strengths. Unexpectedly, we find that the
helical tubules form, even though the monomer geometry is designed for
nonhelical tubules. We present the detailed dynamics of the tubule
self-assembly process and show that the interaction strengths must be in a
limited range to allow rearrangement within clusters. We extended previous
theoretical methods to treat our system and to calculate the boundaries between
different structures in the diagram.Comment: 15 pages, 11 figure
Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut.
The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes
Synthesis and anticancer activity of epipolythiodiketopiperazine alkaloids
The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure–activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines and kill cancer cells via induction of apoptosis. Several traits that bode well for the translational potential of the ETP class of natural products include concise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sites that should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo.National Institute of General Medical Sciences (U.S.) (Grant GM089732)American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipCamille & Henry Dreyfus Foundation. Teacher-Scholar Awards Progra
Concise total synthesis of (+)-gliocladins B and C
The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel–Crafts-based strategy to provide an efficient multigram-scale access to the C3-(3′-indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first-generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C.National Institute of General Medical Sciences (U.S.) (GM089732)Amgen Inc.National Science Foundation (U.S.) (CHE-0946721
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STRUCTURAL ANALYSIS AND SYNTHETIC PROGRESS TOWARDS SMALL MOLECULES AS MODULATORS OF ANGIOGENESIS AT THE CELLULAR AND TRANSCRIPTIONAL LEVELS
Progress towards the design and the application of small molecules as inhibitors of angiogenesis is reported. First, the regulation of hypoxia inducible transcription with epipolythiodioxopiperazine (ETP) natural products is discussed, beginning with the exploration of the physical and chemical properties of ETP skeletal analogs, xylylene-linked bis-diketopiperazines (1,4-piperazine-2,5-diones, DKPs).The design, synthesis and solid-state structures of a new class of xylylene-linked bis(1,4-piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs in the solid state. The results suggested that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid-state conformations of xylylene-linked bis(piperazine-2,5-diones).Asymmetric alpha-sulfenylation reactions were designed and performed as a potential route to the synthesis of epipolythiodioxopiperazine natural products. First, a chiral auxiliary approach is reported, sulfenylating chiral azomethines of alpha-amino acids as epipolythiodiketopiperazine precursors in yields of 55% with de as high as 74%. Asymmetric organocatalytic alpha-sulfenylation of substituted piperazine-2,5-diones is also reported, with chiral cinchona alkaloids as bases and benzyl-substituted electrophilic sulfur transfer reagents. The reaction was investigated with varied catalyst loading, type of sulfenylating agent, temperature and solvent. The effects of ring substitution and type of catalyst on yield and enantioselectivity of the reaction are reported. The synthetic utility of the asymmetric alpha-sulfenylation in context of the synthesis of epipolythiodioxopiperazine fungal metabolites is discussed.Finally, chemical approach towards the inhibition of angiogenesis by targeting alpha v beta 3 integrin antagonists with synthetic multifunctional boron neutron capture therapy (BNCT) integrin ligands is presented. The novel synthesis of an alpha v beta 3 integrin antagonist containing a free amine group for peripheral modification is reported, along with the preparation of a bifunctional BNCT integrin ligand and a trifunctional BNCT integrin ligand containing a fluorescent dye. Synthetic challenges and potential therapeutic applications of these ligands are discussed
Polymorphism and phase transition behavior of 6,6′-bisÂ(chloroÂmethÂyl)-1,1′,4,4′-tetraÂmethyl-3,3′-(p-phenylÂenedimethylÂene)bisÂ(piperazine-2,5-dione)
A crystallographic investigation of the title compound, C22H28Cl2N4O4, using crystals obtained under different crystallization conditions, revealed the presence of two distinct polymorphic forms. The molÂecular conformation in the two polymorphs is very different: one adopts a ‘C’ shape, whereas the other adopts an ‘S’ shape. In the latter, the molecule lies across a crystallographic twofold axis. The ‘S’-shaped polymorph undergoes a reversible orthoÂrhomÂbic-to-monoclinic phase transition on cooling, whereas the structure of the ‘C’-shaped polymorph is temperature insensitive
Quinone Methide Signal Amplification: Covalent Reporter Labeling of Cancer Epitopes using Alkaline Phosphatase Substrates
Diagnostic
assays with the sensitivity required to improve cancer
therapeutics depend on the development of new signal amplification
technologies. Herein, we report the development and application of
a novel amplification system which utilizes latent quinone methides
(QMs) activated by alkaline phosphatase (AP) for signal amplification
in solid-phase immunohistochemical (IHC) assays. Phosphate-protected
QM precursor substrates were prepared and conjugated to either biotin
or a fluorophore through an amine-functionalized linker group. Upon
reaction with AP, the phosphate group is cleaved, followed by elimination
of the leaving group and formation of the highly reactive and short-lived
QM. The QMs either react with tissue nucleophiles in close proximity
to their site of generation, or are quenched by nucleophiles in the
reaction media. The reporter molecules that covalently bind to the
tissue were then detected visually by fluorescence microscopy in the
case of fluorophore reporters, or brightfield microscopy using diaminobenzidine
(DAB) in the case of biotin reporters. With multiple reporters deposited
per enzyme, significant signal amplification was observed utilizing
QM precursor substrates containing either benzyl difluoro or benzyl
monofluoro leaving group functionalities. However, the benzyl monofluoro
leaving group gave superior results with respect to both signal intensity
and discretion, the latter of which was found to be imperative for
use in diagnostic IHC assays
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