Discovery of novel triple targeting G‑quadruplex and topoisomerase 1/2 ligands from natural products evodiamine and rutaecarpine

Inspired by the indolopyridoquinazoline scaffold of natural products evodiamine and rutaecarpine, novel triple G4 and Top1/2 ligands were rationally designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compound 15g, which effectively induced and stabilized G4 and inhibited Top1/2 with potent antitumor activity. Compound 15g represents a valuable chemical tool or lead compound for antitumor drug discovery. This proof-of-concept study also validated the feasibility of using planar natural products scaffold as templates to design new G4 ligands.     

A synthetic approach to the phorboxazoles – Synthesis of the C20–C32 central core

An enantiospecific synthesis of the C20–C32 central core of the phorboxazole scaffold, including the non-macrocyclic oxazole is detailed in 17 steps (longest linear sequence) from methacrolein in 7.8% overall yield. All of the stereocenters are communicated from a single Evans aldol reaction, and the final compound is suitably functionalized for further elaboration to the natural products.     

Target family-directed exploration of scaffolds with different SAR profiles

The scaffold concept is widely applied in chemoinformatics and medicinal chemistry to organize bioactive compounds according to common core structures or associate compound classes with specific biological activities. A variety of scaffold analyses have been carried out to derive statistics for scaffold distributions, generate structural organization schemes, or identify scaffolds that preferentially occur in given compound activity classes. Herein we further extend scaffold analysis by identifying scaffolds that display defined SAR profiles consisting of multiple properties. A structural relationship-based scaffold network has been designed as the basic data structure underlying our analysis. From network representations of scaffolds extracted from compounds active against 32 different target families, scaffolds with different SAR profiles have been extracted on the basis of decision trees that capture structural and functional characteristics of scaffolds in different ways. More than 600 scaffolds and 100 scaffold clusters were assigned to 10 SAR profiles. These scaffold sets represent different activity and target selectivity profiles and are provided for further SAR investigations including, for example, the exploration of alternative analog series for a given target of target family or the design of novel compounds on the basis of scaffold(s) with desired SAR profiles.     

Biology‐Oriented Synthesis of a Withanolide‐Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling

Biology‐oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans‐hydrindane dehydro‐δ‐lactone motif defines the characteristic scaffold of the steroid‐like withanolides, a plant‐derived natural product class with a diverse pattern of bioactivity. A withanolide‐inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell‐based assays that monitored biological signal‐transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened.     

Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries

Natural products were analyzed to determine whether they contain appealing novel scaffold architectures for potential use in combinatorial chemistry. Ring systems were extracted and clustered on the basis of structural similarity. Several such potential scaffolds for combinatorial chemistry were identified that are not present in current trade drugs. For one of these scaffolds a virtual combinatorial library was generated. Pharmacophoric properties of natural products, trade drugs, and the virtual combinatorial library were assessed using a self-organizing map. Obviously, current trade drugs and natural products have several topological pharmacophore patterns in common. These features can be systematically explored with selected combinatorial libraries based on a combination of natural product-derived and synthetic molecular building blocks.     

Biosynthesis of DNA-Alkylating Antitumor Natural Products

DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.     

Discovery of Novel Cinchona‐Alkaloid‐Inspired Oxazatwistane Autophagy Inhibitors

The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely‐related oxazatricyclo[4.4.0.0]decane (“oxazatwistane”) scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state‐of‐the‐art C−H functionalization, and metal‐catalyzed cross‐coupling reactions as key late diversity‐generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation.     

Stereoselective Synthesis of Highly Functionalized Hydroindoles as Building Blocks for Rostratins B–D and Synthesis of the Pentacyclic Core of Rostratin C

The stereoselective synthesis of a variety of functionalized hydroindoles suitable as building blocks for thiodiketopiperazine natural products such as rostratins B–D is reported. The key precursor for all transformations is a previously reported hexahydroindole compound. All functional groups were installed with the desired stereochemistry and the feasibility of the synthetic strategy was exemplified by dimerization of two hydroindole units to form the pentacyclic C₂‐symmetric scaffold of rostratin C.     

Fenestranes in Synthesis: Unique and Highly Inspiring Scaffolds

The scaffold of fenestranes is quite unique, as it contains four condensed cycles and a distorted tetracoordinated central carbon atom with bond angles greater than the regular 109°28“. In this Minireview, a detailed overview on the developments regarding this compound class, including their synthesis, is given for the time period since 2006. In the past years, natural products that belong to the class of heterofenestranes have been isolated and their syntheses will also be discussed.     

A collagen(Col)/nano-hydroxyapatite (nHA) biological composite bone scaffold with double multi-level interface reinforcement

IntroductionBone scaffold is expected to possess excellent mechanical and biological properties similar to natural bone tissues. In this study, we aimed to prepare a biomineralized Col and hydroxyapatite composite scaffold consisting of biomimetic bone components and multi-level bionic bone structure to strengthen its mechanical properties.MethodsWe prepared a Col/nano-hydroxyapatite biological composite scaffold with multi-level structure (from nanofibers to micron bionic bone motif to bionc bone scaffold) of biomimetic bone tissue, and biomineralized the scaffold in simulated body fluid (SBF) preheated to 37 °C. X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and Scanning electron microscope, were used to characterize the biomineralized products.ResultsMorphological study confirmed in situ deposition of nHA in the multi-scale hierarchical structure of the biomineralized scaffold. We explored the biomineralization nucleation mechanism of the scaffolds at the atomic level based on the first principles and the mechanisms for growth of mineralized nHA crystal array in its multi-scale structure, and how the double multiscales structure strengthened the mechanical properties of the material.ConclusionsThis synthetic bone scaffold, with bionic bone composition and double multi-level interface reinforcement, provides a new strategy for synthesizing bioactive bone scaffolds with enhanced biomechanical properties.     

Chemoinformatics methods for systematic comparison of molecules from natural and synthetic sources and design of hybrid libraries

Until recently, the field of diversity and library design has more or less ignored natural products as a compound source. This is probably due to at least two reasons. First, combinatorial and reaction-based approaches have been major focal points in the early days of computational library design. In addition, a widespread view is that natural products are often highly complex and not amenable to medicinal chemistry efforts. This contribution introduces recent computational approaches to systematically analyze natural molecules and bridge the gap between natural products and synthetic chemistry programs. Large scale comparisons of natural and synthetic molecules are discussed as well as studies designed to identify `synthetic mimics' of natural products with specific activity. In addition, a concept for the design of natural/synthetic hybrid libraries is introduced. Although research in this area is still in its early stages, an important lesson to be learned from computational analyses is that there is no need to a priori `shy away' from natural products as a source for molecular design.     

Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug‐like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo‐phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure‐based design of subunit‐specific nonpeptidic proteasome‐blockers.     

Design Parameters of Tissue‐Engineering Scaffolds at the Atomic Scale

Stem‐cell behavior is regulated by the material properties of the surrounding extracellular matrix, which has important implications for the design of tissue‐engineering scaffolds. However, our understanding of the material properties of stem‐cell scaffolds is limited to nanoscopic‐to‐macroscopic length scales. Herein, a solid‐state NMR approach is presented that provides atomic‐scale information on complex stem‐cell substrates at near physiological conditions and at natural isotope abundance. Using self‐assembled peptidic scaffolds designed for nervous‐tissue regeneration, we show at atomic scale how scaffold‐assembly degree, mechanics, and homogeneity correlate with favorable stem cell behavior. Integration of solid‐state NMR data with molecular dynamics simulations reveals a highly ordered fibrillar structure as the most favorable stem‐cell scaffold. This could improve the design of tissue‐engineering scaffolds and other self‐assembled biomaterials.     

Intercepting bacterial indole signaling with flustramine derivatives

Indole signaling is one of the putative universal signaling networks in bacteria. We have investigated the use of desformylflustrabromine (dFBr) derivatives for the inhibition of biofilm formation through modulation of the indole-signaling network in Escherichia coli and Staphylococcus aureus . We have found dFBr derivatives that are 10-1000 times more active than indole itself, demonstrating that the flustramine family of indolic natural products represent a privileged scaffold for the design of molecules to control pathogenic bacterial behavior.     

Synthesis of the molecular hybrid inspired by Largazole and Psammaplin A

One important class of HDAC (histone deacetylation enzymes) inhibitors is the sulfur-containing marine natural products with structural diversity. Inspired by two structurally distinguishing examples, Largazole and Psammaplin A, which possess macrocyclic depsipeptide and simple linear amide scaffold respectively, we designed one novel molecular hybrid by replacing the alkene moiety in Largazole with a semirigid amide bond. This hybrid compound has been synthesized from l-malic acid in 10 steps with an overall yield of 7%. The preliminary biological assays suggest that the replacement of trans olefin moiety with amide bond will lead to an unbeneficial effect on the inhibition against HDACs.     

Pentafulvene for the Synthesis of Complex Natural Products: Total Syntheses of (±)‐Pallambins A and B

The first total syntheses of pallambins A and B are enabled by the use of pentafulvene in an unprecedented Diels–Alder reaction. After elaboration of the adduct through chemoselective cyclopropanation, strategic C? H insertion affords the dense tetracyclic core of the natural products. 1,3‐Dipolar cycloaddition and palladium(II)‐catalyzed alkoxycarbonylation were leveraged for the construction of the hexacyclic scaffold en route to both natural products.     

Natural product-likeness score and its application for prioritization of compound libraries

Natural products (NPs) have been optimized in a very long natural selection process for optimal interactions with biological macromolecules. NPs are therefore an excellent source of validated substructures for the design of novel bioactive molecules. Various cheminformatics techniques can provide useful help in analyzing NPs, and the results of such studies may be used with advantage in the drug discovery process. In the present study we describe a method to calculate the natural product-likeness score--a Bayesian measure which allows for the determination of how molecules are similar to the structural space covered by natural products. This score is shown to efficiently separate NPs from synthetic molecules in a cross-validation experiment. Possible applications of the NP-likeness score are discussed and illustrated on several examples including virtual screening, prioritization of compound libraries toward NP-likeness, and design of building blocks for the synthesis of NP-like libraries.     

可降解聚氨酯型组织工程多孔支架材料的制备

本文在可降解型聚氨酯分子设计,聚氨酯型组织工程支架制备方法,可降解聚氨酯多孔支架的生物学性能及可降解聚氨酯多孔支架在组织工程中的应用等几个方面对可降解聚氨酯型组织工程支架的最新研究进展作了综述。重点讨论了静电纺丝、冷冻干燥、相分离等几种聚氨酯多孔支架制备方法以及聚氨酯型组织工程支架的生物降解性质、生长因子嵌入、生物力学性能、生物相容性等生物学性能。目前的研究表明通过聚氨酯分子设计与各种支架制备方法结合可制得满足各种生物学性能的支架材料且这类材料已被证实在血管、软骨、硬质骨等各类组织工程中有重要的应用价值。但如何进一步提高聚氨酯支架材料的力学强度以使其能更好地与硬组织的力学性能相匹配以及如何降低或消除聚氨酯对人体的毒性仍是需要进一步研究的问题。     

藤黄科植物中具有桥环结构的天然产物全合成研究进展

藤黄科植物中含桥环的天然产物具有独特的化学结构和明显的生物活性. 综述了近年来这类天然产物的全合成研究进展.     

The first synthesis of (-)-asperpentyn and efficient syntheses of (+)-harveynone, (+)-epiepoformin and (-)-theobroxide

A generally applicable strategy for the synthesis of a range of polyoxygenated cyclohexane natural products has been developed. The enantioselective syntheses of (-)-theobroxide, a polyoxygenated cyclohexane natural compound with potent growth inducing properties in potato microtubers has been achieved via a 1,2 O-silyl migration between trans-hydroxyl groups and a remote hydroxyl directed epoxidation of an enone derived from quinic acid. A thus derived alpha-iodoenone was subjected to Stille coupling with tetramethylstannane to afford the first title compound. A similar strategy enabled a route to the complete asymmetric synthesis of the acetylenic phytotoxin (+)-harveynone. By selective reduction of (-)-theobroxide, (+)-epiepoformin was also prepared in enantiopure form and similarly, stereoselective reduction of (+)-harveynone completed the first enantioselective synthesis of (-)-asperpentyn, another natural compound with antimicrobial activity.