Bioinspired bola-type peptide dendrimers inhibit proliferation and invasiveness of glioblastoma cells in a manner dependent on their structure and amphipathic properties

(1) Background: Natural peptides supporting the innate immune system studied at the functional and mechanistic level are a rich source of innovative compounds for application in human therapy. Increasing evidence indicates that apart from antimicrobial activity, some of them exhibit selective cytotoxicity towards tumor cells. Their cationic, amphipathic structure enables interactions with the negatively-charged membranes of microbial or malignant cells. It can be modeled in 3D by application of dendrimer chemistry. (2) Methods: Here we presented design principles, synthesis and bioactivity of branched peptides constructed from ornithine (Orn) assembled as proline (Pro)- or histidine (His)-rich dendrons and dendrimers of the bola structure. The impact of the structure and amphipathic properties of dendrons/dendrimers on two glioblastoma cell lines U87 and T98G was studied with the application of proliferation, apoptosis and cell migration assays. Cell morphology/cytoskeleton architecture was visualized by immunofluorescence microscopy. (3) Results: Dimerization of dendrons into bola dendrimers enhanced their bioactivity. Pro- and His-functionalized bola dendrimers displayed cytostatic activity, even though differences in the responsiveness of U87 and T98G cells to these compounds indicate that their bioactivity depends not only on multiple positive charge and amphipathic structure but also on cellular phenotype. (4) Conclusion: Ornithine dendrons/dendrimers represent a group of promising anti-tumor agents and the potential tools to study interrelations between drug bioactivity, its chemical properties and tumor cells’ phenotype

Computational planning of the synthesis of complex natural products

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years(1-7). However, the field has progressed greatly since the development of early programs such as LHASA(1,7), for which reaction choices at each step were made by human operators. Multiple software platforms(6,8-14) are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary(15,16) and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships(17,18), allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts

Interplay of Aromaticity and Antiaromaticity in N-Doped Nanographenes

The aromaticity of three nonplanar, fully conjugated aza-nanographenes built around a pyrrolo[3,2-b]pyrrole core is assessed through the application of two different computational procedures—GIMIC and NICS. We examine the calculated magnetically induced current densities (GIMIC) and nucleus-independent chemical shifts (NICS). The structural differences between these three apparently similar molecules lead to significantly different aromatic properties. GIMIC analysis indicates that the peripheral diatropic ring current of 3.9 nA/T for the studied bowl-shaped diaza-nanographene is the strongest, followed by the double [6]helicene which lacks seven-membered rings, and is practically nonexistent for the double [5]helicene possessing seven-membered rings. The biggest difference however is that in the two not-fully-fused molecules, the central pyrrole rings possess a significant diatropic current of about 4.1 nA/T, whereas there is no such current in the diaza-nanographene. Moreover, the antiaromaticity of the seven-membered rings is increasing while moving from double [5]helicene to diaza-nanographene (from −2.4 to −6.0 nA/T). The induced currents derived from NICSπ,zz-XY-scan analysis for all of the studied systems are in qualitative agreement with the GIMIC results. Subtle differences may originate from σ-electron currents in GIMIC or inaccuracy of NICSπ,zz values due to the nonplanarity of the systems, but the general picture is similar.Peer reviewe

Pd-Catalyzed Carbonylative Carboperfluoroalkylation of Alkynes. Through-Space ¹³C–¹⁹F Coupling as a Probe for Configuration Assignment of Fluoroalkyl-Substituted Olefins

A four-component Pd-catalyzed protocol for direct synthesis of perfluoroalkyl-substituted enones is reported. Under mild conditions and low catalyst loading, alkynes, iodoperfluoroalkanes, (hetero)­arylboronic acids, and carbon monoxide are assembled into highly elaborate products with good yields and excellent regio- and stereoselectivities. The configuration of the products was confirmed by the observation of through-space ¹³C–¹⁹F couplings, accessible through the analysis of routine ¹³C NMR spectra

Synthesis of Polyhydroxylated Quinolizidine and Indolizidine Scaffolds from Sugar-Derived Lactams via a One-Pot Reduction/Mannich/Michael Sequence

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz’s reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky’s diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives