Search

Naphthalene derivatives bearing electron-accepting and electron-donating groups at the 2,6-positions belong to the family of D-π-A push-pull dyes. It has been found that these compounds, e.g., 2-(1-(6-((2-(fluoro)ethyl)(methyl)amino)naphthalen-2-yl)ethylidene)malononitrile (FDDNP), show not only interesting optical properties, such as solvatochromism, but they have the potential to label protein aggregates of different compositions formed in the brain of patients suffering from neurodegenerative diseases like Alzheimer’s (AD). In continuation of our research we set our goal to find new FDDNP analogs, which would inherit optical and binding properties but hopefully show better specificity for tau protein aggregates, which are characteristic for neurodegeneration caused by repetitive mild trauma. In this work we report on the synthesis of new FDDNP analogs in which the acceptor group has been formally replaced with an aromatic five- or six-membered heterocycle. The heterocyclic moiety was annealed to the central naphthalene ring either by classical ring closure reactions or by modern transition metal-catalyzed coupling reactions. The chemical characterization, NMR spectra, and UV/vis properties of all new compounds are reported.

Open fractures and prosthetic joints are prone to bacterial infections, especially those involving biofilms, and are worsened by antibiotic inefficacy and resistance. This highlights the need for targeted treatments against orthopedic infections. LL-37, a human cathelicidin, is known for its antimicrobial properties. This study aimed to synthesize and evaluate LL-37-derived antimicrobial peptides (AMPs) for antibacterial efficacy and toxicity. Several truncated LL-37 analogues were created and tested against 18 bacterial strains, both ATCC and orthopedic clinical isolates, using MIC and MBC assays. Synergy with antibiotics and resistance development were also analyzed, alongside cytotoxicity on NIH-3T3 fibroblasts and hemolytic activity assessments. Six AMPs were synthesized, with FK-16 and GF-17 emerging as the most effective. The MIC values ranged from 4.69 to 18.75 µg/mL and 2.34 to 18.75 µg/mL, respectively, against S. epidermidis and S. aureus, with the MBC values matching the MIC values. Cytotoxicity tests showed no toxicity at concentrations below 75 µg/mL for GF-17 and 150 µg/mL for FK-16. Hemolytic activity was below 1% at 18.75 µg/mL for GF-17 and 75 µg/mL for FK-16. These AMPs showed no synergistic effects with antibiotics and no resistance development. FK-16 and GF-17 effectively removed biofilms, particularly against S. epidermidis. Incorporating these AMPs into surgical materials (hydrogels, cements, etc.) could enhance infection control in orthopedic procedures, warranting further in vivo studies.

RiPP discovery has expanded the scope of post-translational modification chemistry, but genome mining of RiPP classes remains an unsolved challenge. Here, the authors employed bioinformatics and synthetic biology approaches to discover and characterize an unknown class of RiPPs, defined by an unusual amino-modified C-terminus.

Heterogeneity of meroterpenoids arising from their dual biosynthetic origins is constantly provoking synthetic chemists to utilize their ingenuity and revise their retrosynthetic logic. By studying recent publications on meroterpenoid synthesis, tremendous advances in the field of synthetic organic chemistry can be witnessed. This minireview covers some of the most intriguing total syntheses and synthetic studies towards the meroterpenoid class of natural products from the last five years.

Nanographenes and polycyclic aromatic hydrocarbons (PAHs) are important classes of compounds with numerous applications, but challenging to access due to a lack of programmable and diversity-oriented methods. Here, the authors report a diversity-oriented, growth-from-template synthesis of nanographenes enabled by iterative annulative π-extension reactions from small PAH starting materials.

Aromatic compounds are one of the most abundant classes of organic molecules and find utility as precursors for alicyclic hydrocarbon building blocks. While many established dearomatization reactions are exceptionally powerful, dearomatization with concurrent introduction of functionality, i.e. dearomative functionalization, is still a largely underdeveloped field. This review aims to provide an overview of our recent efforts and progress in the development of dearomative functionalization of simple and nonactivated arenes using arenophile-arene cycloaddition platform. These cycloadducts, formed via a visible-light-mediated [4+2]-photocycloaddition, can be elaborated in situ through olefin chemistry or transition-metal-catalyzed ring-opening with carbon-, nitrogen-, and oxygen-based nucleophiles, providing access to diverse structures with functional and stereochemical complexity. Moreover, the dearomatized products are amenable to further elaborations, which effectively install other functionalities onto the resulting alicyclic carbocycles. The utility of the arenophile-mediated dearomatization methods are also highlighted by the facile syntheses of natural products and bioactive compounds through novel disconnections.

Alkaloids isolated from members of the Amaryllidaceae plant family are promising anticancer agents. The purpose of the current study was to determine if the isocarbostyrils narciclasine, pancratistatin, lycorane, lycorine, crinane, and haemanthamine inhibit phenomena related to cancer progression in vitro. To achieve this, we examined the proliferation, adhesion, and invasion of cultured human colon cancer cells via MTT assay and Matrigel-coated Boyden chambers. In addition, Luminex assays were used to quantify the secretion of matrix metalloproteinases (MMP) and cytokines associated with poor clinical outcomes. We found that all alkaloids decreased cell proliferation regardless of TP53 status, with narciclasine exhibiting the greatest potency. The effects on cell proliferation also appear to be specific to cancer cells. Narciclasine, lycorine, and haemanthamine decrease both adhesion and invasion but with various potencies depending on the cell line. In addition, narciclasine, lycorine, and haemanthamine decreased the secretion of MMP-1, -2, and -7, as well as the secretion of the cytokines pentraxin 3 and vascular endothelial growth factor. In conclusion, the present study shows that Amaryllidaceae alkaloids decrease phenomena and cytokines associated with colorectal cancer progression, supporting future investigations regarding their potential as multifaceted drug candidates.

The IFITMs inhibit influenza A virus (IAV) replication in vitro and in vivo. Here, we establish that the antimycotic heptaen, amphotericin B (AmphoB), prevents IFITM3-mediated restriction of IAV, thereby increasing viral replication. Consistent with its neutralization of IFITM3, a clinical preparation of AmphoB, AmBisome, reduces the majority of interferon’s protective effect against IAV in vitro. Mechanistic studies reveal that IFITM1 decreases host-membrane fluidity, suggesting both a possible mechanism for IFITM-mediated restriction and its negation by AmphoB. Notably, we reveal that mice treated with AmBisome succumbed to a normally mild IAV infection, similar to animals deficient in Ifitm3. Therefore, patients receiving antifungal therapy with clinical preparations of AmphoB may be functionally immunocompromised and thus more vulnerable to influenza, as well as other IFITM3-restricted viral infections.