Efficient assembly and anti-tumor evaluation of novel polycyclic [1,2-a]-fused indoles.

Structurally diverse cyclopenta[4,5]pyrrolo[1,2-a]indoles heterocycles were smoothly constructed in good to excellent yields (up to 99 %) with excellent diastereoselectivities (>19:1 dr) through a novel and facile strategy based on BF3-catalyzed Friedel-Crafts alkylation/Aldol/Dehydrative cyclization cascade reaction. The anti-proliferative activity of these newly synthesized polycyclic indoles was screened, and all the functionalized reductive derivatives exhibited favorable anti-tumor activity. Notably, compound 4ae displayed the remarkable inhibitory activity against MCF-7 and HeLa cells with IC50 values of 4.62 µM and 7.71 µM, respectively. Mechanistically, the representative compound 4ae could effectively induce apoptosis of MCF-7 cells in crediting to up-regulate the relative expression of apoptotic protein BAX/Bcl-2, subsequently activate Pro-caspase 9 and cleave PARP, simultaneously block the cell cycle through down- and up-regulate the expression of cyclin B1 and p53, respectively. Moreover, compound 4ae also exhibited promising antineoplastic efficacy in subcutaneous MCF-7 xenograft mice which manifest significant shrunken tumors conspicuous nuclear apoptotic signal and minimal systemic toxicity. This strategy not only established a novel and efficient method for the assembly of structurally complex indole heterocycles, but also provided a series of compounds possessing attractive anti-cancer activity, which holds immense potential for future biomedical applications.

New polycyclic tetramate macrolactams with antimycobacterial activity produced by marine-derived Streptomyces sp. KKMA-0239.

During our screening for anti-mycobacterial agents against Mycobacterium avium complex (MAC), two new polycyclic tetramate macrolactams (PTMs), named hydroxycapsimycin (1) and brokamycin (2), were isolated along with the known PTM, ikarugamycin (3), from the culture broth of marine-derived Streptomyces sp. KKMA-0239. The relative structures of 1 and 2 were elucidated by spectroscopic data analyses, including 1D and 2D NMR. Furthermore, the absolute configuration of 1 was confirmed by a single-crystal X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate antimycobacterial activities against MAC, including clinically isolated drug-resistant M. avium.

Biocatalytic strategy for the construction of sp3-rich polycyclic compounds from directed evolution and computational modelling.

Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp3-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles. Two carbene transferases with complementary regioisomer selectivity were evolved to catalyse the stereoselective cyclization of benzothiophene substrates bearing diazo ester groups at the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were elucidated by a combination of crystallographic and computational analyses. Leveraging these insights, the substrate scope of one of the biocatalysts could be expanded to include previously unreactive substrates, highlighting the value of integrating evolutionary and rational strategies to develop enzymes for new-to-nature transformations. The molecular scaffolds accessed here feature a combination of three-dimensional and stereochemical complexity with 'rule-of-three' properties, which should make them highly valuable for fragment-based drug discovery campaigns.

Total synthesis and structural reassignment of garcinielliptone FC, a polycyclic polyprenylated acylphloroglucinol with diverse bioactivity.

Garcinielliptone FC (GFC) was assigned to be a type A polycyclic polyprenylated acylphloroglucinol (PPAP) and was found to exhibit diverse biological activities. Now we revise the structure of GFC to xanthochymol, a type B PPAP, via NMR and total synthesis methods. The total syntheses of (±)-xanthochymol and (±)-cycloxanthochymol were accomplished in 12 and 13 steps, respectively.

Design, synthesis, and biological evaluation of pleuromutilin derivatives containing 1,2,4-triazole linker.

A series of thioether pleuromutilin derivatives containing 1,2,4-triazole on the side chain of C14 were designed and synthesized. The in vitro antibacterial activities experiments of the synthesized derivatives showed that compounds 72 and 73 displayed superior in vitro antibacterial effect against MRSA minimal inhibitory concentration (MIC = 0.0625 µg/mL) than tiamulin (MIC = 0.5 µg/mL). The results of time-kill study and postantibiotic effect study indicated that compound 72 could inhibit the growth of MRSA quickly (-2.16 log10 CFU/mL) and showed certain postantibiotic effect (PAE) time (exposure to 2 × MIC and 4 × MIC for 2 h, the PAE was 1.30 and 1.35 h) against MRSA. Furthermore, the binding mode between compound 72 and 50S ribosome of MRSA was explored by molecular docking and five hydrogen bonds were formed between compound 72 and 50S ribosome.

Two-Step Synthesis, Structure, and Optical Features of a Double Hetero[7]helicene.

A novel double aza-oxa[7]helicene was synthesized from the commercially available N1,N4-di(naphthalen-2-yl)benzene-1,4-diamine and p-benzoquinone in two steps. Combining the acid-mediated annulation with the electrochemical sequential reaction (oxidative coupling and dehydrative cyclization) afforded this double hetero[7]helicene. Moreover, the structural and optical features of this molecule have been studied using X-ray crystallographic analysis, and the absorption and emission behaviors were rationalized based on DFT calculations.

syn-Cryptophanes: macrocyclic compounds with optimized characteristics for the design of 129Xe NMR-based biosensors.

A new water-soluble xenon host system with great promise for the 129Xe NMR-based biosensing approach is presented: the syn-cryptophane-222-hexacarboxylate. It compares favorably with its already known anti diastereomer, on the one hand, and with cucurbit[6]uril, on the other hand, in particular in terms of xenon binding constant and xenon in-out exchange, a key parameter for the efficiency of the most sensitive HyperCEST method.

Single-Handed Helicene Nanoribbons via Transfer of Chiral Information.

Here we show the access to single-handed helicene nanoribbons by utilizing a [6]helicene building block to induce diastereoselective, photochemical formation of [5]helicene units. Specifically, we have synthesized nanoribbons P1 and P2 with different ratios of [6]helicene "sergeants" to [5]helicene "soldiers", which on average consist of between ∼50 and 60 ortho-annulated benzene rings. These are the longest, optically active helicene backbones that have been prepared to date. The chiroptic properties of P1 and P2 reveal the transfer of stereochemical information from "sergeants" to "soldiers". To gain further insight into the stereo-information relay, we apply the same molecular design to discrete, model oligomers 1-5 and confirm that they also preferentially adopt homochiral geometries.

Circularly Polarized Luminescence in a Möbius Helicene Carbon Nanohoop.

We present the first helicene carbon nanoohop that integrates a [6]helicene into [7]cycloparaphenylene. The [6]helicene endows the helicene carbon nanohoop with chiroptical properties and configurational stability typical for higher helicenes, while the radially conjugated seven para-phenylenes largely determine the optoelectronic properties. The structure of the helicene carbon nanoohop was unambiguously characterized by NMR, MS and X-ray analysis that revealed that it possesses a topology of a Möbius strip in the solid state and in solution. The chirality transfers from the [6]helicene to the para-phenylenes and leads to a pronounced circular dichroism and bright circularly polarized luminescence, which is affected by the structural topology of the nanohoop.

One-Pot Preparation of (NH)-Phenanthridinones and Amide-Functionalized [7]Helicene-like Molecules from Biaryl Dicarboxylic Acids.

A one-pot transformation of biaryl dicarboxylic acids to (NH)-phenanthridinone derivatives based on a Curtius rearrangement and subsequent basic hydrolysis was developed. This method is also applicable for the preparation of optically active amide-functionalized [7]helicene-like molecules. Furthermore, aza[5]helicene derivatives with a phosphate moiety were isolated as a product of the Curtius rearrangement step in the case of substrates that bear chalcogen atoms. The stereostructures of these products, revealed by X-ray diffraction analysis, suggested that chalcogen-bonding and pnictogen-bonding interactions might contribute to their stabilization. The configurational stability of the helicene-like molecules and their chiroptical properties were further investigated.

Discovery of novel pleuromutilin derivatives as potent antibacterial agents.

Novel pleuromutilin derivatives with 3,4-dihydropyrimidin and pyrimidine moieties were designed, synthesized, and evaluated for their antibacterial activities. Most of the synthesized derivatives, especially the compounds bearing the pyrimidine moieties, exhibited potent antibacterial activities against methicillin-resistant Staphylococcus aureus BNCC 337371 (MRSA-337371), Staphylococcus aureus ATCC 25923 (S. aureus-25923) and methicillin-resistant Staphylococcus epidermidis ATCC 51625 (MRSE-51625). Compounds 5a, 5g and 5h exerted the excellent antibacterial activities and selected to evaluate their bacterial killing kinetics. Compound 5h displayed the highest antibacterial activities with bacteriostatic activities against MRSA and further evaluated its efficacy in mouse systemic infection. The results showed that compound 5h exhibited potent in vivo antibacterial effects to significantly improve the survival rate of mice (ED50 = 16.14 mg/kg), reduce the bacterial load and alleviate the pathological changes in the lungs of the affected mice. Furthermore, molecular docking studies revealed that the selected compounds successfully localized in the pocket of 50S ribosomal subunit and the formed hydrogen bonds were the main interaction.

The synthesis and crystal structure of pH-sensitive fluorescent pyrene-based double aza- and diaza[4]helicenes.

Novel pyrene-based double aza- and diaza[4]helicenes have been prepared through a five-step synthetic sequence in overall good yields. Commercially available 2,3-dihaloazines (2,3-dibromopyridine, 2,3-dichloropyrazine and 2,3-dichloroquinoxaline) were used as starting materials. The synthesis employs electrophile-induced cyclizations of ortho-alkynyl bihetaryls as the key steps, leading to the formation of a helical skeleton. To discern the effect of merging azine and pyrene moieties within a helical skeleton, the X-ray structures, UV-vis absorption and fluorescence spectra of the helicenes were investigated and compared with those of the parent [4]helicene, aza- and diaza[4]helicenes. It was found that the emission properties of the synthesized helicenes can be modulated as a function of pH. The basicity of pyrene-based double aza[4]helicenes was estimated by the direct fluorimetric titration method; the pKa value was found to be equal to 1.4.

Enantioselective Recognition of Helicenes by a Tailored Chiral Benzo[ghi]perylene Trisimide π-Scaffold.

Enantioselective molecular recognition of chiral molecules that lack specific interaction sites for hydrogen bonding or Lewis acid-base interactions remains challenging. Here we introduce the concept of tailored chiral π-surfaces toward the maximization of shape complementarity. As we demonstrate for helicenes it is indeed possible by pure van-der-Waals interactions (π-π interactions and CH-π interactions) to accomplish enantioselective binding. This is shown for a novel benzo[ghi]perylene trisimide (BPTI) receptor whose π-scaffold is contorted into a chiral plane by functionalization with 1,1'-bi-2-naphthol (BINOL). Complexation experiments of enantiopure (P)-BPTI with (P)- and (M)-[6]helicene afforded binding constants of 10 700 M-1 and 550 M-1 , respectively, thereby demonstrating the pronounced enantiodifferentiation by the homochiral π-scaffold of the BPTI host. The enantioselective recognition is even observable by the naked eye due to a specific exciplex-type emission originating from the interacting homochiral π-scaffolds of electron-rich [6]helicene and electron-poor BPTI.

CTV Based Sensor for the Detection of Ni2+ Ions With Real Sample Analysis Based on Mechanism of Fluorescence Along with Computational Insights.

Identification and detection of harmful contaminants such as nickel and other materials from soil and water is critical necessity at the present moment. So with this motive to detect and identify harmful pollutants, a novel cyclotriveratrylene based derivative was prepared for the detection and binding of harmful pollutants which had the properties of fluorescence. The newly derivative of Cyclotriveratrylene was found to be highly sensitive and selective towards Ni2+ ions. The complexation behaviour of this newly synthesised molecule was studied in presence of transition elements. Also computational methods such as docking, molecular modelling and DFT were used to study the molecular orbitals and energies of CTG-NBEP. The detection of Ni2+ from water samples were also carried out successfully.

Synthesis and biological evaluation of novel schisanhenol derivatives as potential hepatoprotective agents.

Twenty-one new schisanhenol derivatives were synthesized, and their hepatoprotective effects against liver injury induced by concanavalin A (Con A) were evaluated in vitro using an MTT assay. The data indicated that most derivatives exhibited equivalent or better protective activity than the positive control (dimethyl dicarboxylate biphenyl, DDB) under the same conditions. Among them, compound 1b showed the most potent hepatoprotective activity against Con A-induced immunological injury. Mechanistic studies in vitro revealed that 1b inhibited cell apoptosis and inflammatory responses caused by Con A treatment via IL-6/JAK2/STAT3 signaling pathway. Consistently, it also exhibited significant hepatoprotective activity in mice with Con A-induced immunological liver injury. These results clearly indicated that 1b might be a highly potent hepatoprotective agent targeting IL-6/STAT3 signaling pathway.

A Sensor for the Detection of Cr (III) and Fe (III) Ions Based on "Turn Off" Mechanism of Fluorescence with Computational Studies.

A new and innovative fluorescent structure was constructed on Cyclotriveratrylene affiliated to Dansyl chloride (DNSC) and was used to detect Cr (III) and Fe (III) among the various cations by using spectrofluorimetric method. The characterization of the new compound was carried out using the 1H-NMR, 13C-NMR, and ESI-MS techniques. The interaction and role of DNSC-CTV with cations was reviewed. A change in the spectra of absorption directed to the conclusion that there is substantial interaction of Cr (III) and Fe (III) with DNSC-CTV. Furthermore the interaction of the ligand DNSC-CTV with the metal ions Chromium (III) and Iron (III) showed quenching in the emission spectra. Quantum yield of the complexes were calculated and the stern volmer analysis was done to deduce the quenching mechanism of fluorescence to being either static or dynamic. The molecule DNSC-CTV was further studied with the help of computational methods such as molecular docking to study the binding interactions and properties of the molecule.

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study.

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

The Antioxidant Phytochemical Schisandrin A Promotes Neural Cell Proliferation and Differentiation after Ischemic Brain Injury.

Schisandrin A (SCH) is a natural bioactive phytonutrient that belongs to the lignan derivatives found in Schisandra chinensis fruit. This study aims to investigate the impact of SCH on promoting neural progenitor cell (NPC) regeneration for avoiding stroke ischemic injury. The promoting effect of SCH on NPCs was evaluated by photothrombotic model, immunofluorescence, cell line culture of NPCs, and Western blot assay. The results showed that neuron-specific class III beta-tubulin (Tuj1) was positive with Map2 positive nerve fibers in the ischemic area after using SCH. In addition, Nestin and SOX2 positive NPCs were significantly (p < 0.05) increased in the penumbra and core. Further analysis identified that SCH can regulate the expression level of cell division control protein 42 (Cdc42). In conclusion, our findings suggest that SCH enhanced NPCs proliferation and differentiation possible by Cdc42 to regulated cytoskeletal rearrangement and polarization of cells, which provides new hope for the late recovery of stroke.

Nonplanar Helicene Benzo[4]Helicenium for the Precise Treatment of Renal cell Carcinoma.

Immune and targeted therapy are becoming the first-line treatment for renal cell carcinoma (RCC). However, therapeutic outcomes are limited due to the low efficiency and side effect. Here, it is found that helicenes are able to exhibit an anticancer capability through changing the molecular structure from planar to nonplanar. Furthermore, the cytotoxicity in vitro and cancer inhibition ability of nonplanar helicenes increase with its aromatic rings' number. It is further demonstrated that benzo[4]helicenium shows the specific killing efficiency against the RCC cancer as compared to normal kidney cells. This is majorly originated from a more selective damage of benzo[4]helicenium for mitochondria and DNA in RCC cancer cells, not the normal kidney. The selective killing ability of benzo[4]helicenium makes it have potential to be used as a targeted drug for the precise treatment of RCC.

A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking.

Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5∼1 µg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10-8∼5.10 × 10-5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be -12.0 kcal/mol.