Search Results (80)

Madangamine alkaloids have attracted considerable interest in the scientific community due to their complex polycyclic structures and potent biological activities. The six members identified to date have exhibited diverse and significant cytotoxic activities against various cancer cell lines. Despite their structural complexity, seven total syntheses—covering five of the six members—have been reported to date. These syntheses, involving 28 to 36 steps and global yields ranging from 0.006% to 0.029%, highlight the formidable challenge these compounds present. This review summarizes the key synthetic strategies developed to access critical fragments, including the construction of the ABC diazatricyclic core and the ACE ring systems. Approaches to assembling the ABCD and ABCE tetracyclic frameworks are also discussed. Finally, we highlight the completed total syntheses of madangamines A–E, with a focus on pivotal transformations and strategic innovations that have enabled progress in this field. Full article

Tereancistrum is a common genus of Neotropical monopisthocotylans; however, information on its diversity and phylogeny remains limited. In this study, we describe four new species of Tereancistrum parasitizing the gills of Prochilodus brevis (Characiformes: Prochilodontidae) from a weir in the state of Ceará, Brazil. Tereancistrum spiralocirrum n. sp. and Tereancistrum scleritelongatum n. sp. are characterized by a dextro-ventral vaginal pore and a Y-shaped dorsal bar. Notably, Tereancistrum spiralocirrum n. sp. is the first species in the genus to possess a male copulatory organ (MCO) with multiple rings (16 to 18). In contrast, Tereancistrum ancistrum n. sp. and Tereancistrum kritskyi n. sp. are distinguished by a sinistral vaginal pore, a sclerotized MCO in the form of a coiled tube with slightly more than one clockwise ring, and an accessory piece that is non-articulated with the base of the MCO. However, Tereancistrum ancistrum n. sp. is unique in lacking a dorsal bar. Sequences of the LSU rDNA obtained from seven species of Tereancistrum parasitizing P. brevis and Leporinus piau, along with published sequences of other Dactylogyridae members, were included in the molecular analyses. Phylogenetic reconstructions supported the monophyly of Tereancistrum. Full article

Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC₅₀ = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC₅₀ > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC₅₀ = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC₅₀ = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development. Full article

Azulene has been attracting much attention as a charge transfer material in organic electronics due to its inherent large dipole moment and small band gap, but its application in perovskite solar cells (PSCs) is very limited. Herein, azulene was applied as the core acceptor for hole transport materials (HTMs), and two molecules named Azu-Py-DF and Azu-Py-OMeTPA were designed and synthesized, in which 4-pyridyl was introduced on the 6-position of the 1,3-substituted azulene core to adjust energy levels. The different spatial orientations of pyridine and the azulene core improve the solubility and reduce the crystallinity of the material, which is conducive to creating a thin film morphology. Azu-Py-OMeTPA exhibited good hole and electron mobility compared with standard Spiro-OMeTAD. Applied as an HTM in PSCs, the Azu-Py-OMeTPA-based device achieved a power conversion efficiency (PCE) of 18.10%, which is higher than that of the 6-position unsubstituted counterpart. Nevertheless, the anticipated passivation effect of the 4-pyridyl group was diminished due to the electron-deficient nature of azulene’s seven-membered ring. These results demonstrate that optimizing the structure of azulene-based HTMs can significantly alter molecular spatial structure, film formation properties, electron delocalization characteristics and charge transport, and can lead to improved device performance, providing insights for the future design of novel HTMs. Full article

Midazolam is a benzodiazepine that is utilized for the induction of anesthesia and the facilitation of procedural sedation. Despite the absence of stereogenic centers, the non-planar seven-membered ring devoid of reflection symmetry elements confers planar stereogenicity to the molecule. Due to the rapid conformational inversion of the Rp and Sp enantiomers, which occurs via a simple ring flip, high-performance liquid chromatography (HPLC) enantiomeric separation is restricted to sub-room temperature conditions. In this study, the energy barriers for the racemization of midazolam at five distinct temperatures and in acetonitrile/water mixtures were determined by monitoring the decay of the circular dichroism signal at a specific wavelength over time. The kinetic and thermodynamic data obtained were compared with those determined by dynamic enantioselective high-performance liquid chromatography using the Chiralpak IG-3 chiral stationary phase, which contains the amylose tris(3-chloro-5-methylphenylcarbamate) as the selector. The temperature-dependent dynamic HPLC of midazolam was carried out at the same temperatures and with the same aqueous mixtures used in parallel kinetic off-column experiments. To simulate dynamic chromatographic profiles, a lab-made computer program based on a stochastic model was utilized. The results indicated that the moderate influence of the stationary phase resulted in a slight increase in the activation barriers, which was more pronounced as the time spent in the column increased. This phenomenon was found to be mitigated when switching from a 250 mm × 4.6 mm, 3 µm, Chiralpak IG-3 column to a 50 mm × 4.6 mm, 1.6 µm, Chiralpak IG-U UHPLC column. The outcomes obtained under UHPLC conditions were found to be more closely aligned with those obtained through the ECD technique, with a discrepancy of only 0.1 kcal/mol or less, indicating a high degree of concordance between the two methods. Full article

Ribavirin, 1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide, which is included in the list of drugs recommended in the guidelines for the diagnosis and treatment of SARS-CoV-2 infection, has been the subject of experimental and theoretical investigation. The most thermodynamically stable polymorphic form was studied using ¹H-¹⁴N NQR cross-relaxation, periodic DFT/QTAIM/RDS/3D Hirshfeld surfaces, and molecular docking. For the first time, a ¹H-¹⁴N cross-relaxation spectrum of ribavirin was recorded and interpreted. Twelve resonance frequencies were assigned to four inequivalent nitrogen positions in the molecule using combined experimental techniques and solid-state quantum chemical calculations. The influence of the structural alteration on the NQR parameters was modeled using GGA/RPBE. The differences in the binding pattern of ribavirin, acadesine, inosine, guanosine, and favipiravir-ribofuranosyl in the solid state and the protein-ligand complex were assessed to elucidate the differences in the binding mechanism at the molecular level due to aglycone modification. The replacement of the carbon adjacent to the ribose with nitrogen, in conjunction with the absence of oxygen at the 2-position of the ring, resulted in an increased flexibility of the RBV structure in comparison to the favipiravir-ribofuranosyl structure. The present study identified the intramolecular hydrogen bond NH···N in RBV as playing a crucial role in the formation of a quasi-five-membered ring. However, this bond was proven to be too weak to force positioning of the amide group in the ring plane. The ribofuranosyl in RBV inhibits tautomerism and freezes the conformation of the amide group. The results of the molecular dynamics simulations demonstrated that RBV and favipiravir-ribofuranosyl incorporated into the RNA primer exhibited comparable stability within the protein binding region. The titular anti-butterfly (inverted butterfly) effect is associated with the consequences of both the changes in aglycone moiety and the neighborhood alteration. Seven structure-binding strength indices and six novel quadrupolar indices defined in this study have been proven to facilitate the evaluation of the similarity of binding motifs in the solid state and protein-ligand complex. Full article

Homopolyatomic cations of the main group elements and of the element sulfur, in particular, are used as tutorial examples to teach structure and bonding in inorganic chemistry. So far, the cations [S₄]²⁺, [S₈]²⁺, [S₁₉]²⁺, [S₅]^•+, and [S₈]^•+ are known experimentally. In this report, the generation and crystal structure determination of the salt Na₂[S₂₀]₂[B₁₂Cl₁₂]₃, containing the new homopolyatomic sulfur cation [S₂₀]²⁺, is reported. The structure of the latter cation consists of two seven-membered homocycles, which are bridged by a six-membered sulfur chain. This structure is strongly related to that of [S₁₉]²⁺. The heptasulfur rings show pronounced bond alternation. Comparison with the experimental structures of [S₇X]⁺ (X = I, Br) and the application of quantum chemical calculations show unambiguously that the observed structural features are intrinsic properties of the cationic cyclo-heptasulfur moieties. The latter can occupy different conformations, which only slightly differ in energy. Charge delocalization and negative hyperconjugation contribute to the stability of the observed structures. The discovery of the [S₂₀]²⁺ cation fits well into range of known homopolyatomic sulfur cations, which can be classified by their averaged oxidation state of sulfur. Full article

To prepare novel biodegradable copolymers with functional substituents that are distributed statistically or randomly over the macromolecule chain and have improved characteristics compared to homopolymers, we conducted a series of synthetic experiments with a novel cyclic monomer, 5-(benzyloxy)-1,3-dioxepan-2-one (4). This compound was synthesized, and its homopolymer, as well as its copolymers with L-lactide, ε-caprolactone and trimethylene carbonate, were prepared in a polymerization solution with stannous octoate as the initiator. The formation of the copolymers was confirmed using NMR spectroscopy and DSC data. The distribution of the monomeric units of the substituted 7CC in the copolymers with L-lactide and ε-caprolactone is random, as it is close to a statistical distribution. The copolymer with TMC is a gradient copolymer due to the different rates of monomer polymerization. The copolymer with a composition of 10(ε-CL):1(carbonate 4) can be considered a promising polymer after the deprotection of the hydroxy group for the inoculation of the functional substituents due to its convenience of preparation and properties similar to those of poly(ε-caprolactone). Full article

The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer’s disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate’s bioactivity and its ability to reduce the fraction of antiparallel β-strand. Full article

Ring size-dependent diastereoselective coordination of unsymmetrical diamines containing one azacyclic nitrogen and one exocyclic nitrogen to [(η⁵-C₅Me₅)MCl]⁺ cores where M = Rh, Ir and [Ru(η⁶-cymene)Cl]⁺ is reported herein. Total stereoselectivity was observed with the six- and seven-membered azacycles, whereas the five-derivative proved poorly selective. All complexes were active for transfer hydrogenation but showed no enantioselectivity with prochiral ketones. Full article

Cyclic organic compounds containing sulfur atoms constitute a large group, and they play an important role in the chemistry of heterocyclic compounds. They are valuable intermediates for the synthesis of other compounds or biologically active compounds themselves. The synthesis of heterocyclic compounds poses a major challenge for organic chemists, especially in the context of applying the principles of “green chemistry”. This work is a review of the methods of synthesis of various S-heterocyclic compounds using green solvents such as water, ionic liquids, deep eutectic solvents, glycerol, ethylene glycol, polyethylene glycol, and sabinene. The syntheses of five-, six-, and seven-membered heterocyclic compounds containing a sulfur atom or atoms, as well as those with other heteroatoms and fused-ring systems, are described. It is shown that using green solvents determines the attractiveness of conditions for many reactions; for others, such use constitutes a real compromise between efficiency and mild reaction conditions. Full article

Grafting alters the genetic and anatomical features of plants. Although grafting has been widely applied in plant propagation, the underlying processes that govern the effects of the procedure are not fully understood. Samples were collected to study the long-term influence of grafting on the leaf-shoot morphology, leaf-shoot anatomy, and genetic signature of the grafted plants. Citrulus lanatus (Thunb.) Matsum. & Nakai (cv. Lady) was used as the scion, and Lagenaria siceraria (Molina) Standl (cv. Argentario) as a rootstock. In grafted plants, leaf blades and petioles were 20.92% and 12.82% longer, respectively, while the midrib collenchyma was 35.68% thicker, and the diameter of the vessel member was 11.17% larger than in ungrafted plants. In the stem, grafting affected the arrangement and number of vascular bundles (from 1 to 2 rings). The thickness of the epidermis decreased by 69.79%, and the size of the external fascicular phloem decreased by 23.56%. The diameter of the vessel member of the grafted plants increased by 28.94%. Eight out of ten evaluated primers met the requirements (stability in both watermelons and bottle gourd, tissue-specific). In the genetic tests, we examined whether this change in the gene expression pattern is due to the grafting and, if so, to what extent. Seven out of eight tested Small Auxin Up-Regulated RNA (SAUR) genes were expressed in the ungrafted and grafted C. lanatus lines in four cases; the expression increased by more than 10% after grafting. The morpho-anatomical changes and genetic variation reported in this study for grafted lines of C. lanatus contribute to the understanding of the underlying mechanisms of plant growth observations resulting from grafting. Full article

Through the implementation of a one-pot strategy, five examples of non-symmetrical [N,N-diaryl-11-phenyl-1,2,3,7,8,9,10-heptahydrocyclohepta[b]quinoline-4,6-diimine]iron(II) chloride complexes (aryl = 2,6-Me₂Ph Fe1, 2,6-Et₂Ph Fe2, 2,6-i-Pr₂Ph Fe3, 2,4,6-Me₃Ph Fe4, and 2,6-Et₂-4-MePh Fe5), incorporating fused six- and seven-membered carbocyclic rings and appended with a remote para-phenyl group, were readily prepared. The molecular structures of Fe2 and Fe3 emphasize the variation in fused ring size and the skewed disposition of the para-phenyl group present in the N′,N,N″-ligand support. Upon activation with MAO or MMAO, Fe1–Fe5 all showed high catalytic activity for ethylene polymerization, with an exceptional level of 35.92 × 10⁶ g (PE) mol⁻¹ (Fe) h⁻¹ seen for mesityl-substituted Fe4/MMAO operating at 60 °C. All catalysts generated highly linear polyethylene with good control of the polymer molecular weight achievable via straightforward manipulation of run temperature. Typically, low molecular weight polymers with narrow dispersity (M_w/M_n = 1.5) were produced at 80 °C (MMAO: 3.7 kg mol⁻¹ and MAO: 4.9 kg mol⁻¹), while at temperatures between 40 °C and 50 °C, moderate molecular weight polymers were obtained (MMAO: 35.6–51.6 kg mol⁻¹ and MAO: 72.4–95.5 kg mol⁻¹). Moreover, analysis of these polyethylenes by ¹H and ¹³C NMR spectroscopy highlighted the role played by both β-H elimination and chain transfer to aluminum during chain termination, with the highest rate of β-H elimination seen at 60 °C for the MMAO-activated system and 70 °C for the MAO system. Full article

Density functional theory (DFT) and coupled cluster theory (CCSD(T)) calculations are performed to investigate the geometric and electronic structures and chemical bonding of a series of Cu-doped zinc oxide clusters: Cu_nZn₃O₃ (n = 1–4). The structural evolution of Cu_nZn₃O₃ (n = 1–4) clusters may reveal the aggregation behavior of Cu atoms on the Zn₃O₃ cluster. The planar seven-membered ring of the CuZn₃O₃ cluster plays an important role in the structural evolution; that is, the Cu atom, Cu dimer (Cu₂) and Cu trimer (Cu₃) anchor on the CuZn₃O₃ cluster. Additionally, it is found that Cu_nZn₃O₃ clusters become more stable as the Cu content (n) increases. Bader charge analysis points out that with the doping of Cu atoms, the reducibility of Cu aggregation (Cu_n−1) on the CuZn₃O₃ cluster increases. Combined with the d-band centers and the surface electrostatic potential (ESP), the reactivity and the possible reaction sites of Cu_nZn₃O₃ (n = 1–4) clusters are also illustrated. Full article

This review article discusses the recent progress in synthesizing seven-membered ring 1,3,5-triazepine and benzo[f][1,3,5]triazepine derivatives. These derivatives can be either unsaturated, saturated, fused, or separated. This review covers strategies and procedures developed over the past two decades, including cyclo-condensation, cyclization, methylation, chlorination, alkylation, addition, cross-coupling, ring expansions, and ring-closing metathesis. This review discusses the synthesis of 1,3,5-triazepine derivatives using nucleophilic or electrophilic substitution reactions with various reagents such as o-phenylenediamine, 2-aminobenzamide, isothiocyanates, pyrazoles, thiazoles, oxadiazoles, oxadiazepines, and hydrazonoyl chloride. This article systematically presents new approaches and techniques for preparing these compounds. It also highlights the biological importance of benzo[f][1,3,5]triazepine derivatives, which have been used as drugs for treating nervous system diseases. This review aims to provide researchers with the necessary information to create and develop new derivatives of these compounds as quickly as possible. Full article