Novel heterocyclic amide derivatives containing a diphenylmethyl moiety: systematic optimizations, synthesis, antifungal activity and action mechanism.

BACKGROUND: The development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x-ray diffraction analysis. RESULTS: In this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC50 = 1.11 µg mL-1). Meanwhile, the anti-R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 µg mL-1, which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad. CONCLUSION: The above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. © 2024 Society of Chemical Industry.

Exploratory study of oxatomide derivatives with high P2X7 receptor inhibitory activity.

Various oxatomide derivatives were designed and synthesized to develop novel P2X7 receptor (P2X7R) antagonists. Evaluation for in-vitro P2X7R antagonist assay showed that DPM-piperazine moiety of oxatomide was required to maintain an inhibitory activity. The structure of both alkyl chains and aromatic head groups strongly affected P2X7R inhibitory activity, and the analogue, with C4-type saturated alkyl chain and a non-substituted or fluorine-substituted indole, was 7.3 to 6.4 times more potent as a P2X7R antagonist than oxatomide.

Syntheses and crystal structures of 2-methyl-1,1,2,3,3-penta-phenyl-2-sila-propane and 2-methyl-1,1,3,3-tetra-phenyl-2-silapropan-2-ol.

The sterically hindered silicon compound 2-methyl-1,1,2,3,3-penta-phenyl-2-sila-propane, C33H30Si (I), was prepared via the reaction of two equivalents of di-phenyl-methyl-lithium (benzhydryllithium) and di-chloro-methyl-phenyl-silane. This bis-benzhydryl-substituted silicon compound was then reacted with tri-fluoro-methane-sulfonic acid, followed by hydrolysis with water to give the silanol 2-methyl-1,1,3,3-tetra-phenyl-2-silapropan-2-ol, C27H26OSi (II). Key geometric features for I are the Si-C bond lengths that range from 1.867 (2) to 1.914 (2) Šand a τ4 descriptor for fourfold coordination around the Si atom of 0.97 (indicating a nearly perfect tetra-hedron). Key geometric features for compound II include Si-C bond lengths that range from 1.835 (4) to 1.905 (3) Å, a Si-O bond length of 1.665 (3) Å, and a τ4 descriptor for fourfold coordination around the Si atom of 0.96. In compound II, there is an intra-molecular C-H⋯O hydrogen bond present. In the crystal of I, mol-ecules are linked by two pairs of C-H⋯π inter-actions, forming dimers that are linked into ribbons propagating along the b-axis direction. In the crystal of II, mol-ecules are linked by C-H⋯π and O-H⋯π inter-actions that result in the formation of ribbons that run along the a-axis direction.

Cancer-Associated Intermediate Conductance Ca2+-Activated K⁺ Channel KCa3.1.

Several tumor entities have been reported to overexpress KCa3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca2+ signaling, KCa3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, KCa3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of KCa3.1 in the adaptation of the tumor microenvironment. Combined, this features KCa3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express KCa3.1 thereby contributing to T cell activation. Thus, any strategy targeting KCa3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of KCa3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses.

Functional Roles of the Ca2+-activated K+ Channel, KCa3.1, in Brain Tumors.

BACKGROUND: Glioblastoma is the most aggressive and deadly brain tumor, with low disease-free period even after surgery and combined radio and chemotherapies. Among the factors contributing to the devastating effect of this tumor in the brain are the elevated proliferation and invasion rate, and the ability to induce a local immunosuppressive environment. The intermediateconductance Ca2+-activated K+ channel KCa3.1 is expressed in glioblastoma cells and in tumorinfiltrating cells. METHODS: We first describe the researches related to the role of KCa3.1 channels in the invasion of brain tumor cells and the regulation of cell cycle. In the second part we review the involvement of KCa3.1 channel in tumor-associated microglia cell behaviour. RESULTS: In tumor cells, the functional expression of KCa3.1 channels is important to substain cell invasion and proliferation. In tumor infiltrating cells, KCa3.1 channel activity is required to regulate their activation state. Interfering with KCa3.1 activity can be an adjuvant therapeutic approach in addition to classic chemotherapy and radiotherapy, to counteract tumor growth and prolong patient's survival. CONCLUSION: In this mini-review we discuss the evidence of the functional roles of KCa3.1 channels in glioblastoma biology.

Benzhydryl Ethers of Tartaric Acid Derivatives: Stereochemical Response of a Dynamically Chiral Propeller.

The benzhydryl (diphenylmethyl) group is a molecular propeller that can act as a chirality reporter if it is introduced nearby a stereogenic center by making an ether bond. The hydrophobic character of the benzhydryl group allows transformation of insoluble natural tartaric acid derivatives into soluble entities in a nonpolar environment. Electronic circular dichroism spectra, recorded within the short-wavelength region of the phenyl 1 B transitions (190-200 nm) shows strong bisignate Cotton effects. The signs and magnitudes of these Cotton effects are a function of absolute configuration and conformation of the molecule and do not primarily arise from exciton coupling of chiral benzhydryl chromophores. In crystals, the main-chain conformation is stabilized by intramolecular hydrogen bonds and CH-CO dipolar interactions. The number of the donor NH groups has a pronounced effect on the preferred conformations and inclusion properties of benzhydryl-(R,R)-tartaric acid diamides. Evidence is shown for the solvent dependency of the conformations of NH amides of tartaric acid diphenylmethyl ethers.

Intermediate-conductance Ca2+-activated K+channel:research advances / 国际药学研究杂志

Intermediate-conductance Ca2+-activated K+channel ,also known as KCa3.1,IKCa and SK4,is widely distributed in fibroblasts,proliferating smooth muscle cells,endothelial cells,T lymphocytes,plasma cells,macrophages,and epithelial cells, and involved in the pathological and physiological processes such as vascular contraction,inflammation ,calcification,tissue fibrosis, immune response,malignant tumor,internal and external secretory glands. In recent years,it has been found that blocking the KCa3.1 pathway or knockouting the gene can significantly prevent the pathophysiological process of its involvement. The recent use of the specific blocker TRAM-34 in animals and humans shows its safety and tolerability,providing a new direction for the treatment of related diseases. In this article,the research progress in KCa3.1 related diseases in recent years is reviewed.

Intermediate-conductance Ca2+-activated K+ channel: Research advances / 国际药学研究杂志

Intermediate-conductance Ca2+-activated K+ channel, also known as KCa3.1, IKCa and SK4, is widely distributed in fibroblasts, proliferating smooth muscle cells, endothelial cells, T lymphocytes, plasma cells, macrophages, and epithelial cells, and involved in the pathological and physiological processes such as vascular contraction, inflammation, calcification, tissue fibrosis, immune response, malignant tumor, internal and external secretory glands. In recent years, it has been found that blocking the KCa3.1 pathway or knockouting the gene can significantly prevent the pathophysiological process of its involvement. The recent use of the specific blocker TRAM-34 in animals and humans shows its safety and tolerability, providing a new direction for the treatment of related diseases. In this article, the research progress in KCa3.1 related diseases in recent years is reviewed.

Sensitization of cancer cells to cyclophosphamide therapy by an organoselenium compound through ROS-mediated apoptosis.

Induction of apoptosis has been recognized as an excellent therapeutic approach in cancer. Selenium based compounds are well known for their antitumor and synergistic chemotherapeutic efficacy when combined with a standard antineoplastic drug. Previously, we have reported that an organoselenium compound, diphenylmethyl selenocyanate (DMSE) could effectively protect normal organs and tissues from the toxicity induced by a standard chemotherapeutic drug cyclophosphamide in a tumor bearing mouse model. In this study, as a further step, we have evaluated the effect of DMSE in sensitization of tumor cells to cyclophosphamide-induced cell death. We found that DMSE alone or in combination with cyclophosphamide could induce cell death mainly through apoptosis. Generation of reactive oxygen species (ROS) followed by down-regulation of antioxidant defense system in the tumor cells was hypothesized as the crucial cellular events occurred following DMSE treatment. In addition, DMSE in combination with cyclophosphamide also caused DNA damage in tumor cells which might be due to the consequence of oxidative stress induced by the combined therapy. Moreover, production of ROS subsequently activated p53, which in turn initiated release of mitochondrial cytochrome c via up-regulation of Bax and down-regulation of Bcl-2. Ultimately, the activation of caspase-3 played the major role to cleave PARP that finally led to apoptosis. All the above results together proposed that, DMSE sensitized tumor cells to cyclophosphamide therapy through ROS-induced p53 activation and mitochondria-mediated caspase dependent apoptosis.

Inhibitory actions by ibandronate sodium, a nitrogen-containing bisphosphonate, on calcium-activated potassium channels in Madin-Darby canine kidney cells.

The nitrogen-containing bisphosphonates used for management of the patients with osteoporosis were reported to influence the function of renal tubular cells. However, how nitrogen-containing bisphosphates exert any effects on ion currents remains controversial. The effects of ibandronate (Iban), a nitrogen-containing bisphosphonate, on ionic channels, including two types of Ca2+-activated K+ (KCa) channels, namely, large-conductance KCa (BKCa) and intermediate-conductance KCa (IKCa) channels, were investigated in Madin-Darby canine kidney (MDCK) cells. In whole-cell current recordings, Iban suppressed the amplitude of voltage-gated K+ current elicited by long ramp pulse. Addition of Iban caused a reduction of BKCa channels accompanied by a right shift in the activation curve of BKCa channels, despite no change in single-channel conductance. Ca2+ sensitivity of these channels was modified in the presence of this compound; however, the magnitude of Iban-mediated decrease in BKCa-channel activity under membrane stretch with different negative pressure remained unchanged. Iban suppressed the probability of BKCa-channel openings linked primarily to a shortening in the slow component of mean open time in these channels. The dissociation constant needed for Iban-mediated suppression of mean open time in MDCK cells was 12.2 µM. Additionally, cell exposure to Iban suppressed the activity of IKCa channels, and DC-EBIO or 9-phenanthrol effectively reversed its suppression. Under current-clamp configuration, Iban depolarized the cells and DC-EBIO or PF573228 reversed its depolarizing effect. Taken together, the inhibitory action of Iban on KCa-channel activity may contribute to the underlying mechanism of pharmacological or toxicological actions of Iban and its structurally similar bisphosphonates on renal tubular cells occurring in vivo.

TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery.

The purpose of the present study was to characterize TRPV4 channels in the rat pulmonary artery and examine their role in endothelium-dependent relaxation. Tension, Real-Time polymerase chain reaction (Real-Time PCR) and Western blot experiments were conducted on left and right branches of the main pulmonary artery from male Wistar rats. TRPV4 channel agonist GSK1016790A (GSK) caused concentration-related robust relaxation (Emax 88.6±5.5%; pD2 8.7±0.2) of the endothelium-intact pulmonary artery. Endothelium-denudation nearly abolished the relaxation (Emax 5.6±1.3%) to GSK. TRPV4 channel selective antagonist HC067047 significantly attenuated GSK-induced relaxation (Emax 56.2±6.6% vs. control Emax 87.9±3.3%) in endothelium-intact vessels, but had no effect on either ACh-induced endothelium-dependent or SNP-induced endothelium-independent relaxations. GSK-induced relaxations were markedly inhibited either in the presence of NO synthase inhibitor L-NAME (Emax 8.5±2.7%) or sGC inhibitor ODQ (Emax 28.1±5.9%). A significant portion (Emax 30.2±4.4%) of endothelium-dependent relaxation still persisted in the combined presence of L-NAME and cyclooxygenase inhibitor indomethacin. This EDHF-mediated relaxation was sensitive to inhibition by 60mM K(+) depolarizing solution or K(+) channel blockers apamin (SKCa; KCa2.3) and TRAM-34 (IKCa; KCa3.1). GSK (10(-10)-10(-7)M) caused either modest decrease or increase in the basal tone of endothelium-intact or denuded rings, respectively. We found a greater abundance (>1.5 fold) of TRPV4 mRNA and protein expressions in endothelium-intact vs. denuded vessels, suggesting the presence of this channel in pulmonary endothelial and smooth muscle cells as well. The present study demonstrated that NO and EDHF significantly contributed to TRPV4 channel-mediated endothelium-dependent relaxation of the rat pulmonary artery.

Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats.

The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3-3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. In contrast, intrathecal pretreatment with fluoxetine (0.3-3 nmol/rat) prevented nociception induced by formalin. The peripheral pronociceptive effect of fluoxetine was prevented by the 5-HT2A (ketanserin, 3-10 pmol/paw), 5-HT2B (3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4(1H,3H)-quinazolinedione(+) tartrate, RS-127445, 3-10 pmol/paw), 5-HT2C (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride, RS-102221, 3-10 pmol/paw), 5-HT3 (ondansetron, 3-10 nmol/paw), 5-HT4 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, GR-113808, 3-100 fmol/paw), 5-HT6 (4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride, SB-258585, 3-10 pmol/paw) and 5-HT7 ((R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl) pyrrolidine-1-sulfonyl) phenol hydrochloride, SB-269970, 0.3-1 nmol/paw), but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate, WAY-100635, 0.3-1 nmol/paw), 5-HT1B/1D (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-carboxamide hydrochloride hydrate, GR-127935, 0.3-1 nmol/paw), 5-HT1B (1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine hydrochloride, SB-224289, 0.3-1 nmol/paw), 5-HT1D (4-(3-chlorophenyl)-α-(diphenylmethyl)-1-piperazineethanol hydrochloride, BRL-15572, 0.3-1nmol/paw) nor 5-HT5A ((N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride, SB-699551, 1-3 nmol/paw), receptor antagonists. In marked contrast, the spinal antinociceptive effect of fluoxetine was prevented by the 5-HT1A (WAY-100635, 0.3-1 nmol/rat), 5-HT1B/1D (GR-127935, 0.3-1 nmol/rat), 5-HT1B (SB-224289, 0.3-1 nmol/rat), 5-HT1D (BRL-15572, 0.3-1 nmol/rat) and 5-HT5A (SB-699551, 1-3 nmol/rat), but not by the 5-HT2A (ketanserin, 3-10 pmol/rat), 5-HT2B (RS-127445, 3-10 pmol/rat), 5-HT2C (RS-102221, 3-10 pmol/rat), 5-HT3 (ondansetron, 3-10 nmol/rat), 5-HT4 (GR-113808, 3-100 fmol/rat), 5-HT6 (SB-258585, 3-10 pmol/rat) nor 5-HT7 (SB-269970, 0.3-1 nmol/rat), receptor antagonists. These results suggest that fluoxetine produces nociception at the periphery by activating peripheral 5-HT2A/2B/2C/3/4/6/7 receptors. In addition, intrathecal fluoxetine produces antinociception by activation of spinal 5-HT1A/1B/1D/5A receptors.