Synthesis and complexation of tetrakis(diphenylphosphinomethyl)calix[4]arene adopting the 1,3-alternate conformation

Novel upper-rim modified tetraphosphinocalix[4]arenes (5a-b) adopting 1,3-alternate conformation have been synthesized. Reaction of 5,11,17,23-tetrachloromethyl-25,26,27,28-tetrahydroxycalix[4]arene (1) with Ph₂POEt gave 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrahydroxycalix[4]arene (2). Tetra-O-substitution of 2 with n-propyl iodide or benzyl bromide in the presence of K₂CO₃ carried out to afford 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,26,27,28-tetrapropoxy-(3a) or -benzyloxycalix[4]arene (3b), whereas di-O-substituted calix[4]arene, 5,11,17,23-tetrakis(diphenylphosphinoylmethyl)-25,27-dipropoxy-26,28-dihydroxycalix[4]arene (4), was obtained exclusively when Na₂CO₃ was used as base. Reduction of 3a-b with PhSiHCl₂ afforded 5,11,17,23-tetrakis(diphosphinomethyl)-25,26,27,28-tetrapropoxy-(5a) and -tetrabenzyloxycalix[4]arene (5b). ¹H and ¹³C NMR analysis reveals that the phosphines (5a-b) and the tetra-O-substituted phosphine oxides (3a-b) adopt 1,3-alternate conformation, while the parent tetrahydroxy-(2) and the di-O-propylated phosphine oxide (4) adopt cone-conformation. The X-ray structure indicates that the calix[4]arene moieties in 4 a pinched-cone conformation in solid state. Complexation of the phosphine ligand (5a) with [RuCl₂(p-cymene)]₂ affords the tetranuclear complexes, [{RuCl₂(p-cymene)}₂ · 5a] (6), as 1,3-alternate conformer.     

Direct evidence that an arene oxide is a metabolic intermediate of 2,2',5,5'-tetrachlorobiphenyl.

Radiolabeled arene oxide was recovered from incubations containing [³H]-2,2′,5,5′-tetrachlorobiphenyl (³H-TCB), unlabeled 2,2′,5,5′-tetrachlorobiphenyl-3,4-oxide (TCBAO), 3,3,3-trichloropropene-1,2-oxide (TCPO), NADPH, and liver microsomes from phenobarbital-induced rats. No labeled arene oxide was generated in the absence of NADPH, nor during the metabolism of unlabeled TCB in the presence of [³H]-H₂O. The recovered oxide (radiolabeled and carrier) was characterized by mobility on silica gel and by conversion to 3- and 4-hydroxy-TCB. Formation of a dihydrodiol metabolite was apparently blocked by inhibition of epoxide hydrase. These data provide the first direct evidence that arene oxides are intermediates of halogenated biphenyl metabolism.     

Improvement of catalytic activity of Candida rugosa lipase in the presence of calix[4]arene bearing iminodicarboxylic/phosphonic acid complexes modified iron oxide nanoparticles

In the present study, iron oxide magnetite nanoparticles, prepared through a co-precipitation method, were coated with phosphonic acid or iminodicarboxylic acid derivatives of calix[4]arene to modulate their surfaces with different acidic groups. Candida rugosa lipase was then directly immobilized onto the modified nanoparticles through sol–gel encapsulation. The catalytic activities and enantioselectivities of the two encapsulated lipases in the hydrolysis reaction of (R/S)-naproxen methyl ester and (R/S)-2-phenoxypropionic acid methyl ester were assessed. The results showed that the activity and enantioselectivity of the lipase were improved when the lipase was encapsulated in the presence of calixarene-based additives; the encapsulated lipase with the phosphonic acid derivative of calix[4]arene had an excellent rate of enantioselectivity against the (R/S)-naproxen methyl and (R/S)-2-phenoxypropionic acid methyl esters, with E = 350 and 246, respectively, compared to the free enzyme. The encapsulated lipases (Fe-Calix-N(COOH)) and (Fe-Calix–P) showed good loading ability and little loss of enzyme activity, and the stability of the catalyst was very good; they only lost 6–11% of the enzyme’s activity after five batches.     

Synthesis and characterization of Ru(arene) complexes of bispyrazolylazines: Catalytic hydrogen transfer of ketones

The bis(pyrazol-1-yl)azine ligands 2,3-bis(pyrazol-1-yl)quinoxaline (bpzqnx), 2,3-bis(pyrazol-1-yl)pyrazine (bpzprz) and 3,6-bis(3,5-dimethylpyrazol-1-yl)pyridazine (bpz*pdz) were prepared by the reaction of pyrazolate salts and the corresponding azine dichloride derivatives. The reaction of these ligands with Ru(arene) precursors led to the mononuclear complexes [RuCl(arene)(L)]BPh₄ (arene = p-cymene, L = bpzqnx, 1, bpzprz, 5, bpz*pdz, 7; arene = C₆H₆, L = bpzqnx, 2, bpzprz, 6, bpz*pdz, 8) with the N-donor ligand coordinated in a bidentate chelate way. In general, the ligands coordinate through one pyrazole ring and the azine, except in the cases of 1 and 2 where the two pyrazolyl rings are coordinated to the metal in a symmetrical way. When the reactions between the ruthenium precursors and bpzqnx are carried out in MeOH, the complexes [RuCl(arene)(OMepzqnx)]BPh₄ with partially methanolyzed ligands are isolated (arene = p-cymene, 3; C₆H₆, 4). In this process a methoxy group has replaced one of the pyrazole groups in the ligand. The X-ray structures of 6 and 7 have been determined. These compounds have a three-legged piano-stool structure with cations and anions packed through weak interactions. Complexes 1-8 are active in ketone hydrogenation transfer processes even in the absence of base.     

Synthesis and structural analysis of calix[4]arene-supported iron(III) complexes

The paper describes the reactivity of calix[4]arene dialkyl- or -silylethers H₂R₂calix, R=Me (1), Bz (2), or SiMe₃ (3) (p-tert.butyl-calix[4]arene=H₄calix), towards the iron(III) complex [FeCl(NSiMe₃)₂(thf)] 4. Bis(silylation) of H₄calix was achieved using a mixture of NEt₃ and Me₃SiCl as silylating agent, which is probably the most convenient and cheapest way for the preparation of H₂(Me₃Si)₂calix 3. [FeCl(N{SiMe₃}₂)₂(thf)] 4 has been obtained from the reaction of [FeCl₃] and commercially available K[N(SiMe₃)₂] in THF. The reactions of 4 with H₂Me₂calix and H₂Bz₂calix afford mononuclear iron(III) chloro compounds [FeCl(R₂calix)] 5 (R=Me) and 6 (R=Bz). The usage of calix[4]arene silyl ether 3 leads to a dinuclear complex [Fe₂({Me₃Si}calix)₂] 7, presumably under Me₃SiCl cleavage of a mononuclear calixarene iron(III) chloro complex. The calix[4]arene ether stabilized iron(III) chloro complexes are susceptible to nucleophilic substitution reactions, as exemplified by the reaction of 5 with sodium azide yielding an azido complex [Fe(N₃)(Me₂calix)] 8. The molecular structures of 4, 5, 6, 7, and 8 in the solid state have been determined by X-ray diffraction.     

Synthesis, characterisation and metal complexation reactions of two calix[4]arene derivatives functionalised with pendant benzamide arms

Two calix[4]arene derivatives (3 and 4) functionalised at the lower rim with pendant benzamide arms were successfully synthesised and characterised, with the X-ray crystal structure of 3 being determined. Only 4 took part in some metal ion complexation reactions, namely those involving metal(II) acetate salts, with metals salts containing other anions not being complexed.     

Discovery of highly potent and selective D4 ligands by interactive SAR study

A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with K_i 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with K_i (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands’ arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.     

Anti-inflammatory constituents from the fruits of Vitex rotundifolia

Three new diterpenes (7, 15 and 17) and two new neolignans (19 and 20) along with nineteen known compounds have been isolated from the fruits of Vitex rotundifolia. Their structures were elucidated by a combination of 1D and 2D NMR, HRESI-MS, and CD data. All isolates were tested for their inhibitory activities on LPS-induced nitric oxide production in RAW264.7 cells. Of these, compounds 3, 4, 7, 13, 15, 19, and 24 found to inhibit nitric oxide production with the IC₅₀ values ranging from 11.3 to 24.5 μM.     

Hypocreaterpenes A and B,cadinane-type sesquiterpenes from a marine-derived fungus,Hypocreales sp.

Two new cadinane-type sesquiterpenes, hypocreaterpenes A (1) and B (2), along with five known compounds (3–7) were isolated from a marine-derived fungus Hypocreales sp. strain HLS-104 isolated from a sponge Gelliodes carnosa. Their structures were determined by a combination of spectroscopic methods. All compounds were tested for the inhibitory effects on the nitric oxide (NO) production in lipopolysaccharide (LPS)-treated RAW264.7 cells. Among them, compounds 3 and 6 showed moderate anti-inflammatory activity with average maximum inhibition (E_max) values of 10.22% and 26.46% at 1 μM, respectively.     

Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes

Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η⁶-benzyldimethylamine)tricarbonylchromium 2, [η⁶-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η⁶-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC₅₀ values of 33.9 nM versus 63.1 nM).     

A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: Synthesis,nitric oxide and nitroxyl release,in vitro hemodynamic,and anti-hypertensive studies

1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8 min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2 h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7 mg kg^?1, po dose) provided a significant reduction in the blood pressure of mice up to 3 h post-drug administration. All these data suggest that compound 16 constitutes an attractive ‘lead-compound’ that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.     

Unusual reactivity of copper(I) complexes of functionalised calix[4]arenes

Two functionalised calix[4]arenes, 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)calix[4]arene (L¹) and 5,11,17,23-tetra-tert-butyl-25,27-bis(2-pyridylmethoxy)-26,28-dibutoxycalix[4]arene (L³), were prepared and characterised. The copper(I) complexes of both calix[4]arenes were synthesised and their reactivities were analysed and compared. The presence of the metal induced a radical in the case of L¹ whereas no such radical was observed in the metal complex of ligand L³.     

Nitric oxide inhibits ATPase activity and induces resistance to topoisomerase II-poisons in human MCF-7 breast tumor cells

BackgroundTopoisomerase poisons are important drugs for the management of human malignancies. Nitric oxide (^?NO), a physiological signaling molecule, induces nitrosylation (or nitrosation) of many cellular proteins containing cysteine thiol groups, altering their cellular functions. Topoisomerases contain several thiol groups which are important for their activity and are also targets for nitrosation by nitric oxide.MethodsHere, we have evaluated the roles of ^?NO/^?NO-derived species in the stability and activity of topo II (α and β) both in vitro and in human MCF-7 breast tumor cells. Furthermore, we have examined the effects of ^?NO on the ATPase activity of topo II.ResultsTreatment of purified topo IIα and β with propylamine propylamine nonoate (PPNO), an NO donor, resulted in inhibition of the catalytic activity of topo II. Furthermore, PPNO significantly inhibited topo II-dependent ATP hydrolysis. ^?NO-induced inhibition of these topo II (α and β) functions resulted in a decrease in cleavable complex formation in MCF-7 cells in the presence of m-AMSA and XK469 and induced significant resistance to both drugs in MCF-7 cells.ConclusionPPNO treatment resulted in the nitrosation of the topo II protein in MCF-7 cancer cells and inhibited both catalytic-, and ATPase activities of topo II. Furthermore, PPNO significantly affected the DNA damage and cytotoxicity of m-AMSA and XK469 in MCF-7 tumor cells.General significanceAs tumors express nitric oxide synthase and generate ^?NO, inhibition of topo II functions by ^?NO/^?NO-derived species could render tumors resistant to certain topo II-poisons in the clinic.     

Phenanthrenes from Dendrobium nobile and their inhibition of the LPS-induced production of nitric oxide in macrophage RAW 264.7 cells

Bioactivity-guided isolation of the methanol extract of the stems of Dendrobium nobile yielded a new phenanthrene together with nine known phenanthrenes and three known bibenzyls. Their structures were elucidated by analysis of the spectroscopic data including 2D-NMR. All of the isolates were evaluated for their potential to inhibit the LPS-induced production of nitric oxide in murine macrophage RAW 264.7 cells. Compounds 1–4, 7–13 inhibited nitric oxide production with the IC₅₀ values ranging from 9.6 μM to 35.7 μM.     

Benzothiazole appended lower rim 1,3-di-amido-derivative of calix[4]arene: Synthesis, structure, receptor properties towards Cu, iodide recognition and computational modeling

A new molecular fluorescent sensor (L) for Cu²⁺ has been synthesized by derivatizing the lower rim of calix[4]arene with benzothiazole moiety, through amide linkage to result in 1,3-di-derivative. The receptor molecule, L exhibited fluorescence quenching towards Cu²⁺ among eleven divalent ions, viz., Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, Cd²⁺, Hg²⁺, Ca²⁺, Mg²⁺ and Pb²⁺, studied. The 1:1 stoichiometry of the complex formed between L and Cu²⁺ has been demonstrated by electronic absorption and ESI-MS. The role of calix[4]arene for the selective sensing of Cu²⁺ has been established by comparing the data with that obtained for an appropriate control molecule. The minimum concentration at which L can detect Cu²⁺ has been found to be 403 ppb. The computations carried out at DFT level have provided the coordination and structural features of the Cu²⁺ complex of L as species of recognition. The Cu²⁺ complex thus formed recognizes iodide by bringing change in the color, among the 14 anions studied.     

The acid-catalyzed dehydration of 1-benzylamino-1-deoxy-d-threo-pentulose, 1-dibenzylamino-1-deoxy-d-fructuronic acid,and d-glucuronic acid

Three compounds, 1-benzylamino-1-deoxy-d-threo-pentulose (1), 1-dibenzylamino-1-deoxy-d-fructuronic acid (2), and d-glucuronic acid (3) were converted into 2-furaldehyde in acidified, tritiated water. In the latter system, the 2-furaldehyde derived from 1 contained 13% of the activity of the solvent at the aldehyde carbon and 9% at positions 3–5 of the furan ring; that from 2 contained 8% at the aldehyde carbon and 29% at positions 3–5; and that from 3 contained 18% at positions 3–5 In deuterium oxide, the 2-furaldehyde derived from 1 contained 14 atom % of deuterium at position 3, 5% at position 4, and 0% at position 5. That from 2 contained 50% at position 3, 44% at position 4, and 7% at position 5. That from 3 contained 35% at position 3, 15% at position 4, and 5% at position 5. The data for 1 are discussed relative to prior data on incorporation collected for d-xylose Incorporation data for both 2 and 3 are qualitatively consistent with a decarboxylation step involving a β,γ-unsaturated, carboxylic acid intermediate. A mechanism for the decarboxylation of hexuronic acids is presented.     

New series of fused pyrazolopyridines: Synthesis,molecular modeling,antimicrobial, antiquorum-sensing and antitumor activities

New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial evaluation toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the selected Gram-positive bacteria and A. fumigatus, whereas 5-amino-4-phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that 4a, 6a and 7a-c have strong activity. In vitro antiproliferative assessment of the new derivatives against HepG2, HCT-116 and MCF-7 cancer cells revealed that 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 2a, 7a and 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity toward WI38 and WISH normal cells was also assessed and results assured that all of the investigated analogs have lower cytotoxicity than doxorubicin. DNA-binding affinity and topoisomerase IIβ inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b bind strongly to DNA; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase IIβ inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase IIβ, and results indicated that 7a and 7b have the highest binding affinity toward topoisomerase IIβ. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.     

Labdane diterpenoids and highly methoxylated bibenzyls from the liverwort Frullania inouei

Four undescribed labdane diterpenoids, 1,2-dehydro-3,7-dioxo-manoyl oxide (1), 1,2-dehydro-7β-hydroxy-3-oxo-manoyl oxide (2), 3,7-dioxo-manoyl oxide (3), and 3β-hydroxy-7-oxo-manoyl oxide (4) together with three known diterpenoids (5-7) and four highly methoxylated bibenzyls (8-11) were isolated from the liverwort Frullania inouei. The absolute structures of 1-4 were established by combined analysis of NMR data, CD data coupled with TDDFT CD calculations, and single-crystal X-ray diffraction measurement. Cytotoxicity tests to human tumor KB, KB/VCR, K562 or K562/A02 cells showed bibenzyls 8-11 inhibited cell proliferation with ID₅₀ values ranging from 11.3 to 49.6 μM and overcame the multidrug resistance (MDR) with the reversal fold (RF) values ranging from 3.19 to 10.91 (5 μM) for vincristine-resistant KB/VCR and RF values from 4.40 to 8.26 (5 μM) for adriamycin-resistant K562/A02 cells, respectively. However, none of the diterpenoids were found to be active (ID₅₀ > 50 μM).     

Synthesis,anti-inflammatory,analgesic, COX-1/2 inhibition activities and molecular docking study of pyrazoline derivatives

Design, synthesis and pharmacological activities of a group of 1,3,5-trisubstituted pyrazolines were reported. The chemical structures of the synthesized compounds have been assigned on the basis of IR, MS, ¹H NMR, and ¹³C NMR spectral analyses. The synthesized 1,3,5-trisubstituted pyrazoline derivatives were evaluated in vivo for anti-inflammatory, analgesic activities and in vitro for COX-1/2 inhibition assay. Among the tested compounds, derivatives 4h, 6e, 7a, 7e, and 9 showed more potent anti-inflammatory and analgesic activities than the reference drug celecoxib. On the basis of their higher activities in the in vivo studies compared with celecoxib, the five compounds 4h, 6e, 7a, 7e and 9 were selected to test their inhibitory activities against ovine COX-1/2 using an in vitro cyclooxygenase inhibition assay. Docking study of compounds 7a, 7e and 9 into the COX-2 binding site revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Design,synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury

A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility of the lead compound. Their neuroprotective properties were assessed by several models. The results showed that target compounds displayed positive free radical quenching abilities, superior to that of CAPE. Compounds 6j–k and 7j–k demonstrated remarkable protection effects against damage induced by hydrogen peroxide which were apparently stronger than that of CAPE. Most of target compounds could inhibit nitric oxide production. Additionally, target compounds showed high blood–brain barrier permeability.