β-Diketiminato 3d-metal compounds: Synthesis, characterization and catalytic behavior towards ethylene

The lithium β-diketiminate (1c, [Li{N(2,6-ⁱPr₂C₆H₃)C(Ph)CHC(^tBu)NH}]₂ represented as (LiL)₂) reacted with 3d-metal (II) chlorides to afford the corresponding compounds (2-7). All metal compounds were fully characterized by elemental, spectroscopic analyses and the single-crystal X-ray diffraction. The coordination geometries around the metals are shown to be tetrahedral within the trinuclear Co₂Li compound (2), planar in ML₂ (M = Co, 3), pseudo-tetrahedral conformation in the ML₂ with M as Mn (4), Fe (5) or Zn (6), and square planar in the dinickel compound (7). Indicated by the trimetallic Co₂Li compound 2, a six-membered ring is constructed of three metal atoms and three bridged chlorides as a twisted conformation. An inversion center is present in the centroid of the Ni₂Cl₂ four-membered ring within compound 7. The plausible mechanism of forming ML₂ was proposed through the chloro-bridged multinuclear compounds on the basis of isolated intermediates of trinuclear (2) and dinuclearic (7) compounds. Upon treatment with methylaluminoxane (MAO), the nickel compound 7 possessed good activity towards ethylene oligomerization, whereas the other metal compounds showed moderate activities towards ethylene polymerization.     

Ring transformation and complex formation of 3-acetyl-4,5-dihydro-1,2,4-triazole oximes

Oximic 1,2,4-triazole ligands 2a-e were prepared from the reaction of 3-acetyl-4,5-dihydro-1H-1,2,4-triazoles 1a-e with hydroxylamine hydrochloride at room temperature. At higher temperatures, the reaction afforded, however, the novel ring transformation product 4-amino-2-(4-chlorophenyl)-5-methyl-2H-1,2,3,6-oxatriazine 3. The reaction of the ligands 2a-e with nickel (II) and palladium (II) acetates in ethanol at room temperature yielded the respective square planar complexes 5a-e, 6a,e. X-ray structure determination of one of these complexes (5a) revealed that metallation led to unexpected ring transformation of the triazole ligand. It is probable that such ring transformation generated the imidazole-N-oxide intermediate 4a which coordinated to Ni(II) ion, and the 4N-donor set comprises both imidazole nitrogen and arylhydrazone nitrogen. The whole process is associated with loss of one hydrogen molecule and formation of one new π-bond. The new compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and HRMS.     

Synthesis of regioisomeric 17β-N-phenylpyrazolyl steroid derivatives and their inhibitory effect on 17α-hydroxylase/C17,20-lyase

The reaction of 3β-hydroxy-21-hydroxymethylidenepregn-5-en-3β-ol-20-one (1) with phenylhydrazine (2a) affords two regioisomers, 17β-(1-phenyl-3-pyrazolyl)androst-3-en-3β-ol (5a) and 17β-(1-phenyl-5-pyrazolyl)androst-5-en-3β-ol (6a). The direction of the ring-closure reactions of 1 with p-substituted phenylhydrazines (2b-e) depends strongly on the electronic features of the substituents. Oppenauer oxidation of 3β-hydroxy-17β-exo-heterocyclic steroids 5a-e and 6a-e yielded the corresponding Δ⁴-3-ketosteroids 9a-e and 10a-e. The inhibitory effects (IC₅₀) of these compounds on rat testicular C_17,20-lyase were investigated by means of an in vitro radioligand incubation technique.     

Synthesis, characterization, crystal structure and antitumor activity of organotin(IV) compounds bearing ferrocenecarboxylic acid

Four new organotin(IV) complexes [(Bu₃Sn)(FcCOO)]_n (1), [(μ-Bu₂Sn)₂(μ-Bu₂SnFcCOO)₂(μ₃-O)₂(μ-OCH₃)₂]₂ (2), [Ph₃Sn(FcCOO)(H₂O)](phen) (3) and [{Ph₃Sn(FcCOO)}₂(4,4′-bipy)] (4) [Fc = (η⁵-C₅H₅)Fe(η⁵-C₅H₄)] have been synthesized and characterized by elemental analyses, IR, (¹H and ¹³C) NMR spectra and X-ray single-crystal diffraction analyses. The structure analyses show that all tin atoms in complexes 1-4 are five-coordinated with trigonal bipyramid geometry. Complexes 1-4 and FcCOOH undergo reversible one-electron oxidations in methanol solution. The antitumor activities of complexes 1-4 have also been tested. Complexes 1 and 2 exhibit medium activity towards P388 cell lines and Hela cell lines. Complexes 3 and 4 exhibit medium activity towards P388 cell lines but strong activity towards Hela cell lines. This may result from complexes 3 and 4 including the neutral molecules 1,10-phenanthroline and 4,4′-bipy.     

New pyridyl modified phosphines: Synthesis and late transition-metal coordination studies

Using a phosphorus based Mannich condensation reaction the new pyridylphosphines {5-Ph₂PCH₂N(H)}C₅H₃(2-Cl)N (1-Cl) and {2-Ph₂PCH₂N(H)}C₅H₃(5-Br)N (1-Br) have been synthesised in good yields (60% and 88%, respectively) from Ph₂PCH₂OH and the appropriate aminopyridine. The ligands 1-Cl and 1-Br display variable coordination modes depending on the choice of late transition-metal complex used. Hence P-monodentate coordination has been observed for the mononuclear complexes AuCl(1-Cl) (2), AuCl(1-Br) (3), RuCl₂(p-cymene)(1-Cl) (4), RuCl₂(p-cymene)(1-Br) (5), RhCl₂(Cp^∗)(1-Cl) (6), RhCl₂(Cp^∗)(1-Br) (7), IrCl₂(Cp^∗)(1-Cl) (8), IrCl₂(Cp^∗)(1′-Cl) (8′), IrCl₂(Cp^∗)(1-Br) (9), cis-/trans-PdCl₂(1-Cl)₂ (10), cis-/trans-PdCl₂(1-Br)₂ (11), cis-PtCl₂(1-Cl)₂ (12) and cis-PtCl₂(1-Br)₂ (13). Reaction of Pd(Me)Cl(cod) (cod = cycloocta-1,5-diene) with either 1 equiv. of 1-Br or the known pyridylphosphines 1′-Cl, 1-OH or 1-H gave the P/N-chelate complexes Pd(Me)Cl(1-Br-1-H) (14)-(17). All new compounds have been fully characterised by spectroscopic and analytical methods. Furthermore the structures of 4, 5, 10 and 16 · (CH₃)₂SO have been elucidated by single crystal X-ray crystallography. A crystal structure of the dinuclear metallocycle trans,trans-[PdCl₂{μ-P/N-{Ph₂PCH₂N(H)}C₅H₄N}]₂ · CHCl₃, 18 · CHCl₃, has also been determined. Here 1-H bridges, using both P and pyridyl N donors, two dichloropalladium centres affording a 12-membered ring with the PdCl₂ units adopting a head-to-tail arrangement.     

Ecdysteroids from Polypodium vulgare L

Three new compounds (3, 7, and 11) together with eight known phytoecdysteroids (1, 2, 4-6, and 8-10) were isolated from the rhizomes of common polypody, Polypodium vulgare L. The structures of compounds were elucidated by spectroscopic methods including 1D and 2D NMR measurements. The ¹H and ¹³C NMR assignments of compounds 1, 6, 9 and 10 are included.     

Synthesis and evaluation of isatin analogs as caspase-3 inhibitors: introduction of a hydrophilic group increases potency in a whole cell assay

A series of isatin analogs containing a hydrophilic group, including a pyridine ring, ethylene glycol group, and a triazole ring, have been synthesized, and their inhibition potency for caspase-3 was measured both in vitro (i.e., recombinant enzyme) and in whole cells (HeLa cells). The analogs having a hydrophilic group, including 12, 13, 16, 38, and 40, have dramatically increased activity in vitro and in HeLa cells compared to the corresponding unsubstituted N-phenyl isatin analogs.     

Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents

In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6-12 and 14-24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED₅₀ 1.1-4.3 μg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED₅₀ 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED₅₀ 1.7 and 0.85 μg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1^f11/f11p53^f5&6/f5&6Cre^c mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands.     

Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles

Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 μg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100 μg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, ¹H NMR, and ¹³C NMR data.     

Non-cannabinoid constituents from a high potency Cannabis sativa variety

Six new non-cannabinoid constituents were isolated from a high potency Cannabis sativa L. variety, namely 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone (1), 4,5-dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene (2), 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (3), 4,7-dimethoxy-1,2,5-trihydroxyphenanthrene (4), cannflavin C (5) and β-sitosteryl-3-O-β-d-glucopyranoside-2′-O-palmitate (6). In addition, five known compounds, α-cannabispiranol (7), chrysoeriol (8), 6-prenylapigenin (9), cannflavin A (10) and β-acetyl cannabispiranol (11) were identified, with 8 and 9 being reported for the first time from cannabis. Some isolates displayed weak to strong antimicrobial, antileishmanial, antimalarial and anti-oxidant activities. Compounds 2-4 were inactive as analgesics.     

Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception

We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60 s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 μg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 μg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.     

Structural requirements of (E)-6-benzylidene-4a-methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one derivatives as novel melanogenesis inhibitors

Chalcone type compound 1a ((E)-6′-benzylidene-4a′-methyl-4′,4a′,7′,8′-tetrahydro-3′H-spiro[[1,3]dithiolane-2,2′-naphthalen]-5′(6′H)-one) was discovered as an potent inhibitor in melanogenesis. To define its structure-activity relationship, a series of analogs 1b-n, dithiolane truncated 2a-b and ring A removed 3a-e were prepared and evaluated. The electron donating substitution on the phenyl ring (ring C) rather than an electron withdrawing group and dithiolane motif of 1 are needed for the activity enhancement. The scaffold containing both rings A and B associated with α,β-unsaturated system connected to phenyl of 1 was essential for antimelanogenesis.     

Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.     

KDR inhibitor with the intramolecular non-bonded interaction: conformation-activity relationships of novel indole-3-carboxamide derivatives

We previously reported that compound 1, having a similar conformation to PTK787 (2) by forming a pseudo ring structure with an intramolecular non-bonded S-O interaction, exhibited a potent inhibitory activity against VEGFR2 tyrosine kinase (KDR).¹ Applying the ideas of pseudo ring formations, we have designed three types of novel indole carboxamide derivatives 5-7 with an intramolecular hydrogen bonding or non-bonded S-O interaction. We describe the design and synthesis of 5-7, and also discuss the relationships of their KDR inhibitory activity and conformations that were stabilized by their intramolecular non-bonded interactions.     

Antioxidant, anti-inflammatory and anti-hyperglycaemic activities of heterocyclic homoprostanoid derivatives

A series of 19 heterocyclic homoprostanoids were synthesized from easily available oleic and ricinoleic acids and evaluated for their possible antioxidant, anti-inflammatory and anti-hyperlipidaemic activities. Compounds with thioxo- and oxoimidazole ring (1) and (2) have shown potent antioxidant activity with IC₅₀ values 0.23 ± 0.09 and 0.41 ± 0.01 mM comparable with standard ascorbic acid. Compound (3) with a quinoxaline ring showed maximum inhibition of BSA denaturation at 1 mM concentration and comparable with standard diclofenac. Incorporation of electron withdrawing substitutions like chloro- and nitro-groups in the quinoxaline ring has resulted in an increase anti-inflammatory activity. Test compounds (3), (3a) and (3c) showed modest inhibition of DPP-IV in vitro. However, the unsubstituted quinoxaline (3) and substituted quinoxalines (3b and 3c) reduced plasma glucose levels indicating the presence of hypoglycemic activity.     

Formation of inorganic protonic-acid polymer via inorganic-organic hybridization: Synthesis and characterization of polymerizable olefinic organosilyl derivatives of mono-lacunary Dawson polyoxometalate

A novel polymerizable organosilyl-modified Dawson-type polyoxometalate (POM) [α₂-P₂W₁₇O₆₁{CH₂C(CH₃)COO(CH₂)₃Si}₂O]⁶⁻ (1) was synthesized as both salt (Me₂NH₂-1) and H⁺ form (H-1). They were characterized with complete elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FTIR, (¹H, ¹³C, ²⁹Si, ³¹P and ¹⁸³W) NMR and n-butylamine titration method. H-1 was immobilized to a polymer network through free radical copolymerization with methyl methacrylate (MMA). The acidities of H-1 and hybrid copolymer (H-1-co-MMA) were evaluated using the Hammett indicators (dicinnamalacetone and benzalacetophenone; pK_a values of the protonated indicators are −3.0 and −5.6, respectively). The pK_a value of H-1 was estimated as that between −3.0 and −5.6 in CH₃CN solution and H-1 was immobilized in H-1-co-MMA with the original acidity being retained. Glass transition point (T_g) and molecular weight distribution of H-1-co-MMA were affected by the used amount of H-1 because of the cross-linking effect of H-1.     

Eudistomidins H-K, new β-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus

Four new β-carboline alkaloids, eudistomidins H-K (1-4), were isolated from an Okinawan marine tunicate Eudistoma glaucus and the structures of 1-4 were elucidated on the basis of spectroscopic data. Eudistomidins H (1) and I (2) were new β-carboline alkaloids possessing a unique fused-tetracyclic ring system consisting of a tetrahydro β-carboline ring and a hexahydropyrimidine ring. Eudistomidin J (3) showed relatively potent cytotoxicity against murine leukemia cells P388 and L1210, and human epidermoid carcinoma cells KB in vitro.     

Synthesis, characterization and cytotoxic activity of gallium(III) complexes anchored by tridentate pyrazole-based ligands

Reactions of GaCl₃ with pyrazole-containing ligands of the pyrazole-imine-phenol (HL¹-HL³) or pyrazole-amine-phenol (HL⁴-HL⁶) types led to the synthesis of well-defined [GaL₂]⁺ homoleptic complexes (1-6). Complexes 1-6 were characterized by elemental analysis, ESI-MS (electrospray ionization-mass spectrometry), IR and NMR spectroscopies, and in the case of Complex 1 also by X-ray diffraction analysis. In complexes 1-3, the pyrazole-imine-phenolate ligands act as monoanionic chelators that coordinate to the metal in a meridional fashion, while 4-6 contain monoanionic and facially coordinated pyrazole-amine-phenolate ligands. Complexes 1-3 have a greater stability in solution compared to 4-6, which have shown a more pronounced tendency to release the respective ancillary ligands. The cytotoxicity of 1-6 and of the respective ligands (HL¹-HL⁶) was evaluated against human prostate cancer cells PC-3 and human breast cancer cells MCF-7. The substituents of the phenolate rings strongly influenced the cytotoxicity of the compounds. Complexes 3 and 6 that contain chloride substituents at the phenolate rings have shown the highest cytotoxicity, including in the cisplatin-resistant PC-3 cell line. The cytotoxic profile of 3 and 6 is very similar to the one displayed by the respective anchor ligands, respectively HL¹ and HL⁶. The cytotoxic activity of 3 and 6 is slightly increased by the presence of transferrin, and both complexes provoke cell death mainly by induction of apoptotic pathways.     

Triterpenoid saponins from Echinopsis macrogona (Cactaceae)

Triterpene saponins, pachanosides C1, E1, F1 and G1 (1-4), and bridgesides A1, C1, C2, D1, D2, E1 and E2 (5-11) were isolated from Echinopsis macrogona. Compounds 1-4 were saponins with pachanane type triterpene saponins, while the others (5-11) were oleanane type triterpene saponins. While the aglycones of 2-4 and 8-11 were hitherto unknown, the structure of pachanol C was revised in this paper. Their structures were elucidated on the basis of chemical and physicochemical evidence.