Pyrazoline based MAO inhibitors: synthesis, biological evaluation and SAR studies

Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5-16) were found to be potent inhibitors of hMAO-A isoform with SI_MAO-A in the order 10³ and 10⁴. Ten molecules with unsubstituted ring A and without ring C (21-30), in which eight molecules (21, 23-26, and 28-30) were selective for hMAO-A, one for hMAO-B (22) and the other one non-selective (27). Presence of ring C increases potency as well as SI towards hMAO-A; however its absence decreases both potency and SI towards hMAO-A and hMAO-B.     

Efficient synthesis of 3-O-thia-cPA and preliminary analysis of its biological activity toward autotaxin

The efficient synthesis of 3-O-thia-cPAs (4a-d), sulfur analogues of cyclic phosphatidic acid (cPA), has been achieved. The key step of the synthesis is an intramolecular Arbuzov reaction to construct the cyclic thiophosphate moiety. The present synthetic route enables the synthesis of 4a-d in only four steps from the commercially available glycidol. Preliminary biological experiments showed that 4a-d exhibited a similar inhibitory effect on autotaxin (ATX) as original cPA.     

Thermal solvent-free synthesis of novel pyrazolyl chalcones and pyrazolines as potential antimicrobial agents

A novel approach was adopted for the synthesis of series of new pyrazolyl chalcones (3a-c) by the reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) with different 5-acetylbarbituric acid derivatives (2a-c) under thermal solvent-free condition. The chalcones were then converted to the corresponding pyrazolines (4a-c) under the same condition in excellent yields. All the synthesized compounds were characterized using elemental analysis and spectral data (IR, ¹H NMR, and mass spectrometry). The synthesized compounds were tested for their antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds (3a-4c) showed good antibacterial and antifungal activities, respectively. Among the screened compounds, 3b showed more potent inhibitory activity (MIC = 12.5 μg/ml) nearly to that of standard antibiotics ciprofloxacin, griseofulvin and fluconazole.     

Syntheses of Group 14 bis(tert-butylamido)cyclodiphosph(III)azane dichlorides, and the solid-state structures of the silicon and tin derivatives

To test the synthetic utility of bis(tert-butylamido)cyclodiphosph(III)azanes as ligands we extended the coordination chemistry of these diamides from Group 4 to Group 14. The syntheses of compounds of the formula cis-[^tBuNP(μ-^tBuN)₂PN^tBu]ECl₂, E = Si (1), Ge (2), Sn (3) and the solid-state structures of 1 and 3 are reported. Silicon tetrachloride reacted with dilithiobis(tert-butylamido)cyclodiphosph(III)azane to cleanly produce cis-[^tBuNP(μ-^tBuN)₂PN^tBu]SiCl₂, but for the germanium and tin analogues the interaction of GeCl₄ or SnCl₄ with the diazastannylene cis-[^tBuNP(μ-^tBuN)₂PN^tBu]Sn proved to be a better method. Single-crystal X-ray studies on both 1 and 3 revealed that they had C_s-symmetric structures, the central element being coordinated by two amide nitrogens and two chlorides, in addition to being weakly coordinated by one of the cyclodiphosph(III)azane ring nitrogens. Using structural comparisons between crystallographically-independent 1a and 1b, between 1 and 3, and between 3 and its isomorphous zirconium analogue, the nature of this donor bond is discussed.     

5α,8α-Epidioxysterols from the gorgonian Eunicella cavolini and the ascidian Trididemnum inarmatum: Isolation and evaluation of their antiproliferative activity

Three new (1, 4, 9) and nine previously reported (2, 3, 5-8, 10-12) 5α,8α-epidioxysterols were isolated from the organic extracts of the gorgonian Eunicella cavolini and the ascidian Trididemnum inarmatum. The structures and relative configurations of 1-12 were established on the basis of detailed NMR spectroscopic analyses and comparison with the literature. The growth inhibitory effects of 1-12 were evaluated against MCF-7 human breast cancer cells. Compound 1, bearing a cyclopropyl moiety in the side chain, exhibited the highest antiproliferative activity.     

Synthesis of C-1 homologues of pancratistatin and their preliminary biological evaluation

The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.     

Sargachromanols as inhibitors of Na+/K+ ATPase and isocitrate lyase

Sargachromanols A-P (1-16), 16 meroterpenoids of the chromene class isolated from the brown alga Sargassum siliquastrum, were evaluated for their inhibitory activities toward Na⁺/K⁺ ATPase from porcine cerebral cortex and isocitrate lyase (ICL) from Candida albicans. These studies led to the identification of compounds 4, 6, 8, and 12 as potent Na⁺/K⁺ ATPase inhibitors. Compounds 12, 13, and 16 exhibited moderate ICL inhibitory activity. Compound 12 also showed weak antibacterial activity. The preliminary structure-activity relationship of these compounds is described to elucidate the essential structural requirements.     

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 and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

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.     

Synthesis of some novel androstanes as potential aromatase inhibitors

Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme.     

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.     

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.     

Fungal transformation of isosteviol lactone and its biological evaluation for inhibiting the AP-1 transcription factor

A number of hydroxylated diterpenoids were obtained from the microbial transformation of isosteviol lactone (4α-carboxy-13α-hydroxy-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactone) (2) with Mucorrecurvatus MR 36, Aspergillusniger BCRC 31130, and Absidiapseudocylindrospora ATCC 24169. Incubation of 2 with M. recurvatus and Asp.niger led to isolation of seven known compounds (1 and 3-8). Incubation of 2 with Abs. pseudocylindrospora produced 5 and six previously unreported compounds (9-14). The structures of these isolated compounds were deduced by high-field NMR techniques (¹H, ¹³C, DEPT, COSY, NOESY, HSQC, and HMBC), and those of 9 and 11 were further confirmed by X-ray crystallographic analyses. Subsequently, the inhibitory effects on activator protein-1 (AP-1) activation in lipopolysaccharide-stimulated RAW 264.7 macrophages of all of these compounds were evaluated. Compounds 2-5, 8, 9, 11, and 12 exhibited significant inhibitory activity, while 3 was more potent than the reference compound of dexamethasone.     

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.     

Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl analogues of 5-fluorouracil, N-benzoyl adenine, uracil, thymine, N-benzoyl cytosine and evaluation of their antitumor activities

The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N⁶-benzoyl adenine (6b), uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2′-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N⁶-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2′-position of 5a,b, with simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N⁴-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2′-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the β-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 μM) than the other compounds.     

Cycloartane glycosides from Astragalus aureus

Eight cycloartane-type triterpene glycosides (1-8) were isolated from Astragalus aureus Willd along with ten known cycloartane-type glycosides (9-18). Their structures were established by the extensive use of 1D and 2D-NMR experiments along with ESIMS and HRMS analyses. Compounds 1-5 are cyclocanthogenin glycosides, whereas compounds 6-8 are based on cyclocephalogenin as aglycon, more unusual in the plant kingdom, so far reported only from Astragalus spp. Moreover, for the first time monoglycosides of cyclocanthogenin (5) and cyclocephalogenin (7, 8) are reported. All of the compounds tested for their cytotoxic activities against a number of cancer cell lines. Among the compounds, only 8 exhibited activity versus human breast cancer (MCF7) at 45 μM concentration.     

Ecdysteroids and a sucrose phenylpropanoid ester from Froelichia floridana

Phytoecdysteroid glycosides (1-5) and a phenylpropanoid ester of sucrose (6) were isolated from the whole plant of Froelichia floridana, along with eight known compounds including three ecdysteroids (7-9), four flavonoids (10-13), and one phenolic compound (14). Structures were determined using a combination of spectroscopic techniques. Compounds 1, 2 and 6-14 were tested in vitro for their activity against human DNA topoisomerase I. Compound 13 (diosmetin) showed marginal inhibition against topoisomerase I with IC₅₀ of 130 μM in conjunction with low intercalation ability.     

Steroidal saponins from the whole plants of Agave utahensis and their cytotoxic activity

Phytochemical investigation of the whole plants of Agave utahensis Engelm. (Agavaceae) has resulted in the isolation of 15 steroidal saponins (1-15), including five spirostanol saponins (1-5) and three furostanol saponins (11-13). Structures of compounds 1-5 and 11-13 were determined by spectroscopic analysis and the results of hydrolytic cleavage. The isolated compounds were evaluated for their cytotoxic activity against HL-60 human promyelocytic leukemia cells.