Accessing Bioactive Hydrazones by the Hydrohydrazination of Terminal Alkynes Catalyzed by Gold(I) Acyclic Aminooxy Carbene Complexes and Their Gold(I) Arylthiolato and Gold(III) Tribromo Derivatives: A Combined Experimental and Computational Study.

Hydrohydrazination of terminal alkynes with hydrazides yielding hydrazones 5-14 were successfully catalyzed by a series of gold(I) acyclic aminooxy carbene complexes of the type [{(4-R2-2,6-t-Bu2-C6H2O)(N(R1)2)}methylidene]AuCl, where R2 = H, R1 = Me (1b); R2 = H, R1 = Cy (2b); R2 = t-Bu, R1 = Me (3b); R2 = t-Bu, R1 = Cy (4b). The mass spectrometric evidence corroborated the existence of the catalytically active solvent-coordinated [(AAOC)Au(CH3CN)]SbF6 (1-4)A species and the acetylene-bound [(AAOC)Au(HC≡CPhMe)]SbF6 (3B) species of the proposed catalysis cycle. The hydrohydrazination reaction was successfully employed in synthesizing several bioactive hydrazone compounds (15-18) with anticonvulsant properties using a representative precatalyst (2b). The DFT studies favored the 4-ethynyltoluene (HC≡CPhMe) coordination pathway over the p-toluenesulfonyl hydrazide (NH2NHSO2C6H4CH3) coordination pathway, and that proceeded by a crucial intermolecular hydrazide-assisted proton transfer step. The gold(I) complexes (1-4)b were synthesized from the {[(4-R2-2,6-t-Bu2-C6H2O)(N(R1)2)]CH}+OTf- (1-4)a by treatment with (Me2S)AuCl in the presence of NaH as a base. The reactivity studies of (1-4)b yielded the gold(III) [{(4-R2-2,6-t-Bu2-C6H2O)(N(R1)2)}methylidene]AuBr3 (1-4)c complexes upon reaction with molecular bromine and the gold(I) perfluorophenylthiolato derivatives, [{(4-R2-2,6-t-Bu2-C6H2O)(N(R1)2)}methylidene]AuSC6F5 (1-4)d, upon treatment with C6F5SH.

Discrete Singular Metallophilic Interaction in Stable Large 12-Membered Binuclear Silver and Gold Metallamacrocycles of Amido-Functionalized Imidazole and 1,2,4-Triazole-Derived N-Heterocyclic Carbenes.

Metallophilic interactions were observed in four pairs of 12-membered metallamacrocyclic silver and gold complexes of imidazole-derived N-heterocyclic carbenes (NHCs), [1-(R1)-3-N-(2,6-di-(R2)-phenylacetamido)-imidazol-2-ylidene]2M2 [R1 = p-MeC6H4, R2 = Me, M = Ag (1b) and Au (1c); R1 = Me, R2 = i-Pr, M = Ag (2b) and Au (2c); R1 = Et, R2 = i-Pr, M = Ag (3b) and Au (3c)], and a 1,2,4-triazole-derived N-heterocyclic carbene (NHC), [1-(i-Pr)-4-N-(2,6-di-(i-Pr)-phenylacetamido)-1,2,4-triazol-2-ylidene]2M2 [M = Ag (4b) and Au (4c)]. The X-ray diffraction, photoluminescence, and computational studies indicate the presence of metallophilic interactions in these complexes, which are significantly influenced by the sterics and the electronics of the N-amido substituents of the NHC ligands. The argentophilic interaction in the silver 1b-4b complexes was stronger than the aurophilic interaction in the gold 1c-4c complexes, with the metallophilic interaction decreasing in the order 4b > 1b > 1c > 4c > 3b > 3c > 2b > 2c. The 1b-4b complexes were synthesized from the corresponding amido-functionalized imidazolium chloride 1a-3a and the 1,2,4-triazolium chloride 4a salts upon treatment with Ag2O. The reaction of 1b-4b complexes with (Me2S)AuCl gave the gold 1c-4c complexes.

One pot tandem dual CC and CO bond reductions in the ß-alkylation of secondary alcohols with primary alcohols by ruthenium complexes of amido and picolyl functionalized N-heterocyclic carbenes.

Two different classes of ruthenium complexes, namely, [1-mesityl-3-(2,6-Me2-phenylacetamido)-imidazol-2-ylidene]Ru(p-cymene)Cl (1c) and {[1-(pyridin-2-ylmethyl)-3-(2,6-Me2-phenyl)-imidazol-2-ylidene]Ru(p-cymene)Cl}Cl (2c), successfully catalyzed the one-pot tandem alcohol-alcohol coupling reactions of a variety of secondary and primary alcohols, in moderate to good yields of ca. 63-89%. The mechanistic investigation performed on two representative catalytic substrates, 1-phenylethanol and benzyl alcohol using the neutral ruthenium (1c) complex showed that the catalysis proceeded via a partially reduced CC hydrogenated carbonyl species, [PhCOCH2CH2Ph] (3'), to the fully reduced CO and CC hydrogenated secondary alcohol, [PhCH(OH)CH2CH2Ph] (3). Furthermore, the time dependent study showed that the major product of the catalysis modulated between (3') and (3) during the catalysis run performed over an extended period of 120 hours. Finally, the practical utility of the alcohol-alcohol coupling reaction was demonstrated by preparing five different flavan derivatives (13-17) related to various bioactive flavonoid natural products, in a one-pot tandem fashion.

Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis.

Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of αß-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity.

One-Pot Tandem Hiyama Alkynylation/Cyclizations by Palladium(II) Acyclic Diaminocarbene (ADC) Complexes Yielding Biologically Relevant Benzofuran Scaffolds.

A series of palladium acyclic diaminocarbene (ADC) complexes of the type cis-[(R1NH)(R2)methylidene]PdCl2(CNR1) [R1 = 2,4,6-(CH3)3C6H2: R2 = NC5H10 (2); NC4H8 (3); NC4H8O (4)] were used not only to perform the Csp2 -Csp Hiyama coupling between aryl iodide and triethoxysilylalkynes but also to subsequently carry out the one-pot tandem Hiyama alkynylation/cyclization reaction between 2-iodophenol and triethoxysilylalkynes, giving a convenient time-efficient access to the biologically relevant benzofuran compounds. The palladium ADC complexes (2-4) were conveniently synthesized by the nucleophilic addition of secondary amines, namely, piperidine, pyrrolidine, and morpholine on the cis-{(2,4,6-(CH3)3C6H2)NC}2PdCl2 in moderate yields (ca. 61-66%).

Cyanosilylation of Aromatic Aldehydes by Cationic Ruthenium(II) Complexes of Benzimidazole-Derived O-Functionalized N-Heterocyclic Carbenes at Ambient Temperature under Solvent-Free Conditions.

A series of ruthenium complexes, namely, [{1-(N-R1-2-acetamido)-3-(R2)-benzimidazol-2-ylidine}Ru(p-cymene)Cl]Cl, where {R1 = 2,6-(i-Pr)2C6H3, R2 = i-Pr (1c); R1 = 2,6-(i-Pr)2C6H3, R2 = Et (2c); R1 = 2,4,6-(CH3)3C6H2, R2 = Et (3c)}, of benzimidazole-derived N/O-functionalized N-heterocyclic carbene ligands successfully carried out the cyanosilylation reaction of aromatic aldehydes and heteroaryl aldehydes with trimethylsilyl cyanide, providing good to excellent yields (ca. 60-95%) at room temperature under solvent-free condition. The ruthenium (1-3)c complexes were synthesized from the silver (1-3)b analogues in ca. 67-80% yields. The silver (1-3)b complexes exhibited an argentophilic d 10···d 10 interaction in its dinuclear macrometallacyclic motif, as observed by a short Ag···Ag contact of 3.1894(3) Å in single-crystal X-ray diffraction studies for a representative silver complex 2b and also in photoluminescence studies that showed characteristic emission band(s) at ca. 534-536 nm in the CHCl3 solution and at ca. 482-487 and 530-533 nm in the solid state.

Distinct Mechanoresponsive Luminescence, Thermochromism, Vapochromism, and Chlorine Gas Sensing by a Solid-State Organic Emitter.

In this study, we report a synthetically simple donor-acceptor (D-A)-type organic solid-state emitter 1 that displays unique fluorescence switching under mechanical stimuli. Orange and yellow emissive crystals of 1 (1O, 1Y) exhibit an unusual "back and forth" fluorescence response to mechanical force. Gentle crushing (mild pressure) of the orange or yellow emissive crystal results in hypsochromic shift to cyan emissive fragments (λem = 498-501 nm) with a large wavelength shift Δλem = -71 to -96 nm, while further grinding results in bathochromic swing to green emissive powder λem = 540-550 nm, Δλem = +40 to 58 nm. Single-crystal X-ray diffraction study reveals that molecules are packed by weak interactions, such as C-H···π, C-H···N, and C-H···F, which facilitate intermolecular charge transfer in the crystal. With the aid of structural, spectroscopic, and morphological studies, we established the interplay between intermolecular and intramolecular charge-transfer interaction that is responsible for this elusive mechanochromic luminescence. Moreover, we have also demonstrated the application of this organic material for chlorine gas sensing in solid state.

Potent Anticancer Activity with High Selectivity of a Chiral Palladium N-Heterocyclic Carbene Complex.

Five enantiomeric pairs of palladium complexes of 1,2,4-triazole-derived chiral N-heterocyclic carbene ligands were investigated to probe the influence of chirality on the compound's anticancer activity. Although no chirality-related influence was observed for any of the enantiomeric pair, strong anticancer activity was seen for a particular pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active than the benchmark drug cisplatin for human breast cancer cells, MCF-7 (ca. 24-27-fold), and human cervical cancer cells, HeLa (ca. three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger antiproliferative activity toward B16F10 and MCF-7 relative to their respective noncancerous counterparts, L929 (fibroblast skin cells) and MCF10A (epithelial breast cells), thereby upholding the potential of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1R,2R,5S)-1c induced p53-dependent programmed cell death in MCF-7 cells.

Modeling the Active Site of the Purple Acid Phosphatase Enzyme with Hetero-Dinuclear Mixed Valence M(II)-Fe(III) [M = Zn, Ni, Co, and Cu] Complexes Supported over a [N6O] Unsymmetrical Ligand.

The active site of the purple acid phosphatase enzyme has been successfully modeled by a series of hetero-dinuclear M(II)-Fe(III) [M = Zn, Ni, Co, and Cu] type complexes of an unsymmetrical [N6O] ligand that contained a bridging phenoxide moiety and one imidazoyl and three pyridyl moieties as the terminal N-binding sites. In particular, the hetero-dinuclear complexes, {L[MII(µ-OAc)2FeIII]}(ClO4)2 [M = Zn (3a), Ni (3b), Co (4a), and Cu (4b)], were obtained directly from the phenoxy-bridged ligand (HL), namely 2-{[bis(2-methylpyridyl)amino]methyl}-6-{[((1-methylimidazol-2-yl)methyl)(2-pyridylmethyl)amino]methyl}-4-t-butylphenol (2), upon sequential addition of Fe(ClO4)3·XH2O and M(ClO4)2·6H2O (M = Zn and Ni) or M(OAc)2·XH2O (M = Co and Cu), in a low-to-moderate (ca. 32-53%) yield. The temperature-dependent magnetic susceptibility measurements indicated weak antiferromagnetic coupling interactions occurring between the two metal centers in their high-spin states. All of the 3(a-b) and 4(a-b) complexes successfully carried out the hydrolysis of the bis(2,4-dinitrophenyl)phosphate (2,4-BDNPP) substrate in a mixed CH3CN/H2O (v/v 1:1) medium in the pH range of 5.5-10.5 at room temperature, thereby mimicking the functional activity of the native enzyme. The spectrophotometric titration suggested a monoaquated and dihydroxo species of the type {L[(H2O)MII(µ-OH)FeIII(OH)]}2+ to be the catalytically active species for the phosphodiester hydrolysis reaction within the pH range of ca. 5.80-7.15. Last, the kinetic studies on the hydrolysis of the model substrate, 2,4-BDNPP, divulge a Michaelis-Menten-type behavior for all complexes.

Accessing a Biologically Relevant Benzofuran Skeleton by a One-Pot Tandem Heck Alkynylation/Cyclization Reaction Using Well-Defined Palladium N-Heterocyclic Carbene Complexes.

Well-defined palladium N-heterocyclic carbene (NHC) complexes were employed in the one-pot tandem Heck alkynylation/cyclization sequence for preparing biologically relevant benzofuran compounds under copper-free conditions in a time-efficient step-reduced fashion. In particular, a series of binuclear palladium complexes, 1b-1e and 2b-2e, of the alkyl-bridged NHC ligands, namely, {1,1'-di-R1-4,4'-R2-di-1,2,4-triazoline-5,5'-diylid-2-ene] (R1 = i-Pr; R2 = -(CH2)2-, -(CH2)3-), and their mononuclear analogues, trans-(NHC)PdBr2(pyridine) (3b) and cis-(NHC)PdBr2(PPh3) (3c), successfully catalyzed the one-pot tandem Heck alkynylation/cyclization reaction of 2-iodophenol with a variety of terminal alkyne substrates, yielding 2-substituted benzofuran derivatives. The mononuclear complexes 3b and 3c were nearly half as active as the representative dinuclear analogue 1c under analogous reaction conditions, thereby implying that, at the same mole percent of the palladium loading, the monometallic 3b and 3c and the bimetallic 1c complexes were equally effective as catalysts. The two sites of the bimetallic complex 1c performed as two separate independent catalytic sites, displaying no cooperativity effect in the catalysis. Finally, the practical utility of the aforementioned catalysts was demonstrated for a representative catalyst 1c through the convenient synthesis of a key intermediate, 3-[2-(benzo[d][1,3]dioxol-5-yl)-7-methoxybenzofuran-5-yl]propan-1-ol, in a total-synthesis protocol of the natural product Egonol.

Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization.

In an attempt to discover a potent and selective anticancer agent, gallic acid has been modified to benzylidene indanones as tubulin polymerization inhibitors. These compounds were evaluated against several human cancer cell lines and also evaluated for inhibition of tubulin polymerase in in vitro assays. Three of the analogues exhibited strong cytotoxicity against human cancer cell lines IC(50)=10-880 nM and also showed tubulin polymerization inhibition (IC(50)=0.62-2.04 µM). Compound 9j, the best candidate of the series was found to be non-toxic in acute oral toxicity in Swiss-albino mice up to 1000 mg/kg dose.

A simple and convenient synthesis of 2-methoxyestradiol from estrone.

A simple and straightforward synthesis of 2-methoxyestradiol have been achieved in nine synthetic steps with 21% of overall yield. Being a convenient process, it can be upscaled to industrial process.