ß-Cyclodextrin-conjugated phthalocyanines as water-soluble and recyclable sensitisers for photocatalytic applications.

Two zinc(ii) phthalocyanines substituted with two and four permethylated ß-cyclodextrin moieties at the α positions have been synthesised and immobilised on the surface of adamantane-modified silica nanoparticles through host-guest interactions. These molecular and supramolecular systems can catalyse the photooxygenation of 1-naphthol and 2-furoic acid in organic and aqueous media with high conversion efficiency and reaction yield, and photodegradation of 2-chlorophenol in water. Having a higher photostability and recyclability, the supramolecular nanosystems are particularly promising for these photocatalytic applications.

Synthesis of 2-Monochloropanol Fatty Acid Esters and Their Acute Oral Toxicities in Swiss Mice.

A novel synthetic route was designed, developed, and utilized to synthesize six high-purity 2-monochloropropanediol fatty acid esters (2-MCPD esters), a group of potential processing-induced food contaminants. A chlorine atom was introduced to C-2 of a diethyl malonate molecule, which was reduced by NaBH4 and followed by esterification using fatty acids. The reaction products were isolated and purified using silica gel columns to obtain three 2-MCPD monoesters and three diesters at about 50-54% and 56-59% yields, respectively. In addition, 2-MCPD monopalmitate and dipalmitate were examined for their acute oral toxicities in Swiss mice. The LD50 values of 2-MCPD mono- and dipalmitate were greater than 5000 mg/kg body weight (BW), along with detectable nephrotoxicity and testicular toxicity. The results of this study may promote future investigation of MCPD ester toxicology and detection.

Synthesis of o-chlorophenols via an unexpected nucleophilic chlorination of quinone monoketals mediated by N,N'-dimethylhydrazine dihydrochloride.

An unexpected nucleophilic chlorination of a quinone monoketal while carrying out a pyrazolidine synthesis has led to a general preparation of multisubstituted phenols. The products are obtained in good to high yields under mild conditions. The bridged pyrazolidines that were the original targets are obtained in the presence of a protic solvent.

Room-temperature Pd-catalyzed C-H chlorination by weak coordination: one-pot synthesis of 2-chlorophenols with excellent regioselectivity.

A room-temperature Pd(II)-catalyzed regioselective chlorination reaction has been developed for a facile one-pot synthesis of a broad range of 2-chlorophenols. The reaction demonstrates an excellent regioselectivity and reactivity for C-H chlorination. This reaction represents one of the rare examples of mild C-H functionalization at ambient temperature.

Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors.

A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 µM for MCF-7 and IC(50) = 0.45 µM for WM266.5, IC(50) = 0.22 µM for BRAF(V600E), 3m: IC(50) = 0.97 µM for MCF-7 and IC(50) = 0.72 µM for WM266.5, IC(50) = 0.46 µM for BRAF(V600E), which were comparable with the positive control Erlotinib.

Liberation of copper from amyloid plaques: making a risk factor useful for Alzheimer's disease treatment.

Alzheimer's disease (AD) is a complex multifactorial syndrome. Metal chelator and Aß inhibitor are showing promise against AD. In this report, three small hybrid compounds (1, 2, and 3) have been designed and synthesized utilizing salicylaldehyde (SA) based Schiff bases as the chelators and benzothiazole (BT) as the recognition moiety for AD treatment. These conjugates can capture Cu(2+) from Aß and become dimers upon Cu(2+) coordination and show high efficiency for both Cu(2+) elimination and Aß assembly inhibition. Besides, the complexes have superoxide dismutase (SOD) activity and significant antioxidant capacity and are capable of decreasing intracellular reactive oxygen species (ROS) and increasing cell viability. All these results indicate that the multifunctional metal complexes which have Aß specific recognition moiety and metal ion chelating elements show the potential for AD treatment. Therefore, our work will provide new insights into exploration of more potent amyloid inhibitors.

Access to macrocycles with an endo aryl ether and an endo aryl-aryl bond, development and application.

Macrocyclization methodologies allowing access to macrocycles having an endo aryl ether and an endo aryl-aryl bond, especially those based on an intramolecular S(N)Ar reaction and the Suzuki-Miyaura reaction, are summarized. Total synthesis of complestatin, a bis-macrocyclic natural product, featuring these two technologies are presented.

Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization.

Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration. In this instance, the complexity of the substrate and the reverse macrocyclization order did not diminish the atropodiastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with the analogous substrate used to provide the isolated DEF ring system in our first-generation approach. Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling.

Total synthesis of chloropeptin II (complestatin) and chloropeptin I.

The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.

Design, development, synthesis, and docking analysis of 2'-substituted triclosan analogs as inhibitors for Plasmodium falciparum enoyl-ACP reductase.

A structure-based approach has been adopted to develop 2'-substituted analogs of triclosan. The Cl at position 2' in ring B of triclosan was chemically substituted with other functional groups like NH(2), NO(2) and their inhibitory potencies against PfENR were determined. The binding energies of the 2' substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC(50) and inhibition constant (K(i)) of 2' substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds, 2-(2'-Amino-4'-chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4'-chloro-2'-nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC(50) of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC(50) of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture.

Synthesis of DEFG ring of complestatin and chloropeptin I: highly atropdiastereoselective macrocyclization by intramolecular Suzuki-Miyaura reaction.

Palladium-catalyzed intramolecular Suzuki-Miyaura reaction of linear tripeptide (23) afforded the 16-membered DEFG ring of complestatin (3) in good yield with an excellent atropdiastereoselectivity. Acidic treatment of 3 triggers a stereospecific rearrangement leading to the corresponding DEFG ring 4 of chloropeptin I.

Preparation of 7-Halo-indoles by Thallation of N-formylindoline and their attempted use for synthesis of the right-hand segment of chloropeptin.

7-Substituted (Cl, Br, I) indoles were synthesized by using thallation of N-formylindoline as a key reaction. Two precursor tripeptides for the right-hand segment of chloropeptin were synthesized by using (R)-7'-iodo and 7'-bromotryptophans derived from each 7-substituted indole (I, Br) obtained by the above procedure.

Synthesis of linear tripeptides for right-hand segments of complestatin.

This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is described. Two of them are the precursor tripeptides for macrolactamization to the right-hand segment of complestatin at the last step and the other two are the precursor tripeptides for ring-closing reaction using Suzuki and Stille coupling, respectively, to the right-hand segment of complestatin at the last step. These compounds and the synthetic procedure will serve for both the synthesis of the right-hand segment and total synthesis of complestatin in the near future. In addition, consideration of the smooth acidic isomerization of complestatin to chloropeptin was carried out by density functional theory (DFT) calculation.

Isocomplestatin: total synthesis and stereochemical revision.

A Pd-mediated method for preparation of the strained macrocyclic moiety of complestatins is disclosed. Through stereoselective synthesis of model macrocycles and the S atropisomer of complestatin, the stereochemical identity of the anti-HIV agent complestatin is established. Investigations described herein illustrate that the compound previously reported as isocomplestatin is the same as complestatin. Thus, the S atropisomer of complestatin is the true isocomplestatin and has not been isolated as a natural product.

Total synthesis of anti-HIV agent chloropeptin I.

A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported. Important features of the total synthesis include: (1) the use of Ti-catalyzed cyanide addition to imines to prepare a requisite amino acid moiety, (2) the discovery of the positive effect of MeOH in the Cu-mediated biaryl ether formation to afford one of the two macrocyclic peptide moieties, and (3) the discovery of the positive influence of collidine in the diastereoselective Pd-mediated cross-coupling to result in efficient formation of another macrocycle within this medicinally important molecule. This key step is performed in the presence of four unprotected phenols, two of which reside on dichlorophenylglycines.

New 5-substituted-1-(2-hydroxybenzoyl)-benzotriazoles, potassium channel activators. IV.

This paper reports the synthesis of a series of new 5-substituted-1-(2-hydroxybenzoyl)-benzotriazoles, which have been tested for their activity as possible activators of potassium channels. In rat aortic rings, the 'opened' derivatives 1a-f, intermediates of synthesis, showed vasorelaxing properties, with appreciable values of potency. However, the most remarkable effects were recorded for the 2-hydroxybenzoylbenzotriazoles 3a-f, which showed full vasorelaxing efficacy and high potency values. The introduction of a 2-hydroxybenzyl substituent in the 1 position of the benzotriazole ring (compound 7) strongly decreased the activity, showing the importance of the electron-acceptor carbonyl function. The best compound, 3b, was further investigated, in order to evaluate the possible mechanism of action involved in the vasodilator activity. In the vascular model, different potassium channel blockers inhibited the effects of the compound, and an increase of the levels of membrane depolarisation induced a significant reduction of the recorded responses. Compound 3b was also tested in a model of isolated rat heart, retroperfused through the aorta and submitted to a global ischemia/reperfusion cycle. In such an experimental condition, 3b showed an interesting cardioprotective activity. All the above observations are in agreement with the hypothesis of a mechanism linked to the activation of potassium channels.

Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition.

A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.