Straightforward Synthesis of Bifunctional Phosphorus Phenols via Phosphination of In Situ Generated o-Quinone Methides.

An efficient and practical approach towards bifunctional phosphorus phenols has been developed through a reaction of diphenylphosphine oxide and the o-quinone methides in situ generated from 2-tosylalkyl phenols under basic conditions. This protocol features simple experimental procedures under mild conditions and is easily scaled up. With this method, a variety of diarylmethyl phosphine oxides can be produced with up to 92% yield.

Trapping para-Quinone Methide Intermediates with Ferrocene: Synthesis and Preliminary Biological Evaluation of New Phenol-Ferrocene Conjugates.

The reaction of para-hydroxybenzyl alcohols with ferrocene in the presence of a catalytic amount of InCl3 provided ferrocenyl phenol derivatives, an interesting class of organometallic compounds with potential applications in medicinal chemistry. This transformation exhibited a reasonable substrate scope delivering the desired products in synthetically useful yields. Evidence of involvement of a para-quinone methide intermediate in this coupling process was also provided. Preliminary biological evaluation demonstrated that some of the ferrocene derivatives available by this methodology exhibit significant cytotoxicity against several cancer cell lines with IC50 values within the range of 1.07⁻4.89 µM.

Cytotoxic cochlioquinone derivatives from the endophytic fungus Bipolaris sorokiniana derived from Pogostemon cablin.

Chemical investigation of the liquid culture of the endophytic fungus Bipolaris sorokiniana A606, which was isolated from the medicinal plant Pogostemon cablin resulted in the isolation of four new cytotoxic compounds, named isocochlioquinones D-E (1-2) and cochlioquinones G-H (3-4), along with five known cochlioquinone analogues (5-9). Their structures were determined on the basis of extensive spectroscopic analysis. Isocochlioquinone D (1) possessed a rare benzothiazin-3-one moiety and cochlioquinone G (3) was the first example of cochlioquinones bearing an indole-4,7-dione fragment. All of the isolates (1-9) were evaluated for their cytotoxic activities against MCF-7, NCI-H460, SF-268 and HepG-2 tumor cell lines by the sulforhodamine B (SRB) assay. Compounds 4 and 6-9, featuring a cochlioquinone core, exhibited potent cytotoxicities in vitro against the four tumor cell lines, and a preliminary structure-activity relationship of these compounds was also discussed.

Discovery of Potent Cysteine-Containing Dipeptide Inhibitors against Tyrosinase: A Comprehensive Investigation of 20 × 20 Dipeptides in Inhibiting Dopachrome Formation.

Tyrosinase is an essential copper-containing enzyme required for melanin synthesis. The overproduction and abnormal accumulation of melanin cause hyperpigmentation and neurodegenerative diseases. Thus, tyrosinase is promising for use in medicine and cosmetics. Our previous study identified a natural product, A5, resembling the structure of the dipeptide WY and apparently inhibiting tyrosinase. Here, we comprehensively estimated the inhibitory capability of 20 × 20 dipeptides against mushroom tyrosinase. We found that cysteine-containing dipeptides, directly blocking the active site of tyrosinase, are highly potent in inhibition; in particular, N-terminal cysteine-containing dipeptides markedly outperform the C-terminal-containing ones. The cysteine-containing dipeptides, CE, CS, CY, and CW, show comparative bioactivities, and tyrosine-containing dipeptides are substrate-like inhibitors. The dipeptide PD attenuates 16.5% melanin content without any significant cytotoxicity. This study reveals the functional role of cysteine residue positional preference and the selectivity of specific amino acids in cysteine-containing dipeptides against tyrosinase, aiding in developing skin-whitening products.

Antiplasmodial, cytotoxic activities and characterization of a new naturally occurring quinone methide pentacyclic triterpenoid derivative isolated from Salacia leptoclada Tul. (Celastraceae) originated from Madagascar.

OBJECTIVE: To validate scientifically the traditional use of Salacia leptoclada Tul. (Celastraceae) (S. leptoclada) and to isolate and elucidate the structure of the biologically active compound. METHODS: Bioassay-guided fractionation of the acetonic extract of the stem barks of S. leptoclada was carried out by a combination of chromatography technique and biological experiments in viro using Plasmodium falciparum and P388 leukemia cell lines as models. The structure of the biologically active pure compound was elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. RESULTS: Biological screening of S. leptoclada extracts resulted in the isolation of a pentacyclic triterpenic quinone methide. The pure compound exhibited both in vitro a cytotoxic effect on murine P388 leukemia cells with IC50 value of (0.041±0.020) µg/mL and an antiplasmodial activity against the chloroquine-resistant strain FC29 of Plasmodium falciparum with an IC50 value of (0.052±0.030) µg/mL. Despite this interesting anti-malarial property of the lead compound, the therapeutic index was weak (0.788). In the best of our knowledge, the quinone methide pentacyclic triterpenoid derivative compound is reported for the first time in S. leptoclada. CONCLUSIONS: The results suggest that furthers studies involving antineoplastic activity is needed for the development of this lead compound as anticancer drug.

A new indoloquinazoline alkaloidal glucoside from the nearly ripe fruits of Evodia rutaecarpa.

A new indoloquinazoline alkaloidal glucoside, rutaecarpine-10-O-ß-D-glucopyranoside (1), together with one known alkaloidal glycoside namely rutaecarpine-10-O-rutinoside (2) was isolated from the nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth.. Their structures were elucidated on the basis of extensive spectroscopic methods.

Apaziquone for non-muscle invasive bladder cancer: a critical review.

OBJECTIVE: To describe clinical needs in non-muscle invasive bladder cancer (NMIBC) and review the potential of apaziquone in this respect. METHODS: Epidemiology and clinical practice in NMIBC, as well as new drugs and strategies are reviewed. RESULTS: Bladder cancer is a heterogeneous and frequent disease. Clinical risk factors help in determining additional therapy after initial resection. However, current treatments have clear limitations with regard to efficacy and/or toxicity. New drugs and strategies have been tested recently and are in (pre)clinical use. Intravesical apaziquone (EOquin) is a new drug. It has theoretical advantages for intravesical use, has proven safety and is presently under further clinical evaluation. CONCLUSION: Apaziquone is a promising drug for intravesical use in patients with NMIBC.

Synthesis of lyoniresinol with combined utilization of synthetic chemistry and biotechnological methods.

We have synthesized lyoniresinol with the combined utilization of synthetic chemistry and biotechnological methods, specifically using plant cell cultures as an "enzyme source."

Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations.

Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.