Synthesis and Ready to Use Kit Formulation of EDTMP for the Preparation of 177Lu-EDTMP as a Bone Palliation Radiopharmaceutical.

INTRODUCTION: With its suitable nuclear decay characteristics and large-scale production feasibility with adequate specific activity, 177Lu is regarded as an excellent radionuclide for developing bone pain palliation agent. Ethylenediamine-tetramethylene phosphonic acid (EDTMP) is a preferred carrier molecule for radiolanthanides, such as 177Lu. The present paper describes the synthesis of EDTMP and the development of a ready-to-use kit for the preparation of 177Lu-EDTMP and its quality control in accordance with the quality and safety criteria required for medicinal use. MATERIAL AND METHODS: EDTMP was synthesized by a modified Mannich-type reaction, and the structure was characterized using NMR and IR spectroscopy. Optimization of radiolabeling conditions was done with two different salt forms of EDTMP. The labeling yield was checked by paper chromatography with radiation detection. Kit was developed as a lyophilized mixture of EDTMP and sodium bicarbonate in a maximum volume of 5 mL. Labeling efficiency, radionuclidic purity, radiochemical purity, sterility, and pyrogenicity analysis were performed as the quality control of the labeled kit. RESULTS: The analytical data for the structure determination and purity of the synthesized ligand were in agreement with authentic commercial samples used in radiopharmacy.177Lu-EDTMP complex was prepared using synthesized EDTMP ligand under optimized labeling conditions with high labelling yield (>99%). The radiolabeling yields of the EDTMP kit at room temperature after 30 min and 48 hours were 99.46% and 99.00%. CONCLUSION: The developed EDTMP kit enables an instant one-step preparation of the radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. This enables the routine production of the 177Lu-EDTMP in nuclear medicine clinics without requiring experienced staff.

Design and synthesis of garlic-related unsymmetrical thiosulfonates as potential Alzheimer's disease therapeutics: In vitro and in silico study.

Garlic contains a wide range of organosulfur compounds, which exhibit a broad spectrum of biological activities. Amongst the sulfur-containing compounds in garlic, the thiosulfonates are considerably popular in various fields. In light of this, we decided to investigate the enzyme inhibition ability of thiosulfonates. In this paper, the synthesis and biological activity of a small library of unsymmetrical thiosulfonates as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are described. The activity evaluation revealed nanomolar IC50 and Ki values against both enzymes tested. Furthermore, molecular docking studies allowed for the determination of possible binding interactions between the thiosulfonates and AChE.

Effects of aryl methanesulfonate derivatives on acetylcholinesterase and butyrylcholinesterase.

There is a dire need for new treatments for Alzheimer's disease (AD). Principal drugs have reached maturity, and the number of people affected by AD is growing at a rapid rate. After years of research and many clinical trials, only symptomatic treatments are available. An effective disease-modifying drug for AD needs to be discovered. The research presented in this paper aims to facilitate in the discovery of new potential targets that could help in the ongoing AD research. Aryl methanesulfonate derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. IC50 values between 0.660 and 3.397 µM against AChE and 0.885 and 2.596 µM against BuChE were obtained.

Preparation of Enantiomerically Pure (S)-(-)-1-(1'-naphthyl)-ethanol by the Fungus Alternaria alternata.

(S)-(-)-1-(1'-napthyl)-ethanol (S-NE) is an important intermediate for the preparation of mevinic acid analogs, which is used for the treatment of hyperlipidemia. The objectives of the study were to isolate a microorganism that could effectively reduce 1-acetonaphthone (1-ACN) to S-NE, to determine the influence that the physicochemical parameters would have on the reduction by the isolated microorganism, and to attempt large-scale studies with the microorganism. Over the years fungi have been considered a promising biocatalyst and it has been presumed that many fungal species have not been isolated and therefore the current study focused on possible isolation of these microorganisms. A total of 72 fungal isolates were screened for their ability to reduce 1-ACN to its corresponding alcohol. The isolate, EBK-62, identified as Alternaria alternata, was found to be the most successful at reducing the ketone to the corresponding alcohol in the submerged culture. The reaction conditions were systematically optimized for the reducing agent A. alternata EBK-62, which showed high stereospecificity and good conversion for the reduction. The preparative scale study was carried out in a 2 L bioreactor and a total of 4.9 g of S-NE in optically pure form (>99% enantiomeric excess) was produced in 48 h. Chirality 28:669-673, 2016. © 2016 Wiley Periodicals, Inc.

Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells.

The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter et al., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1µM (Kaschula et al., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange.

Highly enantiomeric reduction of acetophenone and its derivatives by locally isolated Rhodotorula glutinis.

Ninety isolates of microorganisms belonging to different taxonomical groups (30 bacteria, 20 yeast, and 40 fungi) were previously isolated from various samples. These isolates were screened as reducing agents for acetophenone 1a to phenylethanol 2a. It was found that the isolate EBK-10 was the most effective biocatalyst for the enantioselective bioreduction of acetophenone. This isolate was identified as Rhodotorula glutinis by the VITEK 2 Compact system. The various parameters (pH 6.5, temperature 32 degrees C, and agitation 200 rpm) of the bioreduction reaction was optimized, which resulted in conversions up to 100% with >99% enantiomeric excesses (ee) of the S-configuration. The preparative scale bioreduction of acetophenone 1a by R. glutinis EBK-10 gave (S)-1-phenylethanol 2a in 79% yield, complete conversion, and >99% ee. In addition, R.glutinis EBK-10 successfully reduced various substituted acetophenones.

Asymmetric reduction of substituted acetophenones using once immobilized Rhodotorula glutinis cells.

The asymmetric reductions of acetophenone and its analogues using once immobilized Rhodotorula glutinis cells were studied. The performance and reaction parameters of the immobilized cells were also investigated and it was determined that the cells could be used 15 times in batch processes. All chiral alcohols obtained using purification procedures were of sufficient enantiopurity (>99%) of the (S)-enantiomer. The applicability of the optimized process for a preparative scale bioreduction was shown. Under the optimum conditions, 35mM (4.3g) of the product ((S)-1-phenylethanol) was produced from 45mM (5.4g) of the substrate (acetophenone) with one time immobilized R. glutinis EBK-2 cells (6g wet weight). The yield was calculated as 77%. In this study, it was found that the buffer level had a very significant effect on the reaction activity. Our results demonstrate that the optimized process can be implemented on a preparative scale.

Production of (R)-1-phenylethanols through bioreduction of acetophenones by a new fungus isolate Trichothecium roseum.

A total of 120 fungal strains were isolated from soil samples and evaluated in the bioreduction of substituted acetophenones to the corresponding (R)-alcohols. Among these strains, isolate Trichothecium roseum EBK-18 was highly effective in the production of (R)-alcohols with excellent enantioselectivity (ee > 99%). Gram scale preparation of (R)-1-phenylethanol is reported.

Production of (R)-1-(4-Bromo-phenyl)-ethanol by locally isolated Aspergillus niger using ram horn peptone.

Aspergillus niger EBK-9 was isolated from soil sample. This isolate was evaluated for production of (R)-1-(4-Bromo-phenyl)-ethanol 2 from 1-(4-Bromo-phenyl)-ethanone 1. In this work, the production of the 2 was achieved via fermenter. Glucose, yeast extract and ram horn peptone as medium in fermenter for growth of A. niger was used. A. niger EBK-9 isolate was found to be an effective biocatalyst with excellent enantiomeric excess (>99%) and good conversion (100%) for the production of the 2 in batch culture. The 8.2 mmol/l product from 10 mmol substrate under the optimum conditions could be produced. The yield was calculated as 82%. Because of the easy availability of the fungus besides simple reaction conditions, this process and medium must be potentially useful for production of chiral alcohols.