Automated synthesis of N-(2-[18 F]Fluoropropionyl)-l-glutamic acid as an amino acid tracer for tumor imaging on a modified [18 F]FDG synthesis module.

N-(2-[18 F]Fluoropropionyl)-l-glutamic acid ([18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module.

Positron emission tomography imaging of cell death with [(18)F]FPDuramycin.

The noninvasive imaging of cell death, including apoptosis and necrosis, is an important tool for the assessment of degenerative diseases and in the monitoring of tumor treatments. Duramycin is a peptide of 19-amino acids. It binds specifically to phosphatidylethanolamine a novel molecular target for cell death. N-(2-(18)F-Fluoropropionyl)duramycin ([(18)F]FPDuramycin) was prepared as a novel positron emission tomography (PET) tracer from the reaction of duramycin with 4-nitrophenyl 2-[(18)F]fluoropropionate ([(18)F]NFP). Compared with control cells (viable tumor cells), the in vitro binding of [(18)F]FPDuramycin with apoptotic cells induced by anti-Fas antibody resulted in a doubling increase, while the binding of [(18)F]FPDuramycin with necrotic cells induced by three freeze and thaw cycles resulted in a threefold increase. Biodistribution study in mice exhibited its rapid blood and renal clearance and predominant accumulation in liver and spleen over 120 min postinjection. Small-animal PET/CT imaging with [(18)F]FPDuramycin proved to be a successful way to visualize in vivo therapeutic-induced tumor cell death. In summary, [(18)F]FPDuramycin seems to be a potential PET probe candidate for noninvasive visualization of in vivo cell death sites induced by chemotherapy in tumors.

Synthesis and antimetastatic effects of E-salignone amide derivatives.

The preparation of novel E-salignone derivatives and their biological evaluation as potential antimetastatic agents is described. The E-salignone amide derivatives were prepared from epiandrosterone and androsterone, and characterized by analytical (1) H NMR, (13) C NMR, and mass spectrometry. The derivatives were evaluated for antimetastatic activity in MDA-MB-231 cells by using a transwell assay. Comparing with the positive control, LY294002, compounds 19b, 19d, and 19e exhibited significant inhibitory effects on the EGF-induced invasion of MB-MDA-231 cells. Moreover, compound 19b also had antimigration effects in wound-healing assay. Compound 19b may represent a novel antimetastatic agent for treating breast cancer.

Synthesis of enantiopure 18F-trifluoromethyl cysteine as a structure-mimetic amino acid tracer for glioma imaging.

Although 11C-labelled sulfur-containing amino acids (SAAs) including L-methyl-[11C]methionine and S-[11C]-methyl-L-cysteine, are attractive tracers for glioma positron emission tomography (PET) imaging, their applications are limited by the short half-life of the radionuclide 11C (t1/2 = 20.4 min). However, development of 18F-labelled SAAs (18F, t1/2 = 109.8 min) without significant structural changes or relying on prosthetic groups remains to be a great challenge due to the absence of adequate space for chemical modification. Methods: We herein present 18F-trifluoromethylated D- and L-cysteines which were designed by replacing the methyl group with 18F-trifluoromethyl group using a structure-based bioisosterism strategy. These two enantiomers were synthesized stereoselectively from serine-derived cyclic sulfamidates via a nucleophilic 18F-trifluoromethylthiolation reaction followed by a deprotection reaction. Furthermore, we conducted preliminary in vitro and in vivo studies to investigate the feasibility of using 18F-trifluoromethylated cysteines as PET tracers for glioma imaging. Results: The two-step radiosynthesis provided the desired products in excellent enantiopurity (ee > 99%) with 14% ± 3% of radiochemical yield. In vitro cell study demonstrated that both enantiomers were taken up efficiently by C6 tumor cells and were mainly transported by systems L and ASC. Among them, the D-enantiomer exhibited relatively good stability and high tumor-specific accumulation in the animal studies. Conclusion: Our findings indicate that 18F-trifluoromethylated D-cysteine, a new SAA tracer, may be a potential candidate for glioma imaging. Taken together, our study represents a first step toward developing 18F-trifluoromethylated cysteines as structure-mimetic tracers for PET tumor imaging.

N,4-Dimethyl-N-(4-nitro-benz-yl)benzene-sulfonamide.

In the title compound, C(15)H(16)N(2)O(4)S, there is a dihedral angle of 63.30 (8)° between the nitro-benzyl and benzene rings, which are separated by a sulfonamide unit The crystal packing is stabilized by a C-H⋯O inter-action.

Stereocontrolled Synthesis of 2-Deoxy- C-glycopyranosyl Arenes Using Glycals and Aromatic Amines.

An efficient and stereoselective one-pot, two-step tandem α-arylation of glycals from readily available aryl amines via stable diazonium salts has been developed. Moreover, the stereoselective preparation of the challenging ß- C-glycosyl arenes by the anomerization of α- C-glycosides using HBF4 is also described. This protocol has a broad substrate scope and a wide functional-group tolerance. It can be used for the gram-scale preparation of 3-oxo- C-glycosides, which are versatile substrates for the preparation of many biologically important C-glycosides.

α-Alkylation of Chiral Sulfinimines for Constructing Quaternary Chiral Carbons by Introducing Removable Directing Groups.

This study developed a facile and efficient synthetic strategy to construct quaternary chiral centers at the α-position of imines and ketones. High regioselectivity and diastereoselectivity were achieved through the synergetic effect of electron-withdrawing directing groups and N-tert-butyl sulfinamide as chiral auxiliaries. Either of them could be removed under the optimized conditions without any epimerization.

Efficient automated synthesis of 2-(5-[18F]fluoropentyl)-2-methylmalonic acid ([18F]ML-10) on a commercial available [18F]FDG synthesis module.

[18F]ML-10 (2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid) is a small molecule positron emission tomography (PET) probe for apoptosis imaging. Automated synthesis of [18F]ML-10 was developed by using two different purification methods through a direct saponification procedure on a modified commercial [18F]Fluoro-2-Deoxyglucose ([18F]FDG) synthesizer. C18 purification method 1: The final [18F]ML-10 solution containing ethanol was obtained with radiochemical yields of 60±5% (n=5) at the end of bombardment (EOB) and radiochemical purity of 98% in 35min. Al2O3 and SCX purification method 2: To avoid possible side effects of a conventional ethanol-containing formulation, an new ethanol-free solution of [18F]ML-10 was also developed, the radiochemical yields was 50±5% (n=5, EOB) within 45min and the radiochemical purity was 98%.

Total Syntheses and Biological Activities of Vinylamycin Analogues.

Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC50 = 4.86 µM) and be unstable in plasma (t1/2 = 0.54 h). A total of 24 vinylamycin analogues with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having the following: no antimicrobial activity, significantly higher plasma stability (t1/2 = 14.3 h), improved activity against K562 leukemia cells (IC50 = 0.64 µM), and up to 75% cell inhibition without significant toxicities in K562 cells xenograft zebrafish model. Furthermore, compound 1a maintained its activity against the breast cancer cell line MCF-7 under hypoxic conditions. In comparison, the activity of gemcitabine in the same hypoxic in vitro model of MCF-7 cells was 15-fold lower. Therefore, the present results demonstrate that 1a has great potential as an anticancer agent.

Nitro-polyols via Pyridine Promoted C═C Cleavage of 2-Nitroglycals. Application to the Synthesis of (-)-Hyacinthacine A1.

A mild and convenient transformation for the synthesis of nitro-polyols is described. The nitro-polyol derivatives were prepared either from 2-nitroglycals via a pyridine-promoted scission of the carbon-carbon double bond or from glycals via a sequential nitration-scission procedure. The generated nitro-polyols could undergo a stereoselective Michael addition reaction. The utility of the addition products was exemplified by the concise synthesis of (-)-hyacinthacine A1 and 7a-epi-(-)-hyacinthacine A1.

Design, synthesis and bioactivity evaluation of Galf mimics as antitubercular agents.

A series of novel Galf mimics has been synthesized and characterized by IR, (1)H NMR, (13)C NMR, mass spectral and element analysis. All the newly prepared compounds were screened for their antitubercular activities. Bioactivity assays manifested that most of Galf mimics exhibited good antitubercular activities. Especially compound 4d and 4e displayed remarkable antitubercular efficacies, which were comparable to ethambutol.

Lewis acid catalyzed intramolecular [3 + 2] cross cycloadditions of cobalt-alkynylcyclopropane 1,1-diesters with carbonyls for construction of medium-sized and polycyclic skeletons.

A Lewis acid catalyzed intramolecular [3 + 2] cross cycloaddition of cobalt-alkynylcyclopropane 1,1-diesters with carbonyls has been successfully developed. Together with simple and efficient postcycloadditions of the cobalt-alkyne moiety, a general and efficient strategy for construction of structurally complex and diverse medium-sized skeletons and related polycycles was supplied successfully.

Total Synthesis and Determination of the Absolute Configuration of Vinylamycin.

The absolute configurations of the three unknown chiral centers in vinylamycin were predicted according to the structural comparison with microtermolide A and rakicidin A, and then total syntheses of vinylamycin were applied to determine the three unknown chiral centers as 14R, 15R, and 16S.

Molecular PET Imaging of Cyclophosphamide Induced Apoptosis with 18F-ML-8.

In this paper, a novel small-molecular apoptotic PET imaging probe, (18)F-ML-8 with a malonate motif structure, is presented and discussed. After study, the small tracer that belongs to a member of ApoSense family is proved to be capable of imaging merely apoptotic regions in the CTX treated tumor-bearing mice. The experimental result is further confirmed by in vitro cell binding assays and TUNEL staining assay. As a result, (18)F-ML-8 could be used for noninvasive visualization of apoptosis induced by antitumor chemotherapy.

Stereoselective synthesis of tetrahydropyran-3-ones by rearrangement of oxonium ylides generated from metal carbenoids.

The synthesis of tetrahydropyran-3-ones by copper-catalysed reactions of diazo ketone tethered allylic ethers has been explored. Product distribution can be explained by the intermediacy of a free ylide or direct rearrangement of a metal-bound ylide equivalent.

Automated synthesis of [18F]Florbetaben as Alzheimer's disease imaging agent based on a synthesis module system.

An automated synthesis procedure of [(18)F]Florbetaben ([(18)F]BAY94-9172), a radiolabeled imaging agent in phase III study for in vivo mapping of fibrillar amyloid ß (Aß) with PET, was developed using the commercial PET-MF-2V-IT-1 synthesizer. The automated radiosynthesis was carried out via a one-step nucleophilic fluorination of methanesulfonic acid 2-[2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethyl ester, as a new precursor, and separation with semi-preparative high performance liquid chromatography (HPLC). The total synthesis time amounted to 50 min with 20-25% yield (uncorrected for decay) and radiochemical purities of more than 95% in all runs. The described automated radiosynthesis allows the production of [(18)F]Florbetaben using a commercial radiosynthesis module and enables clinical trials of this compound.

Facile and rapid one-step radiosynthesis of [(18)F]BAY94-9172 with a new precursor.

INTRODUCTION: [(18)F]BAY94-9172 (Florbetaben) (Compound 8) is a positron emission tomography (PET) tracer that is currently in Phase III study for in vivo mapping of fibrillar amyloid ß as a pathological hallmark for Alzheimer's disease. This work reports new methods for the synthesis of [(19)F]BAY94-9172 and its two different precursors and radiosynthesis of [(18)F]BAY94-9172 with the two precursors by purification using Sep-Pak cartridge. METHODS: The reference standard [(19)F]BAY94-9172 and the new precursor (Compound 9) were obtained from the reactions of (E)-4-methylamino-4'-hydroxystilbene (Compound 1) with methanesulfonic acid 2-[2-(2-fluoro-ethoxy)-ethoxy]-ethyl ester (Compound 11) and methanesulfonic acid 2-[2-(2-methanesulfonyloxy-ethoxy)-ethoxy]-ethyl ester (Compound 13), respectively. The reported precursor (Compound 6) is an N-BOC-protected mesylate compound, which was obtained from Compound 9. The one-step radiosynthesis of [(18)F]BAY94-9172 was carried out in the modified PET-MF-2V-IT-1 synthesizer by [(18)F]fluorination of the new precursor (Compound 9) and purification with plus C18 Sep-Pak cartridges and was compared with two-step one-pot radiosynthesis using the reported precursor (Compound 6) and Sep-Pak cartridge purification. RESULTS: For one-step radiosynthesis, the uncorrected radiochemical yield of [(18)F]BAY94-9172 was 23 ± 3% (n = 5, based on [(18)F]fluoride) within 30 min and the radiochemical purity was greater than 95%. For two-step one-pot radiosynthesis, the uncorrected radiochemical yield of [(18)F]BAY94-9172 was 17 ± 2% in 45 min (n = 4, based on [(18)F]fluoride) with the radiochemical purity being above 95% after the Sep-Pak cartridge purification. CONCLUSION: [(19)F]BAY94-9172 and the two precursors were synthesized by a short synthetic route. Compared with HPLC purification, the use of Sep-Pak purification of [(18)F]BAY94-9172 reduced the total radiosynthesis time. The one-step radiosynthesis of [(18)F]BAY94-9172 is convenient and can easily be applied to the commercial PET tracer synthesizer for automated synthesis.

Plasmodium falciparum: interaction of shikimate analogues with antimalarial drugs.

The shikimate pathway for aromatic biosynthesis presents a target for antimalarial drug development as this pathway is absent from animals. This study extends previous work on inhibitors of the shikimate pathway, by examining their interaction with the antimalarial drugs pyrimethamine and atovaquone. Combinations of atovaquone with several shikimate analogues exhibited synergistic effects. These findings highlight potential use of shikimate pathway inhibitors in combination therapy.