Design and Synthesis of Fluoro Analogues of Vitamin D.

The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.

Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine.

We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.

[Overview of 43 Years of Studies on Asymmetric Synthesis].

Our investigations of various aspects of organic chemistry over the past 43 years are reviewed in this paper. The following subjects are discussed: 1) the diastereoselective addition reaction to chiral imines and oxazolidines of organometallic reagents and its applications and 2) the reaction and synthesis of fluorine-containing compounds.

General, Practical and Selective Oxidation Protocol for CF3S into CF3S(O) Group.

A simple and efficient protocol for the oxidation of trifluoromethyl, mono- and difluoromethyl sulfides to the corresponding sulfoxides without over-oxidation to sulfones, using TFPAA prepared in situ from trifluoroacetic acid and 15% H2O2 aqueous solution was developed. The methodology is suitable for a wide range of aromatic and aliphatic substrates in milligram and multigram scales.

Anti-Adenoviral Activity of 2-(3-Chlorotetrahydrofuran-2-yl)-4-Tosyl-5-(Perfluoropropyl)-1,2,3-Triazole.

Background and objectives: A considerable increase in the levels of adenoviral diseases among both adults and children necessitate the development of effective methods for its prevention and treatment. The synthesis of the new fluorinated 1,2,3-triazoles, and the study of the mechanisms of their action, are promising for the development of efficient antiviral drugs of our time. Materials and Methods: Antiviral activity and cell cytotoxic effect of 2-(3-chlorotetrahydrofuran-2-yl)-4-tosyl-5-(perfluoropropyl)-1,2,3-triazole (G29) were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The influence of the compound on the infectivity of human adenovirus type 5 (HAdV-5) was carried out via the cytomorphology method. The influence of the compound on the cell cycle under a condition of adenovirus infection was studied using flow cytometric analysis of propidium iodide-stained cells. Results: It was found that G29 suppressed HAdV-5 reproduction by 50% in concentrations of 37 µg/mL. Furthermore, the compound reduced the titer of virus obtained de novo, and inhibited HAdV-5 inclusion bodies formation by 84⁻90%. The use of fluorinated compounds under the conditions of adenovirus infection decreased the number of apoptotic cells by 11% and the number of cells in S phase by 21⁻42% compared to the profile of infected cells. Conclusions: The fluorinated compound G29 showed moderate activity against HAdV-5 based on several mechanisms. It led to the normalization of the life cycle of cells infected with adenovirus to the level of non-infected cells and caused the obstruction of HAdV-5 reproduction, inducing the formation of non-infectious virus progeny.

A novel fluorinated thiosemicarbazone derivative- 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide induces apoptosis in human A549 lung cancer cells via ROS-mediated mitochondria-dependent pathway.

Thiosemicarbazone, a class of compounds with excellent biological activity, especially antitumor activity, have attracted wide attention. In this study, a novel fluorinated thiosemicarbazone derivative, 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide (compound 1) was synthesized and its antitumor activities were further investigated on a non-small cell lung cancer cell line (A549) along with its underlying mechanisms. Compound 1 showed significant anti-proliferative activity on A549 cells, which was further proved by colony formation experiment. Compound 1 also inhibits the invasion of A549 cells in a trans-well culture system. Moreover, compound 1 markedly induced apoptosis on A549 cells, and the ratio of Bcl-2/Bax was decreased while the amount of p53, Cleaved-Caspase 3 and Cleaved-PARP expression were increased significantly. Compound 1 decreased the mitochondrial membrane potential, while the content of reactive oxygen was increased obviously. It is revealed that compound 1 mediated cell cycle arrest in G0/G1 phase by reducing G1 phase dependent proteins, CDK4 and Cyclin D1. As a result, it is indicated that compound 1 induced apoptosis on A549 cells was realized by regulating ROS-mediated mitochondria-dependent signaling pathway.

Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery.

The synthesis of a collection of 3-substituted indole derivatives incorporating partially fluorinated n-propyl and n-butyl groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aqueous solubility, and metabolic stability. The experimental observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit molecular design in medicinal chemistry and, more broadly, in life as well as materials sciences.

Concentração de fluoreto nos dentifrícios a base de MFP/CaCO3 mais vendidos no Brasil, ao final dos seus prazos de validade / Fluoride concentration in most sold MFP/CaCO3 -based Brazilian toothpastes at the expiration time

Dentifrício fluoretado deve conter pelo menos 1.000 ppm (mg F/kg) do seu flúor total (FT) na forma quimicamente solúvel (FST) para ter o potencial máximo de interferir com o processo de cárie. Em formulações de dentifrícios contendo cálcio no abrasivo, a concentração de FST (íon flúor + íon MFP) diminui em função do tempo de armazenamento. Os quatro dentifrícios a base de MFP/CaCO3 mais vendidos no Brasil são capazes de manter 1.000 ppm de FST nos produtos pelo prazo de um ano de fabricação, mas não é conhecido o que ocorre até o final do prazo de validade. Assim, o objetivo deste estudo foi avaliar a concentração de FST nesses dentifrícios ao final do seu prazo de validade. Após as análises iniciais realizadas em 2010, os cremes dentais (n=30) foram armazenados à temperatura laboratorial (25°C) e as concentrações de FT e FST foram novamente determinadas em 2012, próximo a data de vencimento (36 meses). As análises foram feitas utilizando protocolo validado de extração, as determinações foram feitas com eletrodo íon específico e os resultados expressos em ppm F (mg F/kg). A concentração (média±dp;n=30) de FT encontrada (1.415,2±62,8) estava de acordo com o declarado pelo fabricante (1.450 ppm F), porém a de FST foi 44% menor (814,7±74,7). Ao final do prazo de validade, os dentifrícios brasileiros mais vendidos não mantêm uma concentração de FST máxima desejável, mostrando tanto a importância do Cirurgião-Dentista na orientação do paciente como a necessidade da revisão da resolução Anvisa nº 79 que regulamenta a matéria sobre dentifrícios

Fluoride toothpaste should contain at least 1,000 ppm (mg F/kg) of fluoride chemically soluble to have the maximum potential to interfere with the caries process. In formulations containing calcium--based abrasives, the concentration of total soluble fluoride (TSF = fluoride ion + MFP ion) decreases according to the storage time. The four MFP/CaCO3-based toothpastes most consumed in Brazil are able to maintain 1,000 ppm of TSF throughout one year of manufacturing, but it is not known if it would be maintained up to the expiration date. Thus, this study evaluated the concentration of TSF in these toothpastes at the end of expiration date. As control, the total fluoride (TF) concentration was also determined. After the analysis of fresh samples conducted in 2010, the toothpastes tube (n=30) were stored at temperature of 25°C and the determinations of TF and TSF concentrations were again assessed in 2012, close to the expiration date of the toothpastes (3 years). The analyses were made using a validated protocol of extraction, the determinations were made with an ion specific electrode and the results were expressed in ppm F (mg F/kg). The concentration (mean±SD;n=30) of TF found (1.415.2±62.8) was according to the declared by the manufacturer (1.450 ppm), but the TSF was 44% lower (814.7±74.7). At expiration, the most sold MFP/CaCO3-based brazilian toothpastes do not maintain the maximum TSF concentration required, showing not only the relevance of the Dentist to advise the patients about this subject, but also the necessity to review the Brazilian regulation about toothpastes

Synthesis, spectroscopic and catalytic properties of some new boron hybrid molecule derivatives by BF2 and BPh2 chelation.

A new series of Schiff base ligands (L1-L3) and their corresponding fluorine/phenyl boron hybrid complexes [LnBF2] and [LnBPh2] (n=1, 2 or 3) have been synthesized and well characterized by both analytical and spectroscopic methods. The Schiff base ligands and their corresponding fluorine/phenyl boron hybrid complexes have been characterized by NMR ((1)H, (13)C and (19)F), FT-IR, UV-Vis, LC-MS, and fluorescence spectroscopy as well as melting point and elemental analysis. The fluorescence efficiencies of phenyl chelate complexes are greatly red-shifted compared to those of the fluorine chelate analogs based on the same ligands, presumably due to the large steric hindrance and hard π→π(∗) transition of the diphenyl boron chelation, which can effectively prevent molecular aggregation. The boron hybrid complexes were applied to the transfer hydrogenation of acetophenone derivatives to 1-phenylethanol derivatives in the presence of 2-propanol as the hydrogen source. The catalytic studies showed that boron hybrid complexes are good catalytic precursors for transfer hydrogenation of aromatic ketones in 0.1M iso-PrOH solution. Also, we have found that both steric and electronic factors have a significant impact on the catalytic properties of this class of molecules.

Radiosynthesis of [18)F]trifluoroalkyl groups: scope and limitations.

The present paper is concerned with radiochemical methodology to furnish the trifluoromethyl motif labelled with (18)F. Literature spanning the last four decades is comprehensively reviewed and radiochemical yields and specific activities are discussed.

Synthesis and characterization of fluoro-modified polypropylene films for inhibition of biofilm formation.

Surface hydroperoxide-conjugated polypropylene (PP) films were prepared by optimal ozonolysis processing of the films. These hydroperoxide-conjugated groups were then used as initiators at room temperature for redox graft polymerization of the fluoro vinylic monomer 1H,1H-heptaflourobutyl methacrylate (HFBM). The ozonolysis process allows, on one hand, for the formation of the desired hydroperoxide-conjugated groups while, on the other hand, leads to an undesired degradation of the PP. The ozone treatment time was therefore optimized to obtain sufficient hydroperoxide groups for graft polymerization, while maintaining the mechanical strength of the films, which was barely affected. The resulting PP-PolyHFBM (PP-PHFBM) films were characterized by methods such as AFM, ATR, TGA, contact angle goniometry and XPS. The antibiofilm properties of the PP-PHFBM films were evaluated, using two bacterial strains. An 86% inhibition was observed for the Gram-negative Escherichia coli, and a 37% inhibition was observed for the Gram-positive Listeria.

Synthesis and biological evaluation of fluoro analogues of antimitotic phenstatin.

With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7a-l) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50=15 nM) and HL-60(TB) (GI50=23 nM) and on melanoma cell line MDA-MB-435 (GI50=19 nM).

Adva-27a, a novel podophyllotoxin derivative found to be effective against multidrug resistant human cancer cells.

BACKGROUND/AIM: Multidrug resistance poses a serious challenge in cancer therapy. To address this problem, we designed and synthesized Adva-27a, a novel non-ester GEM-difluorinated C-glycoside derivative of podophyllotoxin. MATERIALS AND METHODS: Adva-27a activity was evaluated in a variety of assays including inhibition of topoisomerase IIα, cytotoxic activity in drug-sensitive and drug-resistant cancer cell lines, metabolic stability in human liver microsomes and pharmacokinetic properties in rats. RESULTS: Adva-27a exhibited dose-dependent human topoisomerase IIα inhibitory activity and dose-dependent growth inhibitory activity in several drug-sensitive and two multidrug-resistant cancer cell lines. In the multidrug-resistant cell lines, MCF-7/MDR (breast cancer) and H69AR (small-cell lung cancer), Adva-27a was significantly more potent than etoposide. The metabolic stability of Adva-27a in human liver microsomes and its pharmacokinetic properties in rats were better than those of etoposide. CONCLUSION: Our studies have identified Adva-27a as a novel topoisomerase II inhibitor with superior cytotoxic activity against multidrug-resistant human cancer cells and more desirable pharmacokinetic properties than etoposide.

A convergent, unified approach to functionalized fluoro- and trifluoromethyl alkenes.

A modular, convergent, and operationally simple route to trifluoromethyl alkenes and vinyl fluorides involving a unique carbon-oxygen bond homolysis is reported. Highly functionalized trifluoromethyl alkenes and vinyl fluorides were obtained in good yields and good selectivity.

Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase.

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF(3) as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.

A general solid phase method for the synthesis of sequence independent peptidyl-fluoromethyl ketones.

We present here a new, general, solid phase strategy for the synthesis of sequence independent peptidyl-fluoromethyl ketones using standard Fmoc peptide chemistry. Our method is based on the synthesis of bifunctional linkers which allows the incorporation of amino acid fluoromethyl ketone unit at the C-terminal end of peptide sequences. Application of this approach for the synthesis of activity based probes for SENPs is also described.

Progress in fluoroalkylation of organic compounds via sulfinatodehalogenation initiation system.

The sulfinatodehalogenation reaction represents one of the most important methodologies to incorporate fluorine into organic molecules. Using inexpensive sulfur-containing reactants such as Na(2)S(2)O(4) under mild conditions, per- and polyfluoroalkyl halides (R(F)X, X = Br, I, CCl(3)) can be transformed smoothly into the corresponding sulfinate salts. This method is also used for the perfluoroalkylation of alkenes, dienes, alkynes and aromatics. Notably, after 1998, the sulfinatodehalogenation of perfluoroalkyl chlorides (R(F)Cl) has been realized by using dimethylsulfoxide (DMSO) as a solvent instead of CH(3)CN/H(2)O in the Na(2)S(2)O(4)/NaHCO(3) initiation system. Perfluoroalkyl chlorides, ethyl chlorofluoroacetates and chlorodifluoroacetates, and even nonfluorinated compounds, such as ethyl chloro- or dichloroacetates and chloroform, were either converted into the corresponding sulfinate salts or alkylated alkenes, alkynes and aromatics (including porphyrins). The sulfinatodehalogenation reaction has remarkable advantages. With the increasing demands to utilize the unique properties of fluorine and fluorinated functional groups in medicinal, agricultural and material sciences, we believe that there will continue to be useful developments in sulfinatodehalogenation chemistry and it will be applied more widely in the future.

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases.

A simple protocol for the synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid, with a secondary cyclic amine (morpholine or piperidine) at the 4α position, has been set-up, starting from peracetylated N-acetylneuraminic acid methyl ester that undergoes, sequentially to its direct N-transacylation followed by a C-4 amination, a ß-elimination, and a selective hydrolysis of the ester functions, without affecting the sensitive perfluorinated amide.

A domino approach of Heck coupling for the synthesis of ß-trifluoromethylstyrenes.

A domino approach of Heck coupling was used to synthesize ß-trifluoromethylstyrene derivatives from iodoarenes and 1-iodo-3,3,3-trifluoropropane in moderate to good yields. This method avoids the use of low-boiling, gaseous reagents such as 3,3,3-trifluoropropene, and additives and phosphines in the catalytic system.

Room temperature syntheses of entirely diverse substituted ß-fluorofurans.

Synthesis of highly substituted 3-fluorofurans is reported. The sequence began with preparation of tert-butyldimethylsilyl alk-1-en-3-yn-1-yl ethers from 1,4-disubstituted alk-3-yn-1-ones. Subsequent fluorination of alkenynyl silyl ethers with Selectfluor gave 2-fluoroalk-3-yn-1-ones in almost quantitative yield. Subsequent 5-endo-dig cyclizations using chlorotriphenylphosphine gold(I)/silver trifluoromethanesulfonate (5/5 mol%), N-bromo- or N-iodosuccinimide and gold(I) chloride/zinc bromide (5/20 mol%), all at room temperature, provided a facile method for the generation of substituted 3-fluoro-, 3-bromo-4-fluoro-, and 3-fluoro-4-iodofurans in good yields. Also, 2,2-difluoroalk-3-yn-1-ones were prepared by fluorination of alk-3-yn-1-ones under organocatalytic conditions. The structures of (Z)-tert-butyldimethylsilyl but-1-en-3-yn-1-yl ether, 3-bromo-4-fluorofuran, and 3-fluoro-4-(phenylethynyl)furan were confirmed by X-ray crystallography.