Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India
Speaking at World health congress 2017….JNTUH Hyderabad 22 aug 2017
Recent progress on fluorination in aqueous media
*Corresponding authors
Advances in aqueous fluorination during the last few decades are summarized in this review. Fluorinated compounds have dominated a large percentage of agrochemicals and pharmaceuticals and a mass of functional materials. The incorporation of fluorine atoms into organic molecules has become one of the mainstream technologies for their functional modification. Water is very environmentally friendly and has advantageous physicochemical properties. Fluorination reactions in aqueous media are highly sought-after, and have attracted great attention in research areas ranging from medicinal chemistry to materials science. In early times and for a long time, fluorination was thought to be diametrically opposed to water or moisture. However, recent examples have conflicted with this viewpoint. The successful merger of “untamed” fluorine and “mild” water in chemical reactions has set up a new prospect for green chemistry. A considerable amount of remarkable research works have been carried out using water as a (co)solvent and/or a reactant for transformations including electrophilic, radical, or nucleophilic fluorination. We hope that this review will serve as a guide to better understand and to further broaden the field of fluorine chemistry in aqueous conditions.
Conclusion
The installation of fluorine atoms into organic and organometallic frameworks can dramatically change their physical, chemical, and biological properties. Organofluorides have entered many fields of science and technology with a tremendous impact on these domains. The development of efficient, selective, and mild methods to build C-F bonds is of great importance, which is highly desirable to keep up with the rapidly growing demand of novel fluorine-containing scaffolds. In early times, most fluorination reactions required harsh conditions and moisture-sensitive, highly toxic, and explosive atomic fluorine transfer agents like fluorine gas, xenon difluoride, hypofluorite, antimonytrifluoride, and diethylaminosulfurtrifluoride. The discovery of stable electrophilic fluorination reagents such as Selectflour and NFSI has remarkably changed the dilemma, which realized a large number of safe, mild, and easily controllable electrophilic and radical fluorination reactions in aqueous media. Although the exact mechanisms are still unclear at present, it does never hamper the green fluorination method development with these reagents. A mass of successful examples have confirmed that the aqueous reaction medias have positive impacts on electrophilic and radical fluorination reactions with using the N-F reagents and in many cases water can also be a nucleophile for the entire conversions.
In addition, water was generally thought to be an unsuitable medium for nucleophilic fluorination because the fluoride ions can be “trapped” in aqueous medias by hydrogen bonding and become unreactive. Thus, their use in organic synthesis has been quite limited to polar aprotic solvents. Although the strong hydrogen bond formed between fluoride and water diminished the nucleophilicity of fluoride ions, the recent examples of nucleophilic fluorination in aqueous media have implied that this “negative” effect does not always harm the reaction. Besides, the radioisotope 18F has been considered to be a good choice for PET imaging owing to its desirable radiochemical properties. With a half-life of 110 minutes, the introduction of [ 18F]fluorine atoms into biomolecules has to be completed in a swift manner to minimize the loss of radioactivity. Nucleophilic incorporation of [18F]F‒ in aqueous conditions could rapidly produce [18F]fluorinesubstituted biomolecules, which avoided azeotropic drying process, shortened the production time, and minimized the loss of activity. We summarized the recent aqueous fluorination reactions in three sections according to their possible mechanisms. The successful amalgamation of “ill-tempered” fluorine and “benign” water has boded well for green fluorine chemistry. Water behaves as a cosolvent to dissolve fluorination reagents and/or as a reactant for bifunctionalization. Since the aspects of green chemistry has drawn much attention from the society, the pursuit of more efficient and milder reaction conditions for greener fluorination in aqueous medias will never end. Although a large number of research works have been published in this area, it’s only the tip of the iceberg with a wide scope for improvement. We hope that this review will serve as a guide to understand and to further broaden the field of aqueous fluorine chemistry. To meet the principle of green chemistry in modern synthesis, the development of new fluorination reagents as well as valid catalytic systems is crucial for mild and selective C-F bond formation. It’s undoubted that a growing number of green fluorination methodologies in aqueous media will be witnessed in the near future.
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Ecocatalyzed Suzuki cross coupling of heteroaryl compounds
A bio-based EcoPd was developed for the Suzuki cross coupling of heteroaryl compounds. Based on the ability of Eichhornia crassipes to bioconcentrate Pd in its roots, we addressed the transformation of plant-derived Pd metals to green catalysts. The methodology is based on eco-friendly procedures. It allowed the preparation of a wide range of heterocyclic biaryl and heterocyclic–heterocyclic biaryl compounds, with a low Pd catalyst loading. EcoPd was found to have the ideal microstructure to promote complex Suzuki reactions without ligands or additives. For the first time, post-reaction solution was treated by rhizofiltration. The resulting EcoPd has been reused with the same performance. This work has established the ecocatalysis concept as a powerful strategy for Pd sustainability, with the development of homogeneous catalysts that are easily recycled and reused.
2-Bromothiophene (20 g, 125 mmol), Phenyl boronic acid (16.8 g, 138 mmol), potassium carbonate (20.7 g, 150 mmol) and EcoPd1 (113 mg, 125 µmol of Pd, 13.3 mg of Pd, EcoPd1 at 11.7 wt% of Pd) were suspended into degassed glycerol (200 mL). The mixture was stirred at 120°C for 4h thanks to an oil bath under an argon atmosphere. The reaction was checked for completion by TLC (cyclohexane) and GCMS analysis after a short extraction of the organic material: 10 µL of the crude were added into a 1 mL microtube containing a mixture of water and AcOEt (800 µL, 1:1, v/v) ; the microtube was vortexed before using the organic layer to perform analysis. Deionised water (500 mL) and AcOEt (500 mL) were added into the flask and the mixture filtered through fritted glass to isolate black Pd for recycling. The organic layer was further washed by deionised water (500 mL x 3) before drying over Na2SO4. The organic layer was filtered and concentrated under vacuum. The residue was then purified by chromatography on a silica gel column (250 g) with pure cyclohexane as the mobile phase, giving the desired coupled compound as a white powder (18 g, 112.5 mmol, yield 90%) Rf = 0.7 (cyclohexane).
1H NMR (300 MHz, CDCl3): = 7.10- 7.13 (m, 2H), 7.44-7.26 (m, 5H), 7.38-7.33 (m, 1H).
13C NMR (75.5 MHz, CDCl3): = 123.0, 124.8, 125.9, 127.4, 128.0, 128.8, 134.4, 144.4.
MS (EI): m/z = 160 (M+ , 100%), 128 (21%), 115 (54%), 89 (17%) calcd for C10H8S: 159.99.
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Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry
Open Access
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Indoleamine 2,3-dioxygenase 1 (IDO1) mediates multiple immunoregulatory processes including the induction of regulatory T cell differentiation and activation, suppression of T cell immune responses and inhibition of dendritic cell function, which impair immune recognition of cancer cells and promote tumor growth. On this basis, this enzyme is widely recognized as a valuable drug target for the development of immunotherapeutic small molecules in oncology. Although medicinal chemistry has made a substantial contribution to the discovery of numerous chemical classes of potent IDO1 inhibitors in the past 20 years, only very few compounds have progressed in clinical trials. In this review, we provide an overview of the current understanding of structure–function relationships of the enzyme, and discuss structure–activity relationships of selected classes of inhibitors that have shaped the hitherto few successes of IDO1 medicinal chemistry. An outlook opinion is also given on trends in the design of next generation inhibitors of the enzyme.
Introduction Indoleamine 2,3-dioxygenases (IDOs) are heme-containing proteins that catalyze the oxidative cleavage of the indole ring of tryptophan (L-Trp, 1) to produce N-formyl kynurenine (2) in the first rate limiting step of the kynurenine pathway (Figure 1).1,2 The family includes two related enzymatic isoforms, namely IDO1 and IDO2, sharing ∼60% of sequence similarity and featuring distinct biochemical features.3,4 A third enzyme of the family is the tryptophan-2,3-dioxygenase (TDO2) which is structurally unrelated to IDO1 and IDO2 and is endowed with a more stringent substrate specificity for L-Trp.5 Although TDO2 is expressed almost exclusively in hepatocytes where it regulates L-Trp catabolism in response to the diet, IDO1 and IDO2 are widely expressed in macrophages and dendritic cells exerting immunoregulatory functions.6 These are accomplished through two major mechanisms including depletion of tryptophan and production of bioactive metabolites along the kynurenine pathway. Specifically, the first mechanism postulates that raising levels of Interferon-γ (IFN-γ) induce IDO1 expression in macrophages and dendritic cells during pathogen infection, leading to consumption of L-Trp and growth arrest of pathogens, whose diet is sensitive to this essential nutrient.7 The second mechanism grounds on production of kynurenine metabolites that bind to the aryl hydrocarbon receptor (AhR), activating signaling pathways that enhance immune tolerance.8-10 Among the three proteins, IDO1 is the most characterized enzyme and in recent years a second signal-transducing function was revealed for this protein.11,12 In particular, this signalling function relies on the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the non-catalytic domain of IDO1.13 The immunosuppressive cytokine transforming growth factor-β (TGF-β) stimulates phosphorylation of ITIMs by Sarcoma-family (Src-family) kinases and consequent interaction of the phosphorylated enzyme with Src Homology 2 domain Phosphatase-1 (SHP-1) and Src Homology 2 domain Phosphatase-2 (SHP-2), eventually leading to long-term expression of IDO1 and immune tolerance. Conversely, in pro-inflammatory environmental conditions, increasing levels of interleukin-6 (IL-6) trigger the interaction of
phosphorylated IDO1 with suppressor of cytokine signalling 3 (SOCS3) that tags the enzyme for proteasome degradation, shortening IDO1’s half-life and promoting inflammatory response.14 The breakthrough discovery that IDO1 plays a crucial role in the maintenance of maternal immune tolerance ushered in a great deal of interest on the enzyme, by then considered a master regulatory hub of immunosuppressive pathways in pregnancy, autoimmune diseases, chronic inflammation, and cancer.15 In this framework, elevated levels of IDO1 expression found in several tumour cells were associated to the participation of the enzyme in the tumor immuno-editing process which sets up immune tolerance to tumor antigens.16,17 On this basis, academic groups and pharmaceutical companies have been engaged in the development of IDO1 inhibitors.18 Although part of these efforts has proved successful, with a large array of potent and selective inhibitors being disclosed in literature and patent applications, only few compounds have hitherto entered clinical trials (3-7, Figure 1).2,19-22 At this regard, some studies have highlighted challenges in the development of enzyme inhibitors mostly due to redox properties of the enzyme that may account for unspecific mechanism of inhibition of many compounds discovered in preclinical studies.23,24 Starting with an overview on the architecture of IDO1 and its structure-function relationships, in this article we discuss selected classes of inhibitors that have shaped advances in the medicinal chemistry of IDO1, providing outlooks on future trends in the design of next generation compounds.
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Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions
The deoxydehydration (DODH) of glycerol towards allyl alcohol was revisited under continuous-flow conditions combining a microfluidic reactor setup and a unique reactive dynamic feed solution approach. Short reaction times, high yield and excellent selectivity were achieved at high temperature and moderate pressure in the presence of formic acid, triethyl orthoformate, or a combination of both. Triethyl orthoformate appeared as a superior reagent for the DODH of glycerol, with shorter reaction times, lower reaction temperatures and more robust conditions. In-line IR spectroscopy and computations provided different perspectives on the unique reactivity of glycerol O,O,O-orthoesters.
3b R = NITRO
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Dr. Helen P. KavithaProfessor and Head of the Department |
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Reduction of a wide range of aldehydes and ketones with catalytic amounts of titanocene borohydride in concert with a stoichiometric poly(methylhydrosiloxane) (PMHS) reductant is reported. Preliminary mechanistic studies demonstrate that the reaction is mediated by a reactive titanocene(III) complex, whose oxidation state remains constant throughout the reaction.
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Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules
The hydroxylation of non-native substrates catalysed by wild-type P450BM3 is reported, wherein “decoy molecules”, i.e., native substrate mimics, controlled the stereoselectivity of hydroxylation reactions. We employed decoy molecules with diverse structures, resulting in either a significant improvement in enantioselectivity or clear inversion of stereoselectivity in the benzylic hydroxylation of alkylbenzenes and cycloalkylbenzenes. For example, supplementation of wild-type P450BM3 with 5-cyclohexylvaleric acid-L-phenylalanine (5CHVA-Phe) and Z-proline-L-phenylalanine yielded 53% (R) ee and 56% (S) ee for indane hydroxylation, respectively, although 16% (S) ee was still observed in the absence of any additives. Moreover, we performed a successful crystal structure analysis of 5CHVA-L-tryptophan-bound P450BM3 at 2.00 Å, which suggests that the changes in selectivity observed were caused by conformational changes in the enzyme induced by binding of the decoy molecules.
| M2 | Kazuto Suzuki | \ | suzuki.kazuto*c.mbox.nagoya-u.ac.jp |
| Yoshihito Watanabe | yoshi*nucc.cc.nagoya-u.ac.jp | ||
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2,2,5,5-Tetramethyltetrahydrofuran (TMTHF): a non-polar, non-peroxide forming ether replacement for hazardous hydrocarbon solvents
An inherently non-peroxide forming ether solvent, 2,2,5,5-tetramethyltetrahydrofuran (2,2,5,5-tetramethyloxolane), has been synthesized from readily available and potentially renewable feedstocks, and its solvation properties have been tested. Unlike traditional ethers, its absence of a proton at the alpha-position to the oxygen of the ether eliminates the potential to form hazardous peroxides. Additionally, this unusual structure leads to lower basicity compared with many traditional ethers, due to the concealment of the ethereal oxygen by four bulky methyl groups at the alpha-position. As such, this molecule exhibits similar solvent properties to common hydrocarbon solvents, particularly toluene. Its solvent properties have been proved by testing its performance in Fischer esterification, amidation and Grignard reactions. TMTHF’s differences from traditional ethers is further demonstrated by its ability to produce high molecular weight radical-initiated polymers for use as pressure-sensitive adhesives.
[TMTHF].
1H NMR (400 MHz, CDCl3): δ 1.81 (s, 4H), 1.21 (s, 12H);
13C NMR (400 MHz, CDCl3): δ 29.75, 38.75, 80.75;
IR 2968, 2930, 2968, 1458, 1377, 1366, 1310, 1265, 1205, 1144, 991, 984, 885, 849, 767 cm−1;
m/z (%): (ESI–MS) 128 (40) [M+ ]
Green Chemistry Centre of Excellence, University of York, York YO10 5DD, UK
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NMR predict
[TMTHF].
1H NMR (400 MHz, CDCl3): δ 1.81 (s, 4H), 1.21 (s, 12H);
13C NMR (400 MHz, CDCl3): δ 29.75, 38.75, 80.75;
The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.
, and Hanjie Ying†‡§
