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Friday 27 December 2013

Anti-Markovnikov Hydrohydrazination

A rhodium-based catalyst reverses regioselectivity in the production of hydrazones

Anti-Markovnikov Hydrohydrazination

Friday 6 December 2013

Selection of boron reagents for Suzuki–Miyaura coupling

Graphical abstract: Selection of boron reagents for Suzuki–Miyaura coupling

 Suzuki–Miyaura (SM) cross-coupling is arguably the most widely-applied transition metal catalysed carbon–carbon bond forming reaction to date. Its success originates from a combination of exceptionally mild and functional group tolerant reaction conditions, with a relatively stable, readily prepared and generally environmentally benign organoboron reagent. A variety of such reagents have been developed for the process, with properties that have been tailored for application under specific SM coupling conditions. This review analyses the seven main classes of boron reagent that have been developed. The general physical and chemical properties of each class of reagent are evaluated with special emphasis on the currently understood mechanisms of transmetalation. The methods to prepare each reagent are outlined, followed by example applications in SM coupling.

Review Article

Selection of boron reagents for Suzuki–Miyaura coupling

Corresponding authors
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK

Chem. Soc. Rev., 2014,43, 412-443

DOI: 10.1039/C3CS60197H
Received 12 Jun 2013, First published online 03 Oct 2013 

Sunday 24 November 2013

Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling

ARKIVOC 2014 Part (i): Special Issue 'Reviews and Accounts', PG 1-20
Recent advances on diversity oriented heterocycle synthesis via multicomponent tandem reactions based on A3 coupling (14-8183LR) [pp. 1-20]
Yunyun Liu, a,b
a  Key Laboratory of Functional Small Organic Molecule, Ministry of Education, 
Jiangxi Normal University, Nanchang 330022, P. R. China 
b College of Chemistry and Chemical Engineering, Jiangxi Normal University, 

Nanchang 330022, P. R. China 

Full Text: PDF (235K)http://www.arkat-usa.org/get-file/48824/

A3 coupling reactions are the reactions between aldehydes, amines and alkynes, which yield
propargylamine derivatives under various catalyst conditions. By making use of the versatile
reactivity of propargylamines, tandem reactions initiated by the functional group(s) in the in situ
generated propargylamines constitute one of the most important applications of A3
These tandem reactions are especially useful for the synthesis of heterocyclic compounds. In this
review, the progress on multicomponent tandem reactions based on A3
 coupling is summarized.

Conclusions and Outlook

During the last decade, A3
 coupling reaction has evolved to a classical three-component protocol
for accessing various propargylamines. Numerous papers have been published on the
investigation of this synthetic method and spectacular advances on A3
 coupling reactions have
been witnessed in terms of green catalyst system, asymmetric catalysis etc. which also promoted
this coupling protocol as the most preferred option for propargylamine synthesis. From the
perspective of application, the propargylamines possessed broad spectrum of diversity andreactivity, and these compounds could serve as main building blocks in the synthesis of many
organic small molecules. From the perspective of atom economics, devising tandem reactions
based on key transformation of A3
 coupling for the synthesis of more complex and structurally
diverse heterocyclic products in one-pot represent a promising direction in modern organic
synthesis. As introduced in the contents, many elegant results have already been reported on this
area. On the other hand, at current state, this kind of tandem reactions were mainly performed by
using the second functional group in aldehyde, amine or alkyne to initiate subsequent
transformations on propargylamine intermediates, although some reactions using additional
components such as carbon dioxide to design tandem synthesis of heterocyclic products have
also been reported, this kind of examples are still rather rare. Thus, deeper and broader explore is
still demanding since using additional substrates for reactions is theoretically able to provide
considerably higher diversity both in reactions and corresponding products. In addition, versions
of asymmetric catalysis on traditional A3
 coupling have already been accomplished with nice
results, while asymmetric catalysis protocols of A3
 coupling-based tandem synthesis of
heterocycles kept unexplored, more systematic and advanced approaches of asymmetrical
catalysis on these tandem reactions are expected in future.


Some of the thousands of life-sizeTerracotta Warriors of the Qin Dynasty, ca. 210 BCE

The Great Wall of China was built by several dynasties over two thousand years to protect the sedentary agricultural regions of the Chinese interior from incursions by nomadic pastoralists of the northern steppes

Detail from Along the River During the Qingming Festival, a 12th-century painting showing everyday life in the Song Dynasty's capital city, Bianjing (today's Kaifeng)

Shanghai skyline

The Great Hall of the People in Beijing, where the National People's Congress convenes


Thursday 21 November 2013

TAK 593

Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor

 Original Research Article
Pages 2333-2345
Naoki Miyamoto, Nozomu Sakai, Takaharu Hirayama, Kazuhiro Miwa, Yuya Oguro, Hideyuki Oki, Kengo Okada, Terufumi Takagi, Hidehisa Iwata, Yoshiko Awazu, Seiji Yamasaki, Toshiyuki Takeuchi, Hiroshi Miki, Akira Hori, Shinichi Imamura

Graphical abstract

.................. PAPER describes the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50 value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C = 8%).

Full-size image (20 K)
Reagents: (a) ethyl (chloroacetyl)carbamate, Na2HPO4, DMA; (b) Ba(OH)2, NMP/H2O; (c) R1COCl, DMA; (d) 3-aminophenol, K2CO3, DMF; (e) 3-fluorobenzoyl chloride, DMA.


 TAK-593 is an oral formulation containing a small-molecule receptor tyrosine kinase inhibitor of both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with potential antineoplastic activity. TAK-593 selectively binds to and inhibits VEGFR and PDGFR, which may result in the inhibition of angiogenesis and tumor cell proliferation. Check for active clinical trials or closed clinical trials using this agent.

TAK-593 was highly selective for these families, with an IC(50) >1 μM when tested against more than 200 protein and lipid kinases. TAK-593 displayed competitive inhibition versus ATP. In addition, TAK-593 inhibited VEGFR2 and PDGFRβ in a time-dependent manner, classifying it as a type II kinase inhibitor. Analysis of enzyme-inhibitor preincubation experiments revealed that the binding of TAK-593 to VEGFR2 and PDGFRβ occurs via a two-step slow binding mechanism. Dissociation of TAK-593 from VEGFR2 was extremely slow (t(1/2) >17 h), and the affinity of TAK-593 at equilibrium (K(i)*) was less than 25 pM. Ligand displacement analysis with a fluorescent tracer confirmed the slow dissociation of TAK-593. The dissociation rate constants were in good agreement between the activity and ligand displacement data, and both analyses supported slow dissociation of TAK-593. The long residence time of TAK-593 may achieve an extended pharmacodynamic effect on VEGFR2 and PDGFRβ kinases in vivo that differs substantially from its observed pharmacokinetic profile. (source: Biochemistry. 2011 Feb 8;50(5):738-51. Epub 2011 Jan 10.). 

TAK-493 is  currently in Phase I clinical trials and is being developed by Millennium Pharmaceuticals, Inc. (a part of Takeda Pharmaceutical Company Limited).
 1. Biochemical Characterization of TAK-593, a Novel VEGFR/PDGFR Inhibitor with a Two-Step Slow Binding Mechanism. By Iwata, Hidehisa; Imamura, Shinichi; Hori, Akira; Hixon, Mark S.; Kimura, Hiroyuki; Miki, Hiroshi. From Biochemistry (2011), 50(5), 738-751.

2. Fused heterocyclic derivatives as kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. By Sakai, Nozomu; Imamura, Shinichi; Miyamoto, Naoki; Hirayama, Takaharu. From PCT Int. Appl. (2008), WO 2008016192 A2 20080207.

Sunday 17 November 2013

Venoms to Drugs, Peptides from Mamba Venom as Pain Killers

Thumbnail image of graphical abstract

The black mamba snake here illustrates the structure of mambaglin-1, a pain-relieving peptide found in its venom. Thick gray lines lines represent the four disulfide bonds linking Cys1–3, 2–4, 5–6, and 7–8. The N-terminus of the 57 amino acid peptide is at the head of the snake and the C-terminus at the tail. The peptide has potential as a pharmacological probe or drug lead. Image design by David Craik and drawing by Peta Harvey, University of Queensland.

Prof. David J. Craik and Christina I. Schroeder
Article first published online: 4 FEB 2013 | DOI: 10.1002/anie.201209851

Angewandte Chemie International Edition

Volume 52Issue 11pages 3071–3073March 11, 2013

Craik, D. J. and Schroeder, C. I. (2013), Peptides from Mamba Venom as Pain Killers . Angew. Chem. Int. Ed., 52: 3071–3073. doi: 10.1002/anie.201209851
  1. Work in the authors’ laboratory on toxins and pain is supported by grants from the Australian Research Council (DP1093115) and the National Health and Medical Research Council (631457, 1010552, and 1026501.

    The black mamba snake here illustrates the structure of mambaglin-1, a pain-relieving peptide found in its venom. Thick gray lines lines represent the four disulfide bonds linking Cys1–3, 2–4, 5–6, and 7–8. The N-terminus of the 57 amino acid peptide is at the head of the snake and the C-terminus at the tail. The peptide has potential as a pharmacological probe or drug lead. Image design by David Craik and drawing by Peta Harvey, University of Queensland.

    Mambalgins Mambalgins classified as being part of the family of three-finger toxins. There are two isoforms of mambalgin which have been given the names of mambalgin-1 and mambalgin-2. Both of these isopeptides are made of a 57 aminoacidic chain with 8 residues of cysteine. These two isoforms differ only in the residue located in the fourth position of the chain. 
    Mambalgin-1 presents a three-dimensional structure which consists of 3 loops emerging from the nucleus of this protein. A triple chain with antiparallel β-sheets connects loops II and III, and a double chain, also formed by antiparallel β-sheets, allows the formation and bonding of loop I. Moreover, the protein presents a concave area, which is typical of neurotoxins, stabilized by four disulphide bonds. 
    Mambalgins also show a high electrostatic potential which is necessary for the bounding with the ASIC ionic channelshttp://flipper.diff.org/app/items/5368 which are negatively charged.
    These toxins have been proved to have a strong analgesic effect in both central and peripheral nerves, being able to be as potent as morphine but better because they cause less tolerance and no respiratory distresshttp://www.ncbi.nlm.nih.gov/pubmed/?term=mambalgine
    While morphine acts on the opioid pathway of the brain causing addiction, headaches, difficulty thinking and vomiting, mambalgins avoid pain using a completely different route, which is potentially capable of causing fewer side effects. Mambalgins have been found to take away pain by inhibiting acid-sensing ion channels (ASIC) in the peripheral and central nervous system. 
    When an external pain stimulus is received by the body, our damaged cells release an inflammatory soupcontaining ions and other chemicals. The ions released by the damaged cells are detected by the ASICchannels, which open up due to a change in the pH levels that the ions cause. As the protein ion channels open, they trigger the electric impulse sent to the brain telling him that the body is suffering. 
    What mambalgins do in order to avoid pain is that they bind to these ASIC channels and prevent them from opening, thus causing the body not to send pain messages to the brain and acting as a powerful analgesic. 
    Finally it is important to remember that mambalgins do not block all ion channels, because these kinds of toxins are normally highly specific. Researchers have found that mambalgins have a potent, rapid and reversible effect in homomeric ASIC1 and heteromeric ASIC1a+ASIC2a or ASIC1a+ASIC2b channels, which are the entire ASIC channel subtypes found in the central nervous system. On the other hand, they have no effect on ASIC2a, ASIC3, ASIC1a+ASIC3 and ASIC1b+ASIC3 channels. 
    Bringing mambalgins to a practical use, these peptides could be useful in the analgesic treatments of patients with chronic respiratory diseases, given that their effect seems not to affect the respiratory system, in contrast to morphine which can cause respiratory distress. In addition, this new potential drug seems to deal with the problem of tolerance using morphine, in other words, needing an increasingly higher dose each time to obtain the same effect. This would be of great use for the chronically ill, as they could take the analgesic as many times as they wanted without becoming addicts or dependant on the drug.

    black mamba snake venom pain killer
    Image of black mamba snake courtesy of Wikimedia Commons/Bill Love/Blue Chameleon Ventures
    A bite from the black mamba snake (Dendroaspis polylepis) can kill an adult human within 20 minutes. But mixed in with that toxic venom is a new natural class of compound that could be used to help develop new painkillers.
    Named “mambalgins,” these peptides block acute and inflammatory pain in mice as well as morphine does, according to a new study.
    Researchers, led by Sylvie Diochot, of the Institute of Molecular and Cellular Pharmacology at Nice University, Sophia Antipolis in France, purified the peptides from the venom and profiled the compounds’ structure. They then were able to test the mambalgins in strains of mice with various genetic tweaks to their pain pathways. Diochot and her colleagues determined that the mambalgins work by blocking an as-yet untargeted set of neurological ion channels associated with pain signals. The findings were published online October 3 in Nature (Scientific American is part of Nature Publishing Group).
    As a bonus, mambalgins did not have the risky side effect of respiratory depression that morphine does. And the mice developed less tolerance to them over time than is typical with morphine.
    black mamba snake venom painkillers
    Image of black mamba's black mouth courtesy of Wikimedia Commons/Tad Arensmeier
    Experimenting with the newfound compounds should also help researchers learn more about the mechanisms that drive pain. As the researchers noted in their paper, “It is essential to understand pain better to develop new analgesics. The black mamba peptides discovered here have the potential to address both of these aims.”
    Venoms from plenty of other species of animals, including spiders, scorpions, ants and even snails, have also been studied for their analgesic potential.
    Just don’t try extracting any of this venom in the wild. There is antivenom for the black mamba snake’s bite, but it is not always available, and without it, the bites are usually fatal. These snakes can move along at speeds up to about 20 kilometers per hour and grow to up to 4.4 meters in length.The African black mamba’s bite has been called “the kiss of death”—and for good reason. It has been estimated that just 10 to 15 mg of venom from the world’s deadliest snake, triggering severe pain, vomiting, shock, and limb paralysis, can kill a person within hours.

    Yet within the black mamba’s venomous brew of toxins, a French research team has discovered a small fraction of peptides with surprising properties. Called “mambalgins,” they are not toxic, and, at least in mice, they produce a potent analgesia that equals the pain-relieving effect of morphine—but with fewer adverse effects.

    Eric Lingueglia and his colleagues at the Institut de Pharmacologie Moléculaire et Cellulaire in Valbonne, France, including Sylvia Diochot—an engineer specializing in animal venoms and toxins—and Anne Baron, reported the findings in the October 3 Nature.

    The new study shows the mambalgins inhibit the activity of multiple acid-sensing ion channels (ASICs), which are major players in pain pathways responding to tissue acidification—a common feature of many pain-generating conditions including acute heat pain and inflammation. The peptides suppress ASIC channel activity both in central neurons and in peripheral nociceptors.

    In addition to their potential for yielding novel painkillers with superior side effect profiles, the mambalgins are already revealing unappreciated functions of ASIC channels and new therapeutic targets.

    ASICs, first cloned in the 1990s, are cationic channels activated by extracellular protons. They are expressed both in the central nervous system and in peripheral nerves. In rodents, six types are known, arising from four genes—ASIC1-4. Four subtypes are splice variants: ASIC1a, 1b, 2a, and 2b. ASICs can be homomeric—containing one channel type—or heteromeric, made up of different combinations of variants. The roles of ASIC types and subtypes in pain sensation are being explored by the Lingueglia group and others, using snake, spider, and other venoms to both activate and inhibit them.

    “Mambalgins have the unique property of being potent, rapid, and reversible inhibitors of recombinant homomeric ASIC1a and heteromeric ASIC1a/2a or ASIC1a/2b channels—that is, all the ASIC subtypes expressed in the central nervous system,” the authors note. Mambalgins had no effect on ASIC2a, ASIC3, ASIC1a/3, and ASIC1b/3 channels.

    The functional studies were done in mice, but the investigators showed that the peptides inhibited human ASICs in vitro. “We don’t know if they will have the same effects in humans,” says Lingueglia, “but we are confident, because the peptides act on the human channels, and most of the pain pathways we studied are highly conserved between mice and humans.” Lingueglia reported the peptides have been licensed to a pharmaceutical company in Valbonne for development of human applications.

    Opioid-independent actions
    The Lingueglia group previously used two other venom toxins, PcTx1 (from tarantula) and APETx2 (from sea anemone), to functionally define certain ASIC channels. Now, in a screen for additional ASIC-blockers, the team identified black mamba venom as a potent, reversible inhibitor of ASIC1a expressed in Xenopusoocytes. Two active fractions were collected—isopeptides they named mambalgin-1 and mambalgin-2. They belong to the class of snake venoms termed “three-finger “ peptides, reflecting their distinctive structure.

    When injected intrathecally, mambalgins produced strong analgesia against heat pain as assessed with the tail-flick and paw-flick tests, but the effect disappeared in ASIC1a knockout mice, demonstrating the essential involvement of ASIC1a-containing channels. The effect was as potent as that of morphine, but was not reduced by naloxone, indicating that the inhibited channels were independent of opioid pathways. Moreover, in repeated administration, morphine was associated with tolerance such that after five days, its analgesic powers had all but vanished, while mambalgin-1 continued to be effective—additional evidence of a non-opioid mechanism of action.

    In experiments looking at peripheral action, injections of mambalgin-1 into mouse paws reduced acute pain and reversed or prevented inflammatory hyperalgesia created by intraplantar injection of carrageenan. Curiously, the researchers found, mambalgin-1 continued to produce analgesia in peripheral pain pathways in the ASIC1a knockouts. If ASIC1a was not responsible, the scientists wondered, what was? Peripheral nociceptors express both ASIC1a and ASIC1b, but the latter’s role in pain was not known. Mambalgin-1 blocks both ASIC1a and ASIC1b in dorsal root ganglion neurons, the scientists noted; therefore, analgesia induced by mambalgin-1 in the ASIC1a knockouts suggests a critical role of ASIC1b in pain sensation. To prove that, the researchers knocked down ASIC1b, and showed that loss of the channel mimicked the effect of mambalgin to reduce pain in the mice.

    “ASIC1b at the periphery—nociceptors—was never associated with any type of pain before,” notes Lingueglia. Also, he says, “the heteromeric channel made of ASIC1a+ASIC2a subunits in central neurons was also not known to be involved in pain before this work.”

    “Our results indicate that mambalgins have analgesic effects by targeting both primary nociceptors and central neurons, but through different ASIC subtypes,” the authors say.

    The effects of mambalgins stand in contrast to those of the tarantula PcTx1 toxin, which also induces analgesia via inhibition of central ASIC1a, but in an opioid-dependent manner (Mazzuca et al., 2007). The mambalgin experiments, together with these previous findings, indicate that “different pathways involving different subtypes of ASIC channels can lead to different types of central analgesia (opioid sensitive or insensitive),” the authors note.

    Mambalgins create analgesia by inhibiting different ASIC channels in the central nervous system and peripheral nociceptors. Unlike the ASIC1a-targeted spider toxin PcTx1, the central actions of mambalgins do not involve endogenous opioid pathways. Image: Nature.