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Annual Review of Pharmacology and... Jan 2023After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65... (Review)
Review
After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Two plant cannabinoids, Δ-tetrahydrocannabinol and cannabidiol, are approved drugs. However, the endogenous cannabinoids and the anandamide-like constituents have not yet been well investigated in humans. For me, intellectual freedom-the ability to do research based on my own scientific interests-has been the most satisfying part of my working life. Looking back over the 91 years of my long life, I conclude that I have been lucky, very lucky, both personally and scientifically.
Topics: Humans; Child; Cannabinoids; Endocannabinoids; Polyunsaturated Alkamides; Dronabinol
PubMed: 35850522
DOI: 10.1146/annurev-pharmtox-051921-083709 -
International Journal of Molecular... Feb 2022The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the "click... (Review)
Review
The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the "click chemistry" concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, bioconjugation strategies, and supramolecular and material sciences. Although many CuAAC reactions are performed under homogenous conditions, heterogenous copper-based catalytic systems are gaining exponential interest, relying on the easy removal, recovery, and reusability of catalytically copper species. The present review covers the most recently developed copper-containing heterogenous solid catalytic systems that use solid inorganic/organic hybrid supports, and which have been used in promoting CuAAC reactions. Due to the demand for 1,2,3-triazoles as non-classical bioisosteres and as framework-based drugs, the CuAAC reaction promoted by solid heterogenous catalysts has greatly improved the recovery and removal of copper species, usually by simple filtration. In so doing, the solving of the toxicity issue regarding copper particles in compounds of biological interest has been achieved. This protocol is also expected to produce a practical chemical process for accessing such compounds on an industrial scale.
Topics: Alkynes; Azides; Catalysis; Click Chemistry; Copper; Cycloaddition Reaction; Triazoles
PubMed: 35216495
DOI: 10.3390/ijms23042383 -
Chemical & Pharmaceutical Bulletin 2020Oxygen atoms have a lone pair of electrons, so they have high chelation ability, high nucleophilic ability, stabilizing ability of adjacent cations, and take a chelate... (Review)
Review
Oxygen atoms have a lone pair of electrons, so they have high chelation ability, high nucleophilic ability, stabilizing ability of adjacent cations, and take a chelate or oxocarbenium ion structure with Lewis acids and metals. I took advantage of these properties to develop three new reactions, 1) asymmetric synthesis of chiral quaternary carbon centers, 2) asymmetric synthesis using acetal functions, and 3) organic chemistry using acetal-type reactive salt chemical species, and applied them to biologically active natural products synthesis. New reactions described here are all innovative and useful for natural products synthesis. In particular, the first asymmetric synthesis of fredericamycin A, and concise asymmetric synthesis of anthracycline antibiotics, scyphostatin, (+)-Sch 642305, (-)-stenine, clavolonine, (+)-rubrenolide, (+)-rubrynolide, (+)-centrolobine, and decytospolide A and B, etc., are noteworthy. Furthermore, since reactions using acetal-type reactive salt chemical species allow the coexistence of functional groups that normally cannot coexist, the reactions using reactive salts have potential to change the retrosynthesis planned based on conventional reactions.
Topics: Acetals; Alkaloids; Alkynes; Amides; Anthracyclines; Catalysis; Chemistry Techniques, Synthetic; Isoquinolines; Macrolides; Oxygen; Pyrans; Pyrones; Quinolizines; Spiro Compounds; Stereoisomerism
PubMed: 32999145
DOI: 10.1248/cpb.c20-00178 -
Chembiochem : a European Journal of... Jun 2020Conformational changes in α-synuclein (α-syn) are central to its biological function and Parkinson's disease pathology. Here, terminal alkynes (homopropargylglycine)...
Conformational changes in α-synuclein (α-syn) are central to its biological function and Parkinson's disease pathology. Here, terminal alkynes (homopropargylglycine) were employed as environmentally sensitive Raman probes at residues 1, 5, 116, and 127 to characterize soluble (disordered), micelle-bound (α-helical), and fibrillar (β-sheet) α-syn. Along with the full-length protein, a disease-related C-terminal truncation (1-115) was also studied. For the first time, β-sheet α-syn amyloid structure was detected by the amide-I band in N27 dopaminergic rat cells, where a reciprocal relationship between levels of fibrils and lipids was seen. Site-specific spectral features of the terminal alkynes also revealed the heterogeneity of the cellular environment. This work shows the versatility of Raman microspectroscopy and the power of unnatural amino acids in providing structural and residue-level insights in solution and in cells.
Topics: Alkynes; Amyloid; Animals; Cell Line; Cloning, Molecular; Dopaminergic Neurons; Escherichia coli; Gene Expression; Genetic Vectors; Glycine; Humans; Hydrophobic and Hydrophilic Interactions; Lysophosphatidylcholines; Micelles; Molecular Probes; Rats; Recombinant Proteins; Sequence Deletion; Spectrum Analysis, Raman; alpha-Synuclein
PubMed: 31960993
DOI: 10.1002/cbic.202000026 -
Accounts of Chemical Research Jan 2020Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in... (Review)
Review
Cycloaddition reactions are a hallmark in organic synthesis because they provide an efficient way to construct highly substituted carbo- and heterocycles found in natural products and pharmaceutical agents. Most cycloadditions occur under thermal or photochemical conditions, but transition-metal complexes can promote reactions that occur beyond these circumstances. Transition-metal complexation with alkynes, alkenes, allenes, or dienes often alters the reactivity of those π-systems and facilitates access to diverse cycloaddition products. This Account describes our efforts toward the design of novel five-carbon synthons for use in rhodium-catalyzed (5 + ) cycloadditions, which include 3-acyloxy-1,4-enynes (ACEs) for (5 + 1) and (5 + 2) cycloadditions and 3-hydroxy-1,4-enynes (HYEs) for (5 + 1) cycloadditions. Furthermore, this Account includes relevant computational information, mechanistic insights, and applications of these cycloadditions in the synthesis of various highly substituted carbo- and heterocycles. The (5 + ) cycloaddition reactions presented herein share the following common mechanistic features: the 1,2-migration of an acyloxy group in propargyl esters or the ionization of a hydroxyl group in propargylic alcohols, oxidative cyclization to form a metallacycle, insertion of the one- or two-carbon component, and reductive elimination to yield the final product. In conjunction with a cationic rhodium catalyst, we used ACEs for the intramolecular (5 + 2) cycloaddition with tethered alkynes, alkenes, and allenes. In some cases, an electron-deficient phosphine ligand improved the reaction yields, especially when the ACE featured an internal alkyne. We also demonstrated that chirality could be efficiently transferred from a relatively simple starting material to a more complex bicyclic product. Products derived from ACEs with tethered alkenes and allenes contained one or more stereocenters, and high diastereoselectivity was achieved in most of these cases. For ACEs tethered to an allene, the reaction preferentially occurred at the internal alkene. We also switched the positions of the alkene and the alkyne in the 1,4-enyne of our original ACE to provide an inverted ACE variant, which produced products with complementary functionalities. After we successfully developed the Rh-catalyzed intramolecular (5 + 2) cycloaddition, we optimized conditions for the intermolecular version, which required a neutral rhodium catalyst and phosphine ligand. When a terminal alkyne was used as the two-carbon component, high regioselectivity was observed. While investigating the effect of esters on the rate of the intermolecular (5 + 2) cycloadditions, we determined that an electron-rich ester significantly accelerated the reaction. Subsequently, we demonstrated that (5 + 1) cycloadditions undergo this rate enhancement as well in the presence of an ester. Aside from ACEs, we synthesized HYEs in four steps from commercially available 2-aminobenzoic acid for use in the (5 + 1) cycloaddition. Mechanistically, HYEs were designed so that the aniline nitrogen could serve as the nucleophile and the -OH could serve as the leaving group. Using HYEs, we developed a novel method to make substituted carbazoles, dibenzofurans, and tricyclic compounds with a cyclohexadienone moiety. Although the occurrence of transition-metal-catalyzed acyloxy migrations has been known for decades, only recently has their synthetic value been realized. We hope our studies that employ readily available 1,4-enynes as the five-carbon components in (5 + ) cycloadditions can inspire the design of new two-component and multicomponent cycloadditions.
Topics: Alkynes; Carbon; Catalysis; Cycloaddition Reaction; Cycloparaffins; Molecular Structure; Rhodium
PubMed: 31820914
DOI: 10.1021/acs.accounts.9b00477 -
Clinical Infectious Diseases : An... May 2021
Topics: Alkynes; Benzoxazines; Cyclopropanes; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Pyridones
PubMed: 32667998
DOI: 10.1093/cid/ciaa982 -
Accounts of Chemical Research Sep 2022The activation of weakly polarized bonds represents a challenging, yet highly valuable process. In this context, precious metal catalysts have been used as reliable... (Review)
Review
The activation of weakly polarized bonds represents a challenging, yet highly valuable process. In this context, precious metal catalysts have been used as reliable compounds for the activation of rather inert bonds for the last several decades. Nevertheless, base-metal complexes including cobalt, iron, or nickel are currently promising candidates for the substitution of noble metals in order to develop more sustainable processes. In the past few years, manganese(I)-based complexes were heavily employed as efficient catalysts for (de)hydrogenation reactions. However, the vast majority of these complexes operate via a metal-ligand bifunctionality as already well implemented for precious metals decades ago. Although high reactivity can be achieved in various reactions, this concept is often not applicable to certain transformations due to outer-sphere mechanisms. In this Account, we outline the potential of alkylated Mn(I)-carbonyl complexes for the activation of nonpolar and moderately polar E-H (E = H, B, C, Si) bonds and disclose our successful approach for the utilization of complexes in the field of homogeneous catalysis. This involves the rational design of manganese complexes for hydrogenation reactions involving ketones, nitriles, carbon dioxide, and alkynes. In addition to that, the reduction of alkenes by dihydrogen could be achieved by a series of well-defined manganese complexes which was not possible before. Furthermore, we elucidate the potential of our Mn-based catalysts in the field of hydrofunctionalization reactions for carbon-carbon multiple bonds. Our investigations unveiled novel insights into reaction pathways of dehydrogenative silylation of alkenes and -1,2-diboration of terminal alkynes, which was not yet reported for transition metals. Due to rational catalyst design, these transformations can be achieved under mild reaction conditions. Delightfully, all of the employed complexes are bench-stable compounds. We took advantage of the fact that Mn(I) alkyl complexes are known to undergo migratory insertion of the alkyl group into the CO ligand, yielding an unsaturated acyl intermediate. Hydrogen atom abstraction by the acyl ligand then paves the way to an active species for a variety of catalytic transformations which all proceed via an inner-sphere process. Although these textbook reactions have been well-known for decades, the application in catalytic transformations is still in its infancy. A brief historical overview of alkylated manganese(I)-carbonyl complexes is provided, covering the synthesis and especially iconic stoichiometric transformations, e.g., carbonylation, as intensively examined by Calderazzo, Moss, and others. An outline of potential future applications of defined alkyl manganese complexes will be given, which may inspire researchers for the development of novel (base-)metal catalysts.
Topics: Alkenes; Alkynes; Carbon Dioxide; Catalysis; Cobalt; Coordination Complexes; Hydrogen; Ions; Iron; Ketones; Ligands; Manganese; Metals; Nickel; Nitriles
PubMed: 36074912
DOI: 10.1021/acs.accounts.2c00470 -
Current Opinion in Chemical Biology Apr 2020Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop... (Review)
Review
Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop novel Pt-based anticancer drugs and to better understand the biological effects of Pt-based anticancer drugs at a cellular level. Innovative azide-alkyne cycloaddition-based approaches are being used to functionalise Pt-based complexes with biomolecules to enhance tumour targeting. Valuable information in relation to the mechanisms of action and resistance of Pt-based drugs is also being revealed through click-based detection, isolation and tracking of Pt drug surrogates in biological and cellular environments. Although less well-explored, inorganic Pt-click reactions enable synthesis of novel (potentially multimetallic) Pt complexes and provide plausible routes to introduce functional groups and monitoring Pt-azido drug localisation.
Topics: Alkynes; Antineoplastic Agents; Azides; Cellular Microenvironment; Click Chemistry; Copper; Cycloaddition Reaction; Drug Development; Drug Resistance; Fluorescent Dyes; Gold; Humans; Ligands; Molecular Structure; Organometallic Compounds; Platinum; Triazoles
PubMed: 31945705
DOI: 10.1016/j.cbpa.2019.12.001 -
Molecules (Basel, Switzerland) May 2021The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile... (Review)
Review
The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile reaction conditions amenable to both small and biological molecules. Many nucleoside analogs are known for their marked impact in cancer therapy and for the treatment of virus diseases and new targeted oligonucleotides have been developed for different purposes. The click chemistry allowing the tolerated union between units with a wide diversity of functional groups represents a robust means of designing new hybrid compounds with an extraordinary diversity of applications. This review provides an overview of the most recent works related to the use of click chemistry methodology in the field of nucleosides, nucleotides and nucleic acids for pharmacological applications.
Topics: Adenosine; Alkynes; Animals; Azides; Cell Line, Tumor; Click Chemistry; Cycloaddition Reaction; DNA; ErbB Receptors; Humans; Mice; Nucleic Acids; Nucleosides; Nucleotides; Oligonucleotides, Antisense; Reproducibility of Results; Technology, Pharmaceutical; Triazoles; RNA, Guide, CRISPR-Cas Systems
PubMed: 34067312
DOI: 10.3390/molecules26113100 -
Yakugaku Zasshi : Journal of the... 2021The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and... (Review)
Review
The interaction between transition metals and ligands is important for catalytic reactions. The ligands are largely dominated by the covalent X-type (hydride, alkyl and halogen) and/or dative L-type ligands (e.g., P, N, CO, olefin, etc.). Therefore, the interaction of the Z-type ligands (B, Al and Si, etc.) with transition metals is emerging as a new concept for the reactivity of the metal center. Recently, we developed the synthesis of the gold complex Au(DPB)X (DPB=diphosphine-borane) featuring the Z-type ligand, and their catalytic reaction. The gold catalysts showed a high activity compared to the general catalysts (without Z-ligand) for the various cyclization reactions due to the electron-withdrawing effect of the Z-ligand on the coordinating gold center. In this review, first the structure analysis of the synthesized Au→Z complex is introduced in detail, and second, the catalytic reactions based on the alkyne activation are described.
Topics: Alkynes; Catalysis; Cyclization; Electrons; Gold; Gold Compounds; Ligands; Molecular Structure
PubMed: 33642496
DOI: 10.1248/yakushi.20-00179-1