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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Introduction: Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I1R and I2R). I2Rs are associated with depression, Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. A few positron emission tomography (PET) probes for I2Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I2Rs by PET. We labeled a selective I2R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with 11C and performed the first imaging of I2Rs by PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD). Methods: [11C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [11C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [11C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated. Results: [11C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant reduction in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite analysis, unchanged [11C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were observed in regions with a high density of I2R. The radioactivity levels and VT values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control. Conclusion: [11C]FTIMD showed specific binding to I2Rs in rat brains with a high density of I2R.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Final Thoughts on Chemistry for Tetrakis(acetonitrile)palladium(II) tetrafluoroborate

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Multicavity [Pdn(L)4]2n+ metallosupramolecular cages based on long backboned ligands are an attractive approach to increasing molecular size without loss of the binding specificity conferred by small cavity [Pd2(L)4]4+ assemblies. We herein report the synthesis of two double cavity polypyridyl [Pd3(L)4]6+ cages that bind cisplatin [Pt(NH3)2Cl2] within their internal cavities and interact with triflate (TfO-) on their exohedral faces. We also report the first example of a triple cavity [Pd4(L)4]8+ cage. This cage differs in that the central cavity is phenyl-linked rather than having the pyridyl core as in the peripheral cavities. The difference in cavity character results in selective guest binding of cisplatin in the peripheral cavities, with triflate binding within the central cavity and on the exohedral faces of the peripheral palladium(II) ions. All the cavities could be simultaneously filled by introducing both cisplatin and triflate concurrently, providing the first example of a discrete metallosupramolecular architecture with segregated guest binding in different designed internal cavities. The ligands and cages were characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and, in one case, X-ray crystallography.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, alpha-quaternary cyclopentanones were isolated in yields up to >99% with ee’s up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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A novel fluoroaryl-substituted PCP ligand has been synthesized and used to generate the corresponding Pd complexes. The bonding of the fluoroaryl phosphine has been investigated by X-ray crystallography, NMR spectroscopy, and a competition experiment, which indicate that the ligand is sterically comparable to its well-known phenyl analogue but clearly imparts significant electronic differences to the metal center.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

New explortion of Tris(dibenzylideneacetone)dipalladium-chloroform

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An efficient synthesis of the polypropionate framework of callystatin A has been achieved by utilizing the Shimizu reaction in an iterative fashion.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists. In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Extended knowledge of Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

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Two Pd-catalyzed methods to access 6-heteroaryl 2-aminopurine ribonucleosides from 6-chloroguanosine are described. First, Pd-132-catalyzed Suzuki-Miyaura cross-coupling using a series of boron substrates and 6-chloroguanosine forms 6-heteroaryl-2-aminopurines in a single step. The versatility of 6-chloroguanosine is further demonstrated using a modified Sonogashira coupling employing potassium iodide as an additive. Finally, the utility of the 6-alkynyl-2-aminopurine ribonucleoside as a dipolarophile in [3 + 2] cycloadditions is presented, affording triazoles and isoxazoles when reacted with azide and isonitrile 1,3-dipoles, respectively.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

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Reactions of Pd(PPh3)4 with P(=E)(N iPr2)(naph) (6, E = S; 7, E = O) (naph = 1,8-naphthylene) having a strained four-membered P(V)-phosphacycle gave dimeric complexes [Pd{kappa2P,C-mu2-PEP(=E)(NiPr 2)(naph)}(PPh3)]2 (9, E = S; 10, E = O), in which a Pd metal has been inserted into a P-C bond of the phosphacycle to form a phosphapalladacycle having a P(V) donor, and the two phosphapalladacycle units have been mutually bridged with E=P groups, as confirmed by X-ray structure analysis for thermodynamically more stable racemic isomers 9a and 10a. The meso-to-racemic isomerization observed for the simultaneously formed meso isomer 9b, and probably also for the corresponding meso isomer 10b, indicated partial dissociation of 9 and 10 taking place to their monomer units in solution, which were actually trapped as [Pd{kappa2P,C-P(=E)(NiPr 2)(naph)}(dppe)] by treatment with bidentate dppe (dppe = 1,2-bis(diphenylphosphino)ethane). On the other hand, a similar treatment of 9a with monodentate PMe3 and PEt2Ph resulted in a trivial substitution of both PPh3 ligands to give dimeric PMe3 and PEt2Ph analogues of 9a, respectively. 10a was found to react with O2 to form an unprecedented oxidation product, [Pd{kappa 2P,O-mu2-PO-PO(=O)(NiPr2)(naph)}(PPh 3)]2, 17, in which an oxygen atom has been inserted into each P(V)-Pd bond. 9a and 10a exhibited moderate catalytic activities for a Heck reaction between PhI and styrene. The mercury test indicated that metallic Pd nanoparticles released from 9a and 10a would be practical catalysts.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method

Discovery of Bis(dibenzylideneacetone)palladium

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Reductive elimination from Pd(II) aryl trifluoromethyl complexes is a challenging and elusive step which is accompanied by a number of kinetically more favorable side reactions giving rising to a complex mixture. We report herein the synthesis and isolation of several arylPd(II) trifluoromethyl complexes (2a-c) and study their electronic structures, photophysical properties and reductive elimination reactivities. A remarkable concentration effect on chemoselectivity is observed for thermal decomposition of (Xantphos)Pd(II)(Ar)(CF3) (2c) that favors the formation of Ar-CF3 at lower concentrations, but gives increasingly more Ar-Ar homocoupling product to a dominant extent as the concentration of 2c increases. This is solid evidence for the involvement of an intermolecular Ar/CF3 ligand exchange/Ar-Ar reductive elimination mechanism that has been proposed based on DFT computational studies. The interplay between theory and experiment provides valuable insights into the mechanism and kinetics of the key elementary reaction of reductive elimination at Pd(II), and may thus prompt the design of more efficient Pd-mediated nucleophilic trifluoromethylation reactions.

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Reference:
Chapter 1 An introduction to palladium catalysis,
Palladium/carbon catalyst regeneration and mechanical application method