Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.     

Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy

Lysine‐specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A‐tri‐/di‐methylated histone 3 protein–protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple‐negative breast cancer (TNBC) cell lines, MDA‐MB‐231 and 4T1. Finally, 1 exhibited potent anti‐tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal‐based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.     

Covalent‐Bond Formation in the Course of the Inhibition of δ‐Chymotrypsin with trans‐Decalin‐Type Organophosphates: 31P‐NMR Evidence

Earlier investigations have shown that the irreversible inhibition of δ‐chymotrypsin with the axially substituted trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phosphabicyclo[4.4.0]decan‐3‐one (=2‐(2,4‐dinitrophenoxy)hexahydro‐4H‐1,3,2‐benzodioxaphosphorin 2‐oxide) proceeds under inversion of the configuration at the P‐atom. Since this assignment is based on the comparison of the respective chemical shifts with model compounds, the covalent nature of the binding interaction between enzyme and inhibitor was formulated in analogy. To prove this assumption, inhibition experiments were performed with the deuterated inhibitor (±)‐trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phospha(1,5,5‐²H₃)bicyclo[4.4.0]decan‐3‐one ((±)‐ 6a ). ³¹P{²H}‐NMR‐Spectroscopic monitoring of the reaction of stoichiometric amounts of the enzyme with (±)‐ 6a at pH 7.8 yielded the diastereoisomeric adducts 9 (−3.88 ppm) and 9′ (−3.96 ppm). Comparing the ³¹P chemical shifts of the corresponding deuterated covalent phosphoserine model compounds 8a/8a′ (−6.70 ppm, axial) and 8b/8b′ (−4.11/−4.13 ppm, equatorial) confirmed the inversion of the configuration at the P‐atom. ¹H‐Correlated ³¹P{²H}‐NMR spectra revealed a cross peak of the Ser¹⁹⁵‐H₂ (4.45 ppm) with the P‐atom of the inhibitor at −3.88/−3.96 ppm, thus establishing the covalent nature of the Ser¹⁹⁵−O−P bond.     

Preparation and Characterization of Uranium–Iron Triple‐Bonded UFe(CO)3− and OUFe(CO)3− Complexes

We report the preparation of UFe(CO)₃⁻ and OUFe(CO)₃⁻ complexes using a laser‐vaporization supersonic ion source in the gas phase. These compounds were mass‐selected and characterized by infrared photodissociation spectroscopy and state‐of‐the‐art quantum chemical studies. There are unprecedented triple bonds between U 6d/5f and Fe 3d orbitals, featuring one covalent σ bond and two Fe‐to‐U dative π bonds in both complexes. The uranium and iron elements are found to exist in unique formal U(I or III) and Fe(−II) oxidation states, respectively. These findings suggest that there may exist a whole family of stable df–d multiple‐bonded f‐element‐transition‐metal compounds that have not been fully recognized to date.     

Covalent Photosensitizer–Polyoxometalate‐Catalyst Dyads for Visible‐Light‐Driven Hydrogen Evolution

A general concept for the covalent linkage of coordination compounds to bipyridine‐functionalized polyoxometalates is presented. The new route is used to link an iridium photosensitizer to an Anderson‐type hydrogen‐evolution catalyst. This covalent dyad catalyzes the visible‐light‐driven hydrogen evolution reaction (HER) and shows superior HER activity compared with the non‐covalent reference. Hydrogen evolution is observed over periods >1 week. Spectroscopic, photophysical, and electrochemical analyses give initial insight into the stability, electronic structure, and reactivity of the dyad. The results demonstrate that the proposed linkage concept allows synergistic covalent interactions between functional coordination compounds and reactive molecular metal oxides.     

Chiral Self‐Sorting of [2+3] Salicylimine Cage Compounds

An inherently chiral C₃‐symmetric triaminotribenzotriquinacene was condensed in racemic and enantiomerically pure form with a bis(salicylaldehyde) to form [2+3] salicylimine cage compounds. Investigations on the chiral self‐sorting revealed that while entropy favors narcissistic self‐sorting in solution, selective social self‐sorting can be achieved by exploiting the difference in solubility between the homochiral and heterochiral cages. Gas sorption measurements further showed that seemingly small structural differences can have a significant impact on the surface area of microporous covalent cage compounds.     

Covalent hydration energies for purine analogs by quantum chemical methods

In this work, covalent hydration energies for a variety of azanaphthalenes and purine analogs have been calculated using a variety of quantum chemical methods. On the basis of these results, we recommend the CPCM(UA0)‐B3LYP/6‐31+G(d,p) level for rapid prediction of covalent hydration energies. However, we caution the use of this methodology for computing covalent hydration energies for fluorine‐containing compounds. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Nonpeptidic Selective Inhibitors of the Chymotrypsin‐Like (β5 i) Subunit of the Immunoproteasome

Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide‐based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin‐like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell‐based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i‐selective probes for possible application in noncancer diseases related to the immunoproteasome.     

Crystal‐Field and Covalency Effects in Uranates: An X‐ray Spectroscopic Study

The electronic structure of U^V‐ and U^VI‐containing uranates NaUO₃ and Pb₃UO₆ was studied by using an advanced technique, namely X‐ray absorption spectroscopy (XAS) in high‐energy‐resolution fluorescence‐detection (HERFD) mode. Due to a significant reduction in core–hole lifetime broadening, the crystal‐field splittings of the 5f shell were probed directly in HERFD‐XAS spectra collected at the U 3d edge, which is not possible by using conventional XAS. In addition, the charge‐transfer satellites that result from U 5f–O 2p hybridization were clearly resolved. The crystal‐field parameters, 5f occupancy, and degree of covalency of the chemical bonding in these uranates were estimated by using the Anderson impurity model by calculating the U 3d HERFD‐XAS, conventional XAS, core‐to‐core (U 4f–3d transitions) resonant inelastic X‐ray scattering (RIXS), and U 4f X‐ray photoelectron spectra. The crystal field was found to be strong in these systems and the 5f occupancy was determined to be 1.32 and 0.84 electrons in the ground state for NaUO₃ and Pb₃UO₆, respectively, which indicates a significant covalent character for these compounds.     

An electron localization function investigation of bonding in some simple four‐coordinate nitrogen and phosphorus compounds

The bonding in some simple four‐coordinate species involving nitrogen and phosphorus has been studied by the electron localization function (ELF) approach and compared to that in their conventionally singly and doubly bonded counterparts. Despite evidence suggesting the presence of a conventional multiple bond in certain cases of the four‐coordinate species, the ELF study shows this not to be the case. Rather, the situation is better pictured as, for example, in the case of H₃PCH₂as where both ionic and covalent interactions are present, a type of bond we term cov‐ionic. While the ionic interaction is generally strong, the covalent part can be weak, as in the case of the four‐coordinate nitrogen compounds, or strong, as in the case of the four‐coordinate phosphorus species. The quantum mechanically determined properties of the cov‐ionic bonded compounds are consistent with this picture. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:341–352, 2000     

Metal@COFs: Covalent Organic Frameworks as Templates for Pd Nanoparticles and Hydrogen Storage Properties of Pd@COF‐102 Hybrid Material

Three‐dimensional covalent organic frameworks (COFs) have been demonstrated as a new class of templates for nanoparticles. Photodecomposition of the [Pd(η³‐C₃H₅)(η⁵‐C₅H₅)]@COF‐102 inclusion compound (synthesized by a gas‐phase infiltration method) led to the formation of the Pd@COF‐102 hybrid material. Advanced electron microscopy techniques (including high‐angle annular dark‐field scanning transmission electron microscopy and electron tomography) along with other conventional characterization techniques unambiguously showed that highly monodisperse Pd nanoparticles ((2.4±0.5) nm) were evenly distributed inside the COF‐102 framework. The Pd@COF‐102 hybrid material is a rare example of a metal‐nanoparticle‐loaded porous crystalline material with a very narrow size distribution without any larger agglomerates even at high loadings (30 wt %). Two samples with moderate Pd content (3.5 and 9.5 wt %) were used to study the hydrogen storage properties of the metal‐decorated COF surface. The uptakes at room temperature from these samples were higher than those of similar systems such as Pd@metal–organic frameworks (MOFs). The studies show that the H₂ capacities were enhanced by a factor of 2–3 through Pd impregnation on COF‐102 at room temperature and 20 bar. This remarkable enhancement is not just due to Pd hydride formation and can be mainly ascribed to hydrogenation of residual organic compounds, such as bicyclopentadiene. The significantly higher reversible hydrogen storage capacity that comes from decomposed products of the employed organometallic Pd precursor suggests that this discovery may be relevant to the discussion of the spillover phenomenon in metal/MOFs and related systems.     

Metal Organic Polyhedra: A Click‐and‐Clack Approach Toward Targeted Delivery

Mixed self‐assembly of ligands 1 and 2 , PXDA ( 3 ), and Pd(NO₃)₂ afforded metal organic polyhedra ( MOP 1  –  MOP 3 ) which bear 24 covalently attached CB[7] and cyclooctyne moieties. Post assembly modification (PAM) of MOP 3 by covalent strain promoted alkyne azide click reaction provided MOP 4 ^R bearing covalently attached functionality (PEG, sulfonate, biotin, c‐RGD, fluorescein, and cyanine). Orthogonal CB[7]·guest mediated non‐covalent PAM of MOP 4 ^R with Ad‐ FITC afforded MOP 5 ^RGD • Ad‐ FITC and MOP 5 ^biotin • Ad‐ FITC . Flow cytometry analysis of the uptake of MOP 5 ^RGD • Ad‐ FITC toward U87 cells demonstrated improved uptake relative to control MOP lacking c‐RGD ligands. These results suggest a broad applicability of orthogonally functionalizable (covalent and non‐covalent) MOPs in targeted drug delivery and imaging applications.     

Synthesis of Novel Diverse Methoxybenzenes‐substituted 2H/4H‐chromene Derivatives in the Presence of InBr3 (5 mol%) and their Cytotoxic Activity

A series of novel 2‐(trifluoromethyl)‐2H /4H ‐chromene‐3‐carboxylate isomers 3 and 4 functionalized with diverse methoxybenzenes 2 at position 4 in compound 3 and position 2 in compound 4 were prepared in different proportions by nucleophilic substitution on ethyl 2‐hydroxy‐2‐(trifluoromethyl)‐2H ‐chromene‐3‐carboxylate 1 in single step promoted by Indium (III) bromide (5 mol%) a Lewis acid. Regiospecific isomers 3k , 3l , 3m , and 3n prepared by using sterically bulk 1,3,5‐trimethoxy benzene substrate 2e in this reaction. Further, isomers 3a and 4a independently on reaction with amines, only compound 3a could give Michael addition products 5a–c . All the compounds 3a–n , 4a–j , and 5a–c were screened for cytotoxic activity against four human cancer cell lines and found to show high activity at micromolar concentration. The compounds 4h and 5a–c showed promising cytotoxic activity against the tested cancer cell lines. Further, these compounds 4h and 5a–c were docked with protein (1SA0) on colchicine‐binding site of β tubulin suggesting that tubulin inhibition could be the possible mechanism of action for these compounds.     

Synthesizing interlocked molecules dynamically

As the complexity of mechanically interlocked molecular architectures increases, it is important to understand the underlying principles, such as molecular recognition and self‐assembly processes, that govern the practice of template‐directed synthesis necessary to create these particular compounds. In this review, we explain the importance of dynamic processes in the synthesis of mechanically interlocked compounds. We show how many different dynamic covalent bonds have been used in the synthesis of rotaxanes, catenanes, and other higher‐order mechanically interlocked compounds, with the goal of revealing the state of the art in dynamic covalent chemistry. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 136–154; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20173     

Synthesis and Herbicidal Activity of Novel 4‐Acyl‐2,5‐disubstituted‐3‐hydroxypyrazoles and 4‐Arylcarbonyl‐3‐substitutedisoxazol‐5‐ones

Two series of novel 4‐acyl‐2,5‐disubstituted‐3‐hydroxypyrazoles 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h and 4‐arylcarbonyl‐3‐substitutedisoxazol‐5‐ones 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i were synthesized by the Scotton–Baumann reaction of 2,5‐disubstituted‐2,4‐dihydro‐pyrazol‐3‐ones 1 or 3‐substituted‐4H‐isoxazol‐5‐ones 6 and various acyl chlorides, followed by the Fries rearrangement in the presence of calcium hydroxide and calcium oxide as the catalyst. Their structures were confirmed by IR, ¹H NMR, mass spectroscopy, and elemental analyses. ¹H NMR indicated that compounds 3 existed in enol forms and compounds 7 in keto configurations. The results of preliminary bioassays showed that some of the title compounds 3 and 7 exhibited moderate to good herbicidal activities against Brassica campestris L. at the concentration of 100 mg/L. Isoxazole compounds 7 showed better herbicidal activity against B. campestris L. than pyrazole compounds 3 did at the concentration of 100 mg/L. Moreover, most of the isoxazole compounds displayed higher herbicidal activity against B. campestris L. than Echinochloa crus‐galli. However, these compounds showed weak herbicidal activities at the concentration of 10 mg/L.     

ChemInform Abstract: The HgF2 Ionic Switch: A Triumph of Electrostatics Against Relativistic Odds.

DFT calculations (M06‐2X, B97D3, and MP2) indicate that polar covalent bonding in (HgF₂)_n begins at n = 5.     

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

The human KDM7 subfamily histone H3 Nϵ-methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X-linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues. The calculations reveal key roles of a flexible protein environment in productive formation of enzyme-substrate complexes and suggest targeting the flexible KDM7 linker region is of interest from a medicinal chemistry perspective.