Crystal structures of bis- and hexakis[(6,6′-dihydroxybipyridine)copper(II)] nitrate coordination complexes

Two multinuclear complexes synthesized from Cu(NO3)2 and 6,6′-dihydroxybipyridine (dhbp) exhibit bridging nitrate and hydroxide ligands. The dinuclear complex (6,6′-dihydroxybipyridine-2κ2N,N′)[μ-6-(6-hydroxypyridin-2-yl)pyridin-2-olato-1:2κ3N,N′:O2](μ-hydroxido-1:2κ2O:O′)(μ-nitrato-1:2κ2O:O′)(nitrato-1κO)dicopper(II), [Cu2(C10H7N2O2)(OH)(NO3)2(C10H8N2O2)] or [Cu(6-OH-6′-O-bpy)(NO3)(μ-OH)(μ-NO3)Cu(6,6′-dhbp)], (I), with a 2:1 ratio of nitrate to hydroxide anions and one partially deprotonated dhbp ligand, forms from a water–ethanol mixture at neutral pH. The hexanuclear complex bis(μ3-bipyridine-2,2′-diolato-κ3O:N,N′:O′)tetrakis(6,6′-dihydroxybipyridine-κ2N,N′)tetrakis(μ-hydroxido-κ2O:O′)bis(methanol-κO)tetrakis(μ-nitrato-κ2O:O′)hexacopper(II), [Cu6(C10H6N2O2)2(CH4O)2(OH)4(NO3)4(C10H8N2O2)4] or [Cu(6,6′-dhbp)(μ-NO3)2(μ-OH)Cu(6,6′-O-bpy)(μ-OH)Cu(6,6′dhbp)(CH3OH)]2, (II), with a 1:1 NO3–OH ratio and two fully protonated and fully deprotonated dhbp ligands, was obtained by methanol recrystallization of material obtained at pH 3. Complex (II) lies across an inversion center. Complexes (I) and (II) both display intramolecular O—H...O hydrogen bonding. Intermolecular O—H...O hydrogen bonding links symmetry-related molecules forming chains along [100] for complex (I) with π-stacking along [010] and [001]. Complex (II) forms intermolecular O—H...O hydrogen-bonded chains along [010] with π-stacking along [100] and [001]

Iridium Dihydroxybipyridine Complexes Show That Ligand Deprotonation Dramatically Speeds Rates of Catalytic Water Oxidation

We report highly active iridium precatalysts, [Cp*Ir(N,N)Cl]Cl (1-4), for water oxidation that are supported by recently designed dihydroxybipyridine (dhbp) ligands. These ligands can readily be deprotonated in situ to alter the electronic properties at the metal; thus, these catalyst precursors have switchable properties that are pH-dependent. The pKa values in water of the iridium complexes are 4.6(1) and 4.4(2) with (N,N) = 6,6\u27-dhbp and 4,4\u27-dhbp, respectively, as measured by UV-vis spectroscopy. For homogeneous water oxidation catalysis, the sacrificial oxidant NaIO4 was found to be superior (relative to CAN) and allowed for catalysis to occur at higher pH values. With NaIO4 as the oxidant at pH 5.6, water oxidation occurred most rapidly with (N,N) = 4,4\u27-dhbp, and activity decreased in the order 4,4\u27-dhbp (3) \u3e 6,6\u27-dhbp (2) » 4,4\u27-dimethoxybipyridine (4) \u3e bipy (1). Furthermore, initial rate studies at pH 3-6 showed that the rate enhancement with dhbp complexes at high pH is due to ligand deprotonation rather than the pH alone accelerating water oxidation. Thus, the protic groups in dhbp improve the catalytic activity by tuning the complexes\u27 electronic properties upon deprotonation. Mechanistic studies show that the rate law is first-order in an iridium precatalyst, and dynamic light scattering studies indicate that catalysis appears to be homogeneous. It appears that a higher pH facilitates oxidation of precatalysts 2 and 3 and their [B(ArF)4]- salt analogues 5 and 6. Both 2 and 5 were crystallographically characterized

Discovery of the cryptic function of terpene cyclases as aromatic prenyltransferases

Terpene cyclases catalyze the formation of diverse hydrocarbon scaffolds found in terpenoids. Here, the authors report the cryptic function of class I terpene cyclases as aromatic prenyltransferases and the universality of this cryptic feature is confirmed using enzymes from different sources

Identification of HDAC10 Inhibitors that Modulate Autophagy in Transformed Cells

Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are valid tools to assess HDAC functions. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are ill-defined. This lack of knowledge is due to a lack of specific and potent HDAC10 inhibitors with cellular activity. Here, we have synthesized and characterized piperidine-4-acrylhydroxamates as potent and highly selective inhibitors of HDAC10. This was achieved by targeting the acidic gatekeeper residue Glu274 of HDAC10 with a basic piperidine moiety that mimics the interaction of the polyamine substrate of HDAC10. We have confirmed the binding modes of selected inhibitors using X-ray crystallography. Promising candidates were selected based on their specificity by in vitro profiling using recombinant HDACs. The most promising HDAC10 inhibitors 10c and 13b were tested for specificity in acute myeloid leukemia (AML) cells with the FLT3-ITD oncogene. By immunoblot experiments we assessed the hyperacetylation of histones and tubulin-α, which are class I and HDAC6 substrates, respectively. As validated test for HDAC10 inhibition we used flow cytometry assessing autolysosome formation in neuroblastoma and AML cells. We demonstrate that 10c and 13b inhibit HDAC10 with high specificity over HDAC6 and with no significant impact on class I HDACs. The accumulation of autolysosomes is not a consequence of apoptosis and 10c and 13b are not toxic for normal human kidney cells. These data show that 10c and 13b are nanomolar inhibitors of HDAC10 with high specificity. Thus, our new HDAC10 inhibitors are tools to identify the downstream targets and functions of HDAC10 in cells

Iridium Dihydroxybipyridine Complexes Show That Ligand Deprotonation Dramatically Speeds Rates of Catalytic Water Oxidation

We report highly active iridium precatalysts, [Cp*Ir­(N,N)­Cl]­Cl (<b>1</b>–<b>4</b>), for water oxidation that are supported by recently designed dihydroxybipyridine (dhbp) ligands. These ligands can readily be deprotonated in situ to alter the electronic properties at the metal; thus, these catalyst precursors have switchable properties that are pH-dependent. The p<i>K</i>_a values in water of the iridium complexes are 4.6(1) and 4.4(2) with (N,N) = 6,6′-dhbp and 4,4′-dhbp, respectively, as measured by UV–vis spectroscopy. For homogeneous water oxidation catalysis, the sacrificial oxidant NaIO₄ was found to be superior (relative to CAN) and allowed for catalysis to occur at higher pH values. With NaIO₄ as the oxidant at pH 5.6, water oxidation occurred most rapidly with (N,N) = 4,4′-dhbp, and activity decreased in the order 4,4′-dhbp (<b>3</b>) > 6,6′-dhbp (<b>2</b>) ≫ 4,4′-dimethoxybipyridine (<b>4</b>) > bipy (<b>1</b>). Furthermore, initial rate studies at pH 3–6 showed that the rate enhancement with dhbp complexes at high pH is due to ligand deprotonation rather than the pH alone accelerating water oxidation. Thus, the protic groups in dhbp improve the catalytic activity by tuning the complexes’ electronic properties upon deprotonation. Mechanistic studies show that the rate law is first-order in an iridium precatalyst, and dynamic light scattering studies indicate that catalysis appears to be homogeneous. It appears that a higher pH facilitates oxidation of precatalysts <b>2</b> and <b>3</b> and their [B­(Ar^F)₄]⁻ salt analogues <b>5</b> and <b>6</b>. Both <b>2</b> and <b>5</b> were crystallographically characterized

Iridium Dihydroxybipyridine Complexes Show That Ligand Deprotonation Dramatically Speeds Rates of Catalytic Water Oxidation

We report highly active iridium precatalysts, [Cp*Ir­(N,N)­Cl]­Cl (<b>1</b>–<b>4</b>), for water oxidation that are supported by recently designed dihydroxybipyridine (dhbp) ligands. These ligands can readily be deprotonated in situ to alter the electronic properties at the metal; thus, these catalyst precursors have switchable properties that are pH-dependent. The p<i>K</i>_a values in water of the iridium complexes are 4.6(1) and 4.4(2) with (N,N) = 6,6′-dhbp and 4,4′-dhbp, respectively, as measured by UV–vis spectroscopy. For homogeneous water oxidation catalysis, the sacrificial oxidant NaIO₄ was found to be superior (relative to CAN) and allowed for catalysis to occur at higher pH values. With NaIO₄ as the oxidant at pH 5.6, water oxidation occurred most rapidly with (N,N) = 4,4′-dhbp, and activity decreased in the order 4,4′-dhbp (<b>3</b>) > 6,6′-dhbp (<b>2</b>) ≫ 4,4′-dimethoxybipyridine (<b>4</b>) > bipy (<b>1</b>). Furthermore, initial rate studies at pH 3–6 showed that the rate enhancement with dhbp complexes at high pH is due to ligand deprotonation rather than the pH alone accelerating water oxidation. Thus, the protic groups in dhbp improve the catalytic activity by tuning the complexes’ electronic properties upon deprotonation. Mechanistic studies show that the rate law is first-order in an iridium precatalyst, and dynamic light scattering studies indicate that catalysis appears to be homogeneous. It appears that a higher pH facilitates oxidation of precatalysts <b>2</b> and <b>3</b> and their [B­(Ar^F)₄]⁻ salt analogues <b>5</b> and <b>6</b>. Both <b>2</b> and <b>5</b> were crystallographically characterized

First fluorescent acetylspermidine deacetylation assay for HDAC10 identifies selective inhibitors with cellular target engagement

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e.g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of most other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed as a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10-inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was previously associated with HDAC10 inhibition was not observed. Thus, we have developed new chemical probes for HDAC10 that allow further clarification of the biological role of this enzyme

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout

We report the first well-characterized selective chemical probe for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded the HDAC10 chemical probe DKFZ-748, with potency and selectivity demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Co-crystal structures of our aza-SAHA derivatives with HDAC10 provide a structural rationale for potency, and chemoproteomic profiling con-firmed cellular HDAC10-selectivity of DKFZ-748 across the target landscape of HDAC drugs. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a polyamine deacetylase. Finally, in a polyamine-limited in vitro tumor model, DKFZ-748 showed dose-dependent growth inhibition of HeLa cells. We expect DKFZ-748 and related probes to enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines in both physiological and pathological settings

Studies of the Pathways Open to Copper Water Oxidation Catalysts Containing Proximal Hydroxy Groups During Basic Electrocatalysis

Water oxidation can lead to a sustainable source of energy, but for water oxidation catalysts to be economical they must use earth abundant metals. We report here 2:1 6,6′-dihydroxybipyridine (6,6′-dhbp)/copper complexes that are capable of electrocatalytic water oxidation in aqueous base (pH = 10–14). Two crystal structures of the complex that contains 6,6′-dhbp and copper­(II) in a ratio of 2:1 (complex <b>1</b>) are presented at different protonation states. The thermodynamic acid dissociation constants were measured for complex <b>1</b>, and these show that the complex is fully deprotonated above pH = 8.3 (i.e., under water oxidation conditions). CW-EPR, ENDOR, and HYSCORE spectroscopy confirmed that the 6,6′-dhbp ligand is bound to the copper ion over a wide pH range which shows how pH influences precatalyst structure. Additional copper­(II) complexes were synthesized from the ligands 4,4′-dhbp (complex <b>2</b>) and 6,6′-dimethoxybipyridine (complexes <b>3</b> and <b>4</b>). A zinc complex of 6,6′-dhbp was also synthesized (complex <b>5</b>). Crystal structures are reported for <b>1</b> (in two protonation states), <b>3</b>, <b>4</b>, and <b>5</b>. Water oxidation studies using several of the above compounds (<b>1</b>, <b>2</b>, <b>4</b>, and <b>5</b>) at pH = 12.6 have illustrated that both copper and proximal OH groups are necessary for water oxidation at a low overpotential. Our most active catalyst <b>1</b> was found to have an overpotential of 477 mV for water oxidation at a moderate rate of <i>k</i>_cat = 0.356 s^–1 with a competing irreversible oxidation event at a rate of 1.082 s^–1. Furthermore, our combined work supports previous observations in which OH/O^– groups on the bipyridine rings can hydrogen bond with metal bound substrate, support unusual binding modes, and potentially facilitate proton coupled electron transfer