Conformation and electronic configuration of complexes with multiple dimetal units

By using the building blocks Mo2(DAniF)3(O2CCH3) (DAniF = N,N'-di-panisylformamidinate) and [Mo2(cis-DAniF)2(NCCH3)4](BF4)2, a series of complexes with multiple dimolybdenum units, bridged by a variety of linkers and having various oxidation states, has been synthesized and studied by various physical and chemical methods. The isomeric neutral diamidate-bridged molecules, α– and β– (DAniF)3Mo2(ArN(O)CC(O)NAr)Mo2(DAniF)3 (Ar = p-anisyl), have been oxidized to give the PF6 salts of the four cations α1+, α2+, β1+, β2+; all four structures together with supporting evidence show that in α1+ and α2+ the unpaired electrons are localized while in β1+ and β2+ they are delocalized in the time scale of these experiments. It is also found that a hydroxide bridged complex having a [Mo2](µ-OH)2[Mo2] core undergoes a oxidative deprotomation, both in solution and in crystals, to a compound with a [Mo2](µ-O)2[Mo2] core. A probable key intermediate with one OH and one O bridge has also been characterized. One electron oxidation of the tetrabridged compounds [Mo2(cis-DAniF)2]2(µ-X)4, where X is a halogen atom (Cl, Br, I), produces a decrease of about 0.24 Å in the separation between the midpoints of the multiply bonded dimolybdenum units. DFT calculations suggest partial bond formation during the oxidation, which is consistent with NIR, EPR and electrochemical measurements. Additionally, a pair of isomeric cyclic triads containing three [Mo2(cis-DAniF)2]2+ units, bridged by six fluoride anions, have been synthesized and crystallographically characterized. The symmetry of the α isomer is C2v because the three [Mo2] units are oriented in two orthogonal directions while that of the other isomer is D3h because the three [Mo2] units are parallel. No direct interconversion between isomers has been detected by heating or irradiation of solutions but oxidation of the α isomer first generates an α+ species that changes to β+. Finally, reaction of [Mo2(cis-DAniF)2(NCCH3)4](BF4)2 and Bun 4NBH4 in ether gives [Mo2(cis-DAniF)2]2(µ-H)4 (14), a compound whose Mo4H4 core may be described as an elongated tetrahedron in which the four H atoms are along the four long edges and the Mo2 units along the short edges

Expanded redox accessibility via ligand substitution in an octahedral Fe6Br6 cluster

Oxidation of the nominally all-ferrous hexanuclear cluster (HL)2Fe6 with six equivalents of ferrocenium in the presence of bromide ions results in a six-electron oxidation of the Fe6 core to afford the nominally all-ferric cluster (HL)2Fe6Br6. The hexabromide cluster is also structurally characterized in a 4+ core oxidation state. A structural comparison of these two clusters provides an insight into the Fe6 core electronic structure.Chemistry and Chemical Biolog

Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2.

Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo. In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC

Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2

Abstract(#br)Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro , and facilitated tumor growth and metastasis in vivo . Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo . In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC

Synthesis and characterization of a platinum-based antineoplastic agent by collision-induced dissociation tandem mass spectrometry

Platinum-based antineoplastic agents are widely used in cancer chemotherapy. In this study, a novel Pt-HDACi conjugate by combining a key platinum intermediate K[PtCl3(2-picoline)] (TCPP) and a histone deacetylase inhibitor (HDACi) derivative (L01) was designed and synthesized. In comparison to Vorinostat (SAHA), structural derivations in L01 take places in the linker and cap domain. Mass spectrometry analysis was used to characterize the Pt-HDACi conjugate. The peaks at m/z (M+Na)+ and (M-•CH3+Na)+ ions were observed in the full-scan spectrum, suggested the successful synthesis of the Pt-HDACi complex. To obtain more detailed information about the binding of L01 to TCPP and the fragmentation pathway of the final complex, collision-induced dissociation tandem mass spectrometry (CID-MS/MS) using electron spray ionization mass spectrometer with a linear quadrupole ion trap analyzer was performed. The MS/MS spectrum of the precursor ion [M+Na]+ at m/z 620 revealed two prominent fragment ions under a collision energy of 20. A peak at m/z 584 corresponded to the loss of a chlorine atom from the molecule, while a peak at m/z 551 was due to the loss of hydroxylamine (NHOH). Another peak at m/z 483 was a fragment ion resulting from McLafferty rearrangement. The observed fragmentation patterns provided valuable information about the binding strength of each ligand and structural features of the Pt-HDACi conjugate

Modification and synthesis of histone deacetylase inhibitors for combination with platinum anticancer agents

Cancer, the second leading cause of death, is a disease that can initiate in almost any part of the body causing uncontrollable cell growth, exerting physical strain on the host, and exhausting valuable nutrients and energy of the organs. Histone deacetylase enzymes are known to be overexpressed in many types of cancer cells, causing DNA to wrap around the protein more tightly, silencing gene transcription which may include the tumor suppressing genes. Combination of histone deacetylase inhibitors (HDACi) with globally approved chemotherapeutic platinum drugs could potentially produce bifunctional drug candidates with increased specificity and decreased cytotoxicity. Histone deacetylase inhibitors contain three important components: a protein surface recognition domain (cap), a linker, and a zinc binding domain. Structural tuning of inhibitors through any of these components can affect selectivity and binding affinity of the drug. By slightly modifying US FDA approved Vorinostat (SAHA), HDACi derivatives 3, 17, and 30 were designed and synthesized. Derivative 3 has a linker, reduced from a 6-carbon chain to a 5-carbon chain. This derivative would behave as monodentate ligands while reacting with Pt agents. In derivatives 17 and 30, the surface protein recognition domain contains an ethylenediamine group as bidentate coordination sites. General synthesis schemes of the inhibitors include connecting the cap domain and the linker, Boc protection of the amine groups on the cap domain, nucleophilic addition of hydroxylamine to form a hydroxamic acid necessary for zinc binding, and lastly Boc-deprotection. The newly synthesized HDACi derivatives were characterized via ESI-LTQ Mass Spectrometry and 600 MHz Nuclear Magnetic Resonance Spectrometry

Synthesis of Histone Deacetylase Inhibitor Platinum Complexes for Bifunctional Anticancer Agents

Histone Deacetylase (HDAC), an enzyme involved in the regulation of gene expression via chromatin conformation, is overexpressed in many types of cancer and is a popular target for cancer drugs. Cisplatin, an FDA approved anticancer drug, is an alkylating agent that binds to the DNA of cancer cells to induce cell death. By combining HDAC inhibitors (HDACi) and platinum-based alkylating agents into a single drug, the platinum complex with HDACi could have increased specificity and efficacy as a bifunctional anticancer agent. Panobinostat and chidamide, two HDACi, are composed of three groups: a protein-recognition cap domain, a linker, and a zinc binding group. The cap domain fits into a groove at the exterior of the pocket, the linker reaches into the pocket, and the zinc binding group binds to the zinc cofactor of HDAC active site. Derivatives of these molecules were designed by modifying the three parts to alter both length and flexibility of the molecule. By additionally modifying the cap to have a platinum coordination site, the HDACi derivative could form a complex with platinum. The complex is composed of two chloride leaving-group ligands, a non-leaving ammonia ligand, and the HDACi derivative, coordinated similarly to the ammonia ligand. The HDACi derivatives are synthesized via nucleophilic substitution to the cap domain, protection of the coordination site with Boc anhydride, a second nucleophilic substitution, and a condensation reaction to add the zinc binding domain. The Boc protection is then removed and the HDACi will be coordinated to the platinum complex. The synthesized molecules are characterized via NMR spectroscopy, mass spectrometry, and X-ray crystallography. The relative binding efficacy of the HDACi derivatives will be estimated via computational docking studies

Assembly and Reactivity of Formamidinate-Supported Zinc complexes

Mononuclear catalysts have been studied extensively and shown to catalyze various organic reactions. Bimetallic systems seem to behave differently from single metal systems as the second metal allows for cooperativity between the two metals. Recently, dirhodium paddlewheel complexes have exhibited improved catalytic activity compared to monorhodium catalysts for various organic reactions, suggesting the importance of the supporting metal atom. Despite the successes of mononuclear catalysts, there are very few examples involving bimetallic catalysts