Inverse Isotope Effects in Single-Crystal to Single-Crystal Reactivity and the Isolation of a Rhodium Cyclooctane σ-Alkane Complex.

The sequential solid/gas single-crystal to single-crystal reaction of [Rh(CyP(CH)PCy)(COD)][BAr ] (COD = cyclooctadiene) with H or D was followed in situ by solid-state P{H} NMR spectroscopy (SSNMR) and ex situ by solution quenching and GC-MS. This was quantified using a two-step Johnson-Mehl-Avrami-Kologoromov (JMAK) model that revealed an inverse isotope effect for the second addition of H, that forms a σ-alkane complex [Rh(CyP(CH)PCy)(COA)][BAr ]. Using D, a temporal window is determined in which a structural solution for this σ-alkane complex is possible, which reveals an η,η-binding mode to the Rh(I) center, as supported by periodic density functional theory (DFT) calculations.

MicroED characterization of a robust cationic σ-alkane complex stabilized by the [B(3,5-(SF)CH)] anion, on-grid solid/gas single-crystal to single-crystal reactivity.

Microcrystalline (∼1 μm) [Rh(CyPCHCHPCy)(norbornadiene)][S-BAr], [S-BAr] = [B(3,5-(SF)CH)], reacts with H in a single-crystal to single-crystal transformation to form the σ-alkane complex [Rh(CyPCHCHPCy)(norbornane)][S-BAr], for which the structure was determined by microcrystal Electron Diffraction (microED), to 0.95 Å resolution, an on-grid hydrogenation, and a complementary single-crystal X-ray diffraction study on larger, but challenging to isolate, crystals. Comparison with the [BAr] analogue [Ar = 3,5-(CF)(CH)] shows that the [S-BAr] anion makes the σ-alkane complex robust towards decomposition both thermally and when suspended in pentane.

A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study.

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits.

Selectivity of Rh⋅⋅⋅H-C Binding in a σ-Alkane Complex Controlled by the Secondary Microenvironment in the Solid State.

Single-crystal to single-crystal solid-state molecular organometallic (SMOM) techniques are used for the synthesis and structural characterization of the σ-alkane complex [Rh(tBu PCH CH CH PtBu )(η ,η -C H )][BAr ] (Ar =3,5-(CF ) C H ), in which the alkane (norbornane) binds through two exo-C-H⋅⋅⋅Rh interactions. In contrast, the bis-cyclohexyl phosphine analogue shows endo-alkane binding. A comparison of the two systems, supported by periodic DFT calculations, NCI plots and Hirshfeld surface analyses, traces this different regioselectivity to subtle changes in the local microenvironment surrounding the alkane ligand.

The ditungsten decacarbonyl dianion.

We report the synthesis and structural authentication of the ditungsten decarbonyl dianion in [(OC)W-W(CO)][K(18-crown-6)(THF)] (1), completing the group 6 dianion triad over half a century since the area began. The W-W bond is long [3.2419(8) Å] and, surprisingly, in the solid-state the dianion adopts a D eclipsed rather than D staggered geometry, the latter of which dominates the structural chemistry of binary homobimetallic carbonyls.

f-Element Half-Sandwich Complexes: A Tetrasilylcyclobutadienyl-Uranium(IV)-Tris(tetrahydroborate) Anion Pianostool Complex.

Despite there being numerous examples of f-element compounds supported by cyclopentadienyl, arene, cycloheptatrienyl, and cyclooctatetraenyl ligands (C ), cyclobutadienyl (C ) complexes remain exceedingly rare. Here, we report that reaction of [Li {C (SiMe ) }(THF) ] (1) with [U(BH ) (THF) ] (2) gives the pianostool complex [U{C (SiMe ) }(BH ) ][Li(THF) ] (3), where use of a borohydride and preformed C -unit circumvents difficulties in product isolation and closing a C -ring at uranium. Complex 3 is an unprecedented example of an f-element half-sandwich cyclobutadienyl complex, and it is only the second example of an actinide-cyclobutadienyl complex, the other being an inverse-sandwich.

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

Purpose: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors.

Methods: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID).

Results: Thirty-five patients were enrolled across 5 dose levels.

Back-bonding between an electron-poor, high-oxidation-state metal and poor π-acceptor ligand in a uranium(V)-dinitrogen complex.

A fundamental bonding model in coordination and organometallic chemistry is the synergic, donor-acceptor interaction between a metal and a neutral π-acceptor ligand, in which the ligand σ donates to the metal, which π back-bonds to the ligand. This interaction typically involves a metal with an electron-rich, mid-, low- or even negative oxidation state and a ligand with a π* orbital. Here, we report that treatment of a uranium-carbene complex with an organoazide produces a uranium(V)-bis(imido)-dinitrogen complex, stabilized by a lithium counterion.

Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653).

Purpose: Patients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population.

Methods: Patients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible.

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

Background: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used.

Bimetallic Cooperative Cleavage of Dinitrogen to Nitride and Tandem Frustrated Lewis Pair Hydrogenation to Ammonia.

Although reductive cleavage of dinitrogen (N ) to nitride (N ) and hydrogenation with dihydrogen (H ) to yield ammonia (NH ) is accomplished in heterogeneous Haber-Bosch industrial processes on a vast scale, sequentially coupling these elementary reactions together with a single metal complex remains a major challenge for homogeneous molecular complexes. Herein, we report that the reaction of a chloro titanium triamidoamine complex with magnesium effects complete reductive cleavage of N to give a dinitride dititanium dimagnesium ditriamidoamine complex. Tandem H splitting by a phosphine-borane frustrated Lewis pair (FLP) shuttles H atoms to the N , evolving NH .

Reversible coordination of N and H to a homoleptic = 1/2 Fe(i) diphosphine complex in solution and the solid state.

The synthesis and characterisation of the = 1/2 Fe(i) complex [Fe(depe)][BArF4] ([][BArF4]), and the facile reversible binding of N and H in both solution and the solid state to form the adducts [·N] and [·H], are reported. Coordination of N in THF is thermodynamically favourable under ambient conditions (1 atm; Δ = -4.9(1) kcal mol), while heterogenous binding is more favourable for H than N by a factor of ∼300.

Catalytic Dinitrogen Reduction to Ammonia at a Triamidoamine-Titanium Complex.

Catalytic reduction of N to NH by a Ti complex has been achieved, thus now adding an early d-block metal to the small group of mid- and late-d-block metals (Mo, Fe, Ru, Os, Co) that catalytically produce NH by N reduction and protonolysis under homogeneous, abiological conditions. Reduction of [Ti (Tren )X] (X=Cl, 1A; I, 1B; Tren =N(CH CH NSiMe ) ) with KC affords [Ti (Tren )] (2). Addition of N affords [{(Tren )Ti } (μ-η :η -N )] (3); further reduction with KC gives [{(Tren )Ti } (μ-η :η :η :η -N K )] (4).

A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III -Mutant ER-Positive and HER2-Negative Breast Cancer.

Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in -mutant ER breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in mutant ER breast cancer.

Cationic silyldiazenido complexes of the Fe(diphosphine)(N) platform: structural and electronic models for an elusive first intermediate in N fixation.

The first cationic Fe silyldiazenido complexes, [Fe(PP)(NN-SiMe)][BAr] (PP = dmpe/depe), have been synthesised and thoroughly characterised. Computational studies show the compounds to be useful structural and electronic surrogates for the more elusive [Fe(PP)(NN-H)], which are postulated intermediates in the H/e mediated fixation of N by Fe(PP)(N) species.

Selective Catalytic Reduction of N to NH by a Simple Fe Complex.

The catalytic fixation of N by molecular Fe compounds is a rapidly developing field, yet thus far few complexes can effect this transformation, and none are selective for NH production. Herein we report that the simple Fe(0) complex Fe(EtPCHCHPEt)(N) (1) is an efficient catalyst for the selective conversion of N (>25 molecules N fixed) into NH, attendant with the production of ca. one molecule of NH.

Teaching old compounds new tricks: efficient N2 fixation by simple Fe(N2)(diphosphine)2 complexes.

The Fe(0) species Fe(N2)(dmpe)2 exists in equilibrium with the previously unreported dimer, [Fe(dmpe2)2(μ-N2)]. For the first time these complexes, alongside Fe(N2)(depe)2, are shown unambiguously to produce N2H4 and/or NH3 upon addition of triflic acid; for Fe(N2)(depe)2 this represents one of the highest electron conversion efficiencies for Fe complexes to date.

SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer.

Background: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer.

Methods: Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg.

Bypassing a highly unstable frustrated Lewis pair: dihydrogen cleavage by a thermally robust silylium-phosphine adduct.

The thermally robust silylium complex [iPr3Si-PtBu3](+)[B(C6F5)4](-) (1) activates H2/D2 at 90 °C (PhCl); no evidence for dissociation into the separated Lewis pair is found. DFT calculations show H2 cleavage proceeds via Si-P bond elongation to form an encounter complex directly from the adduct, thus avoiding the non-isolable iPr3Si(+)-PtBu3 FLP.

A Convenient Synthetic Protocol to 1,2-Bis(dialkylphosphino)ethanes.

1,2-Bis(dialkylphosphino)ethanes are readily prepared from the parent phosphine oxides, a novel sodium aluminium hydride/sodium hydride reduction protocol of intermediate chlorophosphonium chlorides. This approach is amenable to multi-gram syntheses, utilises readily available and inexpensive reagents, and benefits from a facile non-aqueous work-up in the final reductive step.

A Nonrandomized, Phase II Study of Sequential Irinotecan and Flavopiridol in Patients With Advanced Hepatocellular Carcinoma.

Background: Flavopiridol, a Cdk inhibitor, potentiates irinotecan-induced apoptosis. In a phase I trial of sequential irinotecan and flavopiridol, 2 patients with advanced hepatocellular carcinoma (HCC) had stable disease (SD) for ≥14 months. We thus studied the sequential combination of irinotecan and flavopiridol in patients with HCC.

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer.

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target.

A homologous series of first-row transition-metal complexes of 2,2'-bipyridine and their ligand radical derivatives: trends in structure, magnetism, and bonding.

The organometallic first-row transition-metal complexes [M(2,2'-bipy)(mes)2] (M = Cr (1), Mn (2), Co (4), Ni (5); 2,2'-bipy = 2,2'-bipyridine; mes = 2,4,6-Me3C6H2) were reacted with potassium and a suitable alkali-metal sequestering agent to yield salts of the anionic species [M(2,2'-bipy)(mes)2](-). The neutral parent compounds and their corresponding anionic congeners were characterized by single-crystal X-ray diffraction in [Cr(2,2'-bipy)(mes)2]·1.5C6H6, [Mn(2,2'-bipy)(mes)2], [Co(2,2'-bipy)(mes)2]·THF, [Ni(2,2'-bipy)(mes)2], [K(dibenzo-18-crown-6)·THF][Cr(2,2'-bipy)(mes)2]·2THF, [K(18-crown-6)][Mn(2,2'-bipy)(mes)2]·2THF, [K(18-crown-6)][Mn(2,2'-bipy)(mes)2]·0.

Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway.

Agents inhibiting the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities.

Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors.

Purpose: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).

Experimental Design: Patients received cixutumumab, 6 mg/kg i.v.