Microcrystalline (∼1 μm) Rh(Cy
PCH
CH
PCy
)(norbornadiene)S-BAr
, S-BAr
= B(3,5-(SF
)
C
H
)
, reacts with H
in a single-crystal to single-crystal transformation to form the σ-alkane complex Rh(Cy
...PCH
CH
PCy
)(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
)
(C
H
) shows that the S-BAr
anion makes the σ-alkane complex robust towards decomposition both thermally and when suspended in pentane. Subsequent reactivity with dissolved ethene in a pentane slurry, forms Rh(Cy
PCH
CH
PCy
)(ethene)
S-BAr
, and the catalytic dimerisation/isomerisation of ethene to 2-butenes. The increased stability of S-BAr
salts is identified as being due to increased non-covalent interactions in the lattice, resulting in a solid-state molecular organometallic material with desirable stability characteristics.
Reaction of Li2{C4(SiMe3)4}(THF)2 (1) with U(η5-C5Me5)I2(THF) (2) produced the oxo-centered homotrimetallic uranium–pentamethylcyclopentadienyl complex ...{U(η5-C5Me5)(μ-I)2}3{μ3-O}{Li(THF)3}0.52Li(THF)4 (3) as the only isolable product in a very low yield. In contrast, reaction of 2 with Mg{C4(SiMe3)4}(THF)3 (4) produced the oxo-centered homotrimetallic uranium(IV)–cyclobutadienyl complex {U(C4SiMe34)(μ-I)2}3{μ3-O}Mg(THF)6 (5). The solid state structure of 5 reveals average U–C and U–C4 centroid distances of 2.574(7) and 2.355(7) Å, respectively, and displacements of the silicon atoms from the C4 plane ranging from 0.478(13) to 0.6528(12) Å. Variable-temperature magnetic susceptibility measurements on powdered 5 confirm the exclusively uranium(IV) formulation with no evidence found for any uranium···uranium magnetic coupling. Quantum chemical calculations suggest polarized uranium–cyclobutadienyl bonding interactions but underscore the essentially exclusive π-bonding nature of these linkages with no δ-bonding component. This π-bonding also accounts for the displacements of the silyl groups from the C4 plane, which maximizes U–C4 orbital overlap. The compounds reported here have been variously characterized by single-crystal X-ray diffraction, ATR-IR spectroscopy, elemental analysis, SQUID magnetometry, and quantum chemical calculations.
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)·THFCr(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)2·0.67py·0.67tol, K(2,2,2-crypt)Co(2,2′-bipy)(mes)2, and K(2,2,2-crypt)Ni(2,2′-bipy)(mes)2. These species, along with the previously reported neutral and anionic iron complexes Fe(2,2′-bipy)(mes)20/– (3/3 – ), form a homologous series of compounds which allow for an in-depth study of the interactions between metals and ligands. Single-crystal X-ray diffraction data, DFT calculations, and various spectroscopic and magnetic measurements indicate that the anionic complexes (1 – –5 – ) can be best formulated as M(II) complexes of the 2,2′-bipyridyl radical anion. These findings complement recent studies which indicate that bond metric data from single-crystal X-ray diffraction may be employed as an important diagnostic tool in determining the oxidation states of bipyridyl ligands in transition-metal complexes.
The first cationic Fe silyldiazenido complexes, Fe(PP)2(NN-SiMe3)+BArF4- (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)2(NN-H)+, which are postulated intermediates in the H+/e- mediated fixation of N2 by Fe(PP)2(N2) species.
The sequential solid/gas single-crystal to single-crystal reaction of Rh(Cy2P(CH2)3PCy2)(COD)BArF 4 (COD = cyclooctadiene) with H2 or D2 was followed in situ by solid-state 31P{1H} 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 H2, that forms a σ-alkane complex Rh(Cy2P(CH2)3PCy2)(COA)BArF 4. Using D2, a temporal window is determined in which a structural solution for this σ-alkane complex is possible, which reveals an η2,η2-binding mode to the Rh(I) center, as supported by periodic density functional theory (DFT) calculations. Extensive H/D exchange occurs during the addition of D2, as promoted by the solid-state microenvironment.
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(tBu2PCH2CH2CH2PtBu2)(η2,η2‐C7H12)BArF4 (ArF=3,5‐(CF3)2C6H3), 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. A tertiary periodic structure supporting a secondary microenvironment that controls binding at the metal site has parallels with enzymes. The new σ‐alkane complex is also a catalyst for solid/gas 1‐butene isomerization, and catalyst resting states are identified for this.
Importance of microenvironment: By using solid‐state molecular organometallic (SMOM) techniques, the σ‐alkane complex Rh(tBu2PCH2CH2CH2PtBu2)(η2,η2‐C7H12)BArF4, in which the alkane binds through two exo‐C−H⋅⋅⋅Rh interactions, is synthesized and structurally characterized. This is different from the analogous complex with PCy2 groups. Subtle differences in the microenvironment, as encoded by the diene precursor complex, are shown to determine the selectivity of alkane binding.
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. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (
N
= 18; 51%), fatigue (
N
= 17; 49%), maculo-papular rash (
N
= 16; 46%), diarrhea (
N
= 12; 34%), anorexia (
N
= 11; 31%), and nausea (
N
= 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (
N
= 13) and primarily included fatigue (
N
= 5; 14%) and maculo-papular rashes (
N
= 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients.
Conclusion
The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
The ditungsten decacarbonyl dianion Ostrowski, Joseph P. A; Atkinson, Benjamin E; Doyle, Laurence R ...
Dalton transactions : an international journal of inorganic chemistry,
07/2020, Letnik:
49, Številka:
27
Journal Article
Recenzirano
Odprti dostop
We report the synthesis and structural authentication of the ditungsten decarbonyl dianion in (OC)
5
W-W(CO)
5
K(18-crown-6)(THF)
2
2
(
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
4h
eclipsed rather than
D
4d
staggered geometry, the latter of which dominates the structural chemistry of binary homobimetallic carbonyls. Computational studies at levels of theory from DFT to CCSD(T) confirm that the
D
4d
geometry is energetically preferred in the gas-phase, being ∼18 kJ mol
−1
more stable than the
D
4h
form, since slight destabilisation of the degenerate W-CO π 5d
xz
and 5d
yz
orbitals is outweighed by greater stabilisation of the W-W σ-bond orbital. The gas-phase
D
4h
structure displays a single imaginary vibrational mode, intrinsic reaction coordinate analysis of which links the
D
4h
isomer directly to the
D
4d
forms, which are produced by rotation around the W-W bond by ±45°. It is therefore concluded that the gas-phase transition state becomes a minimum on the potential energy surface when subjected to crystal packing in the solid-state.
The
D
4h
isomer of (OC)
5
W-W(CO)
5
2−
is a gas-phase transition state that becomes a true minimum in the solid state.
Display omitted
•Cp*Fe(Me2PCH2CH2PMe2)(CO)BArF24 is synthesised using a new methodology.•Reduction with NaHBEt3 results in Cp*Fe(dmpe)(CHO) and (η4-C5Me5H)Fe(dmpe)(CO).•Hydride shuttling between ...these powerful hydride donors is mediated by BEt3.
Cp*Fe(Me2PCH2CH2PMe2)(CO)+ BArF24− has been synthesised and characterised using single crystal X-ray diffraction, NMR and IR spectroscopies. Reduction of the CO ligand using NaEt3BH produces the corresponding neutral formyl complex Cp*Fe(Me2PCH2CH2PMe2)(CHO), that is very thermally stable, and which is attributed to the electron-releasing properties of the spectator ligands. This compound is a potent hydride donor which exists in equilibrium with Et3BH−, Et3B, and the structural isomer (η4-C5Me5H)Cp*Fe(Me2PCH2CH2PMe2)(CO), resulting from reversible hydride migration to the Cp* ligand.
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. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100–125 mg/m
2
IV days 1, 8, 15, 22) and UCN-01 (70 mg/m
2
IV day 2, 35 mg/m
2
day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1
S296
on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in
TP53
(53 %). Median overall survival in patients with
TP53
mutant tumors was poor compared to wild type (5.5 vs. 20.3 months,
p
= 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01.
TP53
mutations were associated with a poor prognosis in metastatic TNBC.
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