1,2‐Bis(dialkylphosphino)ethanes are readily prepared from the parent phosphine oxides, via 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.
Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic ...profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.
This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.
Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided.
Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease.
MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented.
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.
·H
BArF4
represents a rare example of a well-defined, open-shell, non-classical dihydrogen complex, as corroborated by ESR spectroscopy. The rapid exchange between N
and H
coordination under ambient conditions is unique for a paramagnetic Fe complex.
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.
The synthesis and characterisation of the S = 1/2 Fe(i) complex Fe(depe)2+BAr4F− (1+BAr4F−), and the facile reversible binding of N2 and H2 in both solution and the solid state to form the adducts ...1·N2+ and 1·H2+, are reported. Coordination of N2 in THF is thermodynamically favourable under ambient conditions (1 atm; ΔG298 = −4.9(1) kcal mol−1), while heterogenous binding is more favourable for H2 than N2 by a factor of ∼300. 1·H2+BAr4F− represents a rare example of a well-defined, open-shell, non-classical dihydrogen complex, as corroborated by ESR spectroscopy. The rapid exchange between N2 and H2 coordination under ambient conditions is unique for a paramagnetic 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 N
H
production. Herein we ...report that the simple Fe(0) complex Fe(Et
PCH
CH
PEt
)
(N
) (1) is an efficient catalyst for the selective conversion of N
(>25 molecules N
fixed) into N
H
, attendant with the production of ca. one molecule of NH
. Notably, the reductant (CoCp*
) and acid (Ph
NH
OTf) used are considerably weaker than conventional chemical H
and e
sources used in previous demonstrations of N
turnover by synthetic Fe compounds. These results show that the direct catalytic conversion of N
to the hydrazine oxidation state on molecular Fe complexes is viable and that the mechanism of NH
formation by such systems may proceed via Fe-N
H
intermediates.
Although reductive cleavage of dinitrogen (N2) to nitride (N3−) and hydrogenation with dihydrogen (H2) to yield ammonia (NH3) 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 N2 to give a dinitride dititanium dimagnesium ditriamidoamine complex. Tandem H2 splitting by a phosphine–borane frustrated Lewis pair (FLP) shuttles H atoms to the N3−, evolving NH3. Isotope labelling experiments confirmed N2 and H2 fixation. Though not yet catalytic, these results give unprecedented insight into coupling N2 and H2 cleavage and N−H bond formation steps together, highlight the importance of heterobimetallic cooperativity in N2 activation, and establish FLPs in NH3 synthesis.
Die Reaktion eines Chlortitantriamidoamin‐Komplexes mit Magnesium ermöglicht die vollständige reduktive Spaltung von N2 und ergibt einen Dinitrid‐Dititan/Dimagnesium‐Komplex (siehe Schema, Mitte). Durch eine gekoppelte H2‐Spaltung mit einem Phosphin/Boran‐basierten frustrierten Lewis‐Paar werden H‐Atome auf das N3−‐Ion übertragen und NH3 wird freigesetzt.
Despite there being numerous examples of f‐element compounds supported by cyclopentadienyl, arene, cycloheptatrienyl, and cyclooctatetraenyl ligands (C5–8), cyclobutadienyl (C4) complexes remain ...exceedingly rare. Here, we report that reaction of Li2{C4(SiMe3)4}(THF)2 (1) with U(BH4)3(THF)2 (2) gives the pianostool complex U{C4(SiMe3)4}(BH4)3Li(THF)4 (3), where use of a borohydride and preformed C4‐unit circumvents difficulties in product isolation and closing a C4‐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. The U−C distances are short (av. 2.513 Å), reflecting the formal 2− charge of the C4‐unit, and the SiMe3 groups are displaced from the C4‐plane, which we propose maximises U−C4 orbital overlap. DFT calculations identify two quasi‐degenerate U−C4 π‐bonds utilising the ψ2 and ψ3 molecular orbitals of the C4‐unit, but the potential δ‐bond using the ψ4 orbital is vacant.
Klavierstuhlkomplex: Das erste Beispiel eines Halbsandwich‐Cyclobutadienylkomplexes eines f‐Elements wird beschrieben, das zugleich erst das zweite Beispiel eines Actinoid‐Cyclobutadienylkomplexes ist. DFT‐Rechnungen zufolge dominiert eine U‐C‐π‐Bindung, ohne δ‐Bindungsanteil.
Catalytic reduction of N2 to NH3 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 NH3 by N2 reduction and protonolysis under homogeneous, abiological conditions. Reduction of TiIV(TrenTMS)X (X=Cl, 1A; I, 1B; TrenTMS=N(CH2CH2NSiMe3)3) with KC8 affords TiIII(TrenTMS) (2). Addition of N2 affords {(TrenTMS)TiIII}2(μ‐η1:η1‐N2) (3); further reduction with KC8 gives {(TrenTMS)TiIV}2(μ‐η1:η1:η2:η2‐N2K2) (4). Addition of benzo‐15‐crown‐5 ether (B15C5) to 4 affords {(TrenTMS)TiIV}2(μ‐η1:η1‐N2)K(B15C5)22 (5). Complexes 3–5 treated under N2 with KC8 and R3PHI, (the weakest H+ source yet used in N2 reduction) produce up to 18 equiv of NH3 with only trace N2H4. When only acid is present, N2H4 is the dominant product, suggesting successive protonation produces {(TrenTMS)TiIV}2(μ‐η1:η1‐N2H4)I2, and that extruded N2H4 reacts further with R3PHI/KC8 to form NH3.
Besser früh als nie: Die katalytische Reduktion von N2 zu NH3 durch einen Ti‐Komplex ergänzt die kleine Gruppe mittlerer bis später d‐Block‐Metalle (Mo, Fe, Ru, Os, Co), die katalytisch NH3 durch N2‐Reduktion und Protonolyse unter homogenen, abiologischen Bedingungen produzieren, um ein frühes d‐Block‐Metall.
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