BH3

Reactivity of (triphosphine)MoIV-nitrido complex generated by N2 splitting, toward boranes is reported. The simple adduct Mo≡N→BH3 is observed with BH3.SMe2 while 1,2 addition is evidenced with 9-BBN leading to H-Mo=NBR2. A second addition of BH3.SMe2 is facile and forms an unprecedented complex featuring two bridging H between two B and the Mo centers. Addition of PMe3 or BH3.SMe2 promotes reductive elimination and N-H bond formation. The full sequence of functionalization at Mo≡N obtained after N2 splitting is therefore evidenced in this work...

The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma). Metabolomics and isotope tracing showed that p53 loss did not drive a common metabolic signature. Instead, cell lines segregated according to cell of origin...

Venetoclax is a Bcl-2 homology domain 3 (BH3) mimetic currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) that has proven to be highly effective in reinstating apoptosis in leukemic cells through the highly selective inhibition of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). Clinically, venetoclax has provided lasting remissions through the inhibition of CLL and AML blasts. However, this activity has often come at the cost of grade III/IV neutropenia due to hematopoietic cells' dependence on Bcl-2 for survival...

This work focuses on the comparison of H2 evolution in the hydrolysis of boron-containing hydrides (NaBH4 , NH3 BH3 , and (CH2 NH2 BH3 )2 ) over the Co metal catalyst and the Co3 O4 -based catalysts. The Co3 O4 catalysts were activated in the reaction medium, and a small amount of CuO was added to activate Co3 O4 under the action of weaker reducers (NH3 BH3 , (CH2 NH2 BH3 )2 ). The high activity of Co3 O4 has been previously associated with its reduced states (nanosized CoBn ). The performed DFT modeling shows that activating water on the metal-like surface requires overcoming a higher energy barrier compared to hydride activation...

TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment...

Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells...

INTRODUCTION: BCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells. METHODS: Co-cultures employing HS5 stromal cells were used to model the interaction with stroma...

The detailed mechanism of transition metal-free-catalyzed monomethylation of 2-naphthyl acetonitrile ( 1a ) with CO2 in the presence of triazabicyclodecene (TBD) and BH3 NMe3 was investigated using density functional theory. The C-methylation process proved to generate formaldehyde followed by the formation of the product via an alcohol rather than a methoxyborane intermediate. During the reaction, CO2 is activated to form the TBD-CO 2 adduct and BH3 NMe3 is changed into TBD-BH 2 ( IM2 ) in the presence of TBD...

BH3-mimetics represent promising anti-cancer agents in tumors that rely on the anti-apoptotic function of B-Cell Lymphoma 2 (BCL2) proteins, particularly in leukemia and lymphoma cells primed for apoptosis. Mechanistically, BH3-mimetics may displace pro-apoptotic binding partners thus inducing BAX/BAK-mediated mitochondrial permeabilization followed by cytochrome c release, activation of the caspase cascade and apoptosis. Here, we describe a novel mode of caspase-independent cell death (CICD) induced by BH3-mimetics in a subset of diffuse large B-cell lymphoma (DLBCL) cells...

A systematic theoretical study was conducted on the triel bonds (TrB) within the BH3 ∙∙∙M(MDA)2 and C5 H4 BX∙∙∙M(MDA)2 (M = Ni, Pd, Pt, X = H, CN, F, CH3 , NH2 , MDA = enolated malondialdehyde) complexes, with BH3 and C5 H4 BX acting as the electron acceptors and the square-coordinated M(MDA)2 acting as the electron donor. The interaction energies of these systems range between -4.71 and -33.18 kcal/mol. The larger the transition metal center M, the greater the enhancement of the TrB, with σ-hole TrBs found to be stronger than π-hole TrBs...

In the last few years, several agents targeting molecules that sustain the survival and the proliferation of chronic lymphocytic leukemia (CLL) cells have become clinically available. Most of these drugs target surface proteins, such as CD19 or CD20, via monoclonal or bispecific monoclonal antibodies (BsAbs), CAR T cells, intracellular proteins like BTK by using covalent or non-covalent inhibitors or BCL2 with first or second generation BH3-mimetics. Since the management of CLL is evolving quickly, in this review we highlighted the most important innovative treatments including novel double and triple combination therapies, CAR T cells and BsAbs for CLL...

A series of two-dimensional (2D) spin-crossover coordination polymers (SCO-CPs) [FeII (TPE)(NCX)2 ]·solv (1: X = BH3 , solv = H2 O·2CH3 OH·DMF; 2: X = Se, solv = H2 O·2CH3 OH·0.5DMF; 3: X = S, solv = H2 O·2CH3 OH·0.5DMF) were synthesized by employing 1,1,2,2-tetra(pyridin-4-yl)ethene (TPE) and pseudohalide (NCX- ) coligands. Magnetic measurements indicated that complexes 1-3 exhibited SCO behaviors with diminishing thermal hysteresis (7/4/0 K) upon decreasing the ligand-field strength...

In this study, we devised a new method to predict facial selectivity by quantifying steric and orbital factors for the nucleophile approaching both π-plane faces. Using this method, we quantified the total electron density and frontier orbital distributions of 163 cyclic ketones with various structures and quantitatively explained the surface selectivity of 323 reactions with eight nucleophiles (BH3 , LiAlH4 , NaBH4 , LiAl(OMe)3 H, MeLi, MeMgI, PhLi, and PnMgI). Importance analysis showed a large orbital effect for BH3 , LiAlH4 , and NaBH4 and the dominance of the steric effect for LiAl(OMe)3 H, MeLi, MeMgI, PhLi, and PhMgI...

We have developed an efficient and versatile approach for the synthesis of a family of 1,2,3-triazole-based mesoionic N-heterocyclic olefin (mNHO) ligands and investigated their coordination to palladium, gold, and boron hydride experimentally and computationally. We reacted mNHOs obtained through deprotonation of the corresponding methylated and ethylated 1,3,4-triaryl-1,2,3-triazolium salts with [Pd(allyl)Cl]2 to give the corresponding [Pd(η3 -allyl)Cl(mNHO)] coordination complexes. 13 C NMR data revealed the strong σ-donor character of the mNHO ligands, consistent with the calculated bond orders and atom-condensed charges...

Apoptosis, programmed cell death pathway, is a vital physiological mechanism that ensures cellular homeostasis and overall cellular well-being. In the context of cancer, where evasion of apoptosis is a hallmark, the overexpression of anti-apoptotic proteins like Bcl2, Bcl-XL, and Mcl-1 has been documented. Consequently, these proteins have emerged as promising targets for therapeutic interventions. The BCL-2 protein family is central to apoptosis and plays a significant importance in determining cellular fate serving as a critical determinant in this biological process...

BAX and BAK are pro-apoptotic members of the BCL2 family that are required to permeabilize the mitochondrial outer membrane. The proteins can adopt a non-activated monomeric conformation, or an activated conformation in which the exposed BH3 domain facilitates binding either to a prosurvival protein or to another activated BAK or BAX protein to promote pore formation. Certain cancer cells are proposed to have high levels of activated BAK sequestered by MCL1 or BCLXL , thus priming these cells to undergo apoptosis in response to BH3 mimetic compounds that target MCL1 or BCLXL ...

The reduction mechanism of aldehyde/ketones with M(BH4 ) n is not fully understood, even though the hydroboration mechanism of weak Lewis base borane complexes is known to involve a four-membered ring transition state. Herein, the reduction mechanism of M(BH4 ) n in aprotic solvents has been elucidated for a six-membered ring, in which hydride transfer to the C atom from the B atom, formation of an L·BH3 adduct, and disproportionation of (BH3 (OR)- ) borane are involved. The metal cations and solvents participate in and significantly influence the reaction procedure...

Half-sandwich zirconium(IV) and hafnium(IV) complexes with amidoborane and hydride ligands have been isolated in the stoichiometric reactions of mono(pentamethylcyclopentadienyl)metal alkyl and amido derivatives with the amine-boranes NHR2 BH3 (R2 = H2 , Me2 , H t Bu). Treatment of the tris(trimethylsilylmethyl) complexes [M(η5 -C5 Me5 )(CH2 SiMe3 )3 ] with NH3 BH3 (3 equiv) gives the seven-coordinate species [M(η5 -C5 Me5 )(NH2 BH3 )3 ] (M = Zr ( 1 ), Hf ( 2 )) with three κ2 N,H -NH2 BH3 ligands...

The attempted synthesis of [{Carb}BaPPh2 ] (1) showed this barium-phosphide and its thf adducts, 1·thf and 1·(thf)2 , to be unstable in solution. Our strategy to circumvent the fragility of these compounds involved the use of phosphinoboranes HPPh2 ·BH3 and HPPh2 ·B(C6 F5 )3 instead of HPPh2 . This allowed for the synthesis of [{Carb}Ae{PPh2 ·BH3 }] (Ae = Ba, 2; Ca, 3), [{Carb}Ca{(H3 B)2 PPh2 }·(thf)] (4), [{Carb}Ba{PPh2 ·B(C6 F5 )3 }] (5), [{Carb}Ba{O(B(C6 F5 )3 )CH2 CH2 CH2 CH2 PPh2 }·thf] (6), [Ba{O(B(C6 F5 )3 )CH2 CH2 CH2 CH2 PPh2 }2 ·(thf)1...

Borane-amines have garnered attention over the last several decades in a variety of applications, ranging from hydrogen storage materials to hypergolic fuel systems. An investigation into the synthesis of borane-amines with high-nitrogen content heterocycles was undertaken in this work. Borane-amines were formed by the reaction of BH3 ·Me2 S in tetrahydrofuran (THF) with the requisite nitrogen-containing heterocycle and isolated by placing the crude reaction mixture in hexanes to precipitate the product...