Neutral and Cationic Rare Earth Metal Alkyl and Benzyl Compounds with the 1,4,6-Trimethyl-6-pyrrolidin-1-yl-1,4-diazepane Ligand and Their Performance in the Catalytic Hydroamination/Cyclization of Aminoalkenes

A new neutral tridentate 1,4,6-trimethyl-6-pyrrolidin-1-yl-1,4-diazepane (L) was prepared. Reacting L with trialkyls M(CH2SiMe3)3(THF)2 (M = Sc, Y) and tribenzyls M(CH2Ph)3(THF)3 (M = Sc, La) yielded trialkyl complexes (L)M(CH2SiMe3)3 (M = Sc, 1; M = Y, 2) and tribenzyl complexes (L)M(CH2Ph)3 (M = Sc, 3; M = La, 4). Complexes 1 and 2 can be converted to their corresponding ionic compounds [(L)M(CH2SiMe3)2(THF)][B(C6H5)4] (M = Sc, Y) by reaction with [PhNMe2H][B(C6H5)4] in THF. Complexes 3 and 4 can be converted to cationic species [(L)M(CH2Ph)2]+ by reaction with [PhNMe2H][B(C6F5)4] in C6D5Br in the absence of THF. The neutral complexes 1-4 and their cationic derivatives were studied as catalysts for the hydroamination/cyclization of 2,2-diphenylpent-4-en-1-amine and N-methylpent-4-en-1-amine reference substrates and compared with ligand-free Sc, Y, and La neutral and cationic catalysts. The most effective catalysts in the series were the cationic L-yttrium catalyst (for 2,2-diphenylpent-4-en-1-amine) and the cationic lanthanum systems (for N-methylpent-4-en-1-amine). For the La catalysts, evidence was obtained for release of L from the metal during catalysis.

Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity

BH3-only proteins are dispensable for apoptosis induced by pharmacological inhibition of both MCL-1 and BCL-XL.

The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines. Furthermore, S63845 synergizes with other BH3 mimetics to induce apoptosis in cell lines derived from both hematological and solid tumors. Although the anti-apoptotic BCL-2 family members in these cell lines interact with a spectrum of pro-apoptotic BH3-only proteins to regulate apoptosis, these interactions alone do not explain the relative sensitivities of these cell lines to BH3 mimetic-induced apoptosis. These findings necessitated further investigation into the requirement of BH3-only proteins in BH3 mimetic-mediated apoptosis. Concurrent inhibition of BCL-XL and MCL-1 by BH3 mimetics in colorectal HCT116 cells induced apoptosis in a BAX- but not BAK-dependent manner. Remarkably this apoptosis was independent of all known BH3-only proteins. Although BH3-only proteins were required for apoptosis induced as a result of BCL-XL inhibition, this requirement was overcome when both BCL-XL and MCL-1 were inhibited, implicating distinct mechanisms by which different anti-apoptotic BCL-2 family members may regulate apoptosis in cancer

Comment on "Craze growth and craze interactions"

SCOPUS: ar.jinfo:eu-repo/semantics/publishe