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https://www.readbyqxmd.com/read/29154478/on-the-dual-reactivity-of-a-nucleophilic-dihydrido-diborane-reaction-at-the-b-b-bond-and-or-the-b-h-bond
#1
Anna Widera, Elisabeth Kaifer, Hubert Wadepohl, Hans-Jörg Himmel
The electron-rich, double-base stabilized dihydrido-diborane(4) [HB(hpp)]2 (hpp = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidinate) combines two different, easily accessible reactive sites: the B-B and B-H bond. We hereby report two basically similar reactions of [HB(hpp)]2 with catecholborane and B-chlorocatecholborane unsuspectedly resulting in two different reactivities. While reaction of the diborane with two equivalents of HB(cat) proceeded under formation of a cationic triborane with a (3c2e) bond, [{HB(μ-hpp)}2(μ-BH2)]+, reaction with ClB(cat) led to hydride-chloride substitution yielding [ClB(hpp)]2...
November 20, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29153883/conformational-dynamics-and-free-energy-of-bhrf1-binding-to-bim-bh3
#2
Mauro Lapelosa
The interaction between the Bim BH3 peptide and the viral protein BHRF1 is pivotal to understanding the fundamental molecular details of the mechanism used by the Epstein-Barr virus to trick the mammalian immune system. Here, we study the mechanism of binding/unbinding and compute the free energy for the association of the Bim peptide to the BHRF1 protein. Key elements of the binding mechanism are the conformational rearrangement together with a main free energy barrier of 11.5kcal/mol. The simulations show complete unbinding and rebinding of the Bim peptide to BHRF1...
November 10, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/29149594/conversion-of-bim-bh3-from-activator-to-inhibitor-of-bak-through-structure-based-design
#3
Jason M Brouwer, Ping Lan, Angus D Cowan, Jonathan P Bernardini, Richard W Birkinshaw, Mark F van Delft, Brad E Sleebs, Adeline Y Robin, Ahmad Wardak, Iris K Tan, Boris Reljic, Erinna F Lee, W Douglas Fairlie, Melissa J Call, Brian J Smith, Grant Dewson, Guillaume Lessene, Peter M Colman, Peter E Czabotar
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29147534/nucleophilic-addition-and-substitution-at-coordinatively-saturated-boron-by-facile-1-2-hydrogen-shuttling-onto-a-carbene-donor
#4
Dominic Auerhammer, Merle Arrowsmith, Holger Braunschweig, Rian D Dewhurst, J Oscar C Jiménez-Halla, Thomas Kupfer
The reaction of [(cAAC(Me))BH3] (cAAC(Me) = 1-(2,6-(i)Pr2C6H3)-3,3,5,5-tetramethylpyrrolidin-2-ylidene) with a range of organolithium compounds led to the exclusive formation of the corresponding (dihydro)organoborates, Li(+)[(cAAC(Me)H)BH2R](-) (R = sp(3)-, sp(2)-, or sp-hybridised organic substituent), by migration of one boron-bound hydrogen atom to the adjacent carbene carbon of the cAAC ligand. A subsequent deprotonation/salt metathesis reaction with Me3SiCl or spontaneous LiH elimination yielded the neutral cAAC-supported mono(organo)boranes, [(cAAC(Me))BH2R]...
October 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29146569/found-in-translation-how-preclinical-research-is-guiding-the-clinical-development-of-the-bcl2-selective-inhibitor-venetoclax
#5
REVIEW
Joel D Leverson, Deepak Sampath, Andrew J Souers, Saul H Rosenberg, Wayne J Fairbrother, Martine Amiot, Marina Konopleva, Anthony Letai
Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax...
November 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29142404/chalepin-a-compound-from-ruta-angustifolia-l-pers-exhibits-cell-cycle-arrest-at-s-phase-suppresses-nuclear-factor-kappa-b-nf-%C3%AE%C2%BAb-pathway-signal-transducer-and-activation-of-transcription-3-stat3-phosphorylation-and-extrinsic-apoptotic-pathway-in-non-small-cell
#6
Jaime Stella Moses Richardson, Norhaniza Aminudin, Sri Nurestri Abd Malek
Background: Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. Objective: A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells...
October 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29141222/jnk-promotes-epithelial-cell-anoikis-by-transcriptional-and-post-translational-regulation-of-bh3-only-proteins
#7
Nomeda Girnius, Roger J Davis
Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29138795/hesperidin-induces-apoptosis-and-g0-g1-arrest-in-human-non-small-cell-lung-cancer-a549-cells
#8
Rongmu Xia, Xin Sheng, Xianlin Xu, Chunbo Yu, Hongling Lu
Lung cancer has high incidence and mortality rates worldwide. In the present study, the mechanisms by which hesperidin decreases the viability and induces the apoptosis of human non-small cell lung cancer (NSCLC) A549 cells were investigated. Initially, MTT and flow cytometric assays were performed to evaluate the effects of hesperidin on the viability and apoptosis of A549 cells and human normal lung epithelial BEAS-2B cells. The results revealed that hesperidin has no negative effects on the human normal lung epithelial BEAS-2B cells and the viability of cells treated with various concentrations of hesperidin was inhibited in a time- and dose-dependent manner compared with the control groups...
November 9, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29137527/binding-modes-of-bcl-2-homology-3-bh3-peptides-with-anti-apoptotic-protein-a1-and-redesign-of-peptide-inhibitors-a-computational-study
#9
Yantao Chen, Jun Wang, Jian Zhang, Wei Wang
The interaction between protein and peptide ligand is a challenging problem in molecular biology and drug design. The binding of the Bcl-2 homology 3 (BH3) peptide to the anti-apoptotic protein A1 was revealed as a critical step in the regulation of apoptosis. These BH3 peptides hold high structural similarity, but are diverse in their regulation abilities. Based on molecular simulations and MM-P(G)BSA methods, this work presented a detailed analysis on binding mechanism of the BH3 peptides derived from PUMA and BMF...
November 15, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29127189/autophagy-promotes-escape-from-phosphatidylinositol-3-kinase-inhibition-in-estrogen-receptor-positive-breast-cancer
#10
Wei Yang, Sarah R Hosford, Nicole A Traphagen, Kevin Shee, Eugene Demidenko, Stephanie Liu, Todd W Miller
Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER(+) breast cancer cells...
November 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29114584/expression-purification-and-characterization-of-hepatitis-b-virus-x-protein-bh3-like-motif-linker-bcl-xl-fusion-protein-for-structural-studies
#11
Hideki Kusunoki, Toshiyuki Tanaka, Toshiyuki Kohno, Hirokazu Kimura, Kazuo Hosoda, Kaori Wakamatsu, Isao Hamaguchi
Hepatitis B virus X protein (HBx) is a multifunctional protein that interacts directly with many host proteins. For example, HBx interacts with anti-apoptotic proteins, Bcl-2 and Bcl-xL, through its BH3-like motif, which leads to elevated cytosolic calcium levels, efficient viral DNA replication and the induction of apoptosis. To facilitate sample preparation and perform detailed structural characterization of the complex between HBx and Bcl-xL, we designed and purified a recombinant HBx BH3-like motif-linker-Bcl-xL fusion protein produced in E...
March 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/29112392/solid-versus-solution-spin-crossover-and-the-importance-of-the%C3%A2-%C3%A2-%C3%A2-%C3%A2-%C3%A2-%C3%A2-%C3%A2-fe-n%C3%A2-c-x-angle
#12
Santiago Rodríguez-Jiménez, Sally Brooker
A new family of mononuclear [Fe(II)(Rdpt)2(NCE)2] complexes (E = S, Se, or BH3) is formed by 1:2 reaction of [Fe(II)(pyridine)4(NCE)2] with the monotopic pyridyl triazole ligand 4-(4-methylphenyl)-3-(2-pyridinyl)-5-phenyl-4H-1,2,4-triazole (tolpyph). The three complexes are obtained as six different solvatomorphs: [Fe(II)(tolpyph)2(NCS)2]·H2O (1·H2O), 1·1.5CH3OH·0.5H2O, [Fe(II)(tolpyph)2(NCSe)2] (2), 2·1.5H2O, [Fe(II)(tolpyph)2(NCBH3)2] (3), and 3·H2O. Single-crystal X-ray diffraction reveals that 1·1...
November 7, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/29100606/bh3-only-protein-bim-an-emerging-target-in-chemotherapy
#13
REVIEW
Shatrunajay Shukla, Sugandh Saxena, Brijesh Kumar Singh, Poonam Kakkar
BH3-only proteins constitute major proportion of pro-apoptotic members of B-cell lymphoma 2 (Bcl-2) family of apoptotic regulatory proteins and participate in embryonic development, tissue homeostasis and immunity. Absence of BH3-only proteins contributes to autoimmune disorders and tumorigenesis. Bim (Bcl-2 Interacting Mediator of cell death), most important member of BH3-only proteins, shares a BH3-only domain (9-16 aa) among 4 domains (BH1-BH4) of Bcl-2 family proteins and highly pro-apoptotic in nature...
December 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29100409/overcoming-imatinib-resistance-conferred-by-the-bim-deletion-polymorphism-in-chronic-myeloid-leukemia-with-splice-switching-antisense-oligonucleotides
#14
Jun Liu, Malini Bhadra, Joanna Rajeswary Sinnakannu, Wan Lin Yue, Cheryl Weiqi Tan, Frank Rigo, S Tiong Ong, Xavier Roca
Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100321/bid-deficient-fish-delay-grass-carp-reovirus-gcrv-replication-and-attenuate-gcrv-triggered-apoptosis
#15
Libo He, Hao Wang, Lifei Luo, Yongming Li, Rong Huang, Lanjie Liao, Zuoyan Zhu, Yaping Wang
Bid, BH3-interacting domain death agonist, is a pro-apoptotic BH3-only member of Bcl-2 family, playing an important role in apoptosis. In the study, Bid genes from grass carp (Ctenopharyngodon idellus) and rare minnow (Gobiocypris rarus), named CiBid and GrBid, were cloned and analyzed. Bid was constitutively expressed in all examined tissues of grass carp, but the expression level varied in different tissues. Following grass carp reovirus (GCRV) stimulation in vivo, Bid and apoptosis related genes Caspase-9 and Caspase-3 was up-regulated significantly at the late stage of infection...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099483/the-bcl-2-arbiters-of-apoptosis-and-their-growing-role-as-cancer-targets
#16
REVIEW
Jerry M Adams, Suzanne Cory
Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These 'BH3 mimetic' drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies...
November 3, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29099481/viewing-bcl2-and-cell-death-control-from-an-evolutionary-perspective
#17
REVIEW
Andreas Strasser, David L Vaux
The last 30 years of studying BCL2 have brought cell death research into the molecular era, and revealed its relevance to human pathophysiology. Most, if not all metazoans use an evolutionarily conserved process for cellular self destruction that is controlled and implemented by proteins related to BCL2. We propose the anti-apoptotic BCL2-like and pro-apoptotic BH3-only members of the family arose through duplication and modification of genes for the pro-apoptotic multi-BH domain family members, such as BAX and BAK1...
November 3, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29077093/why-do-bcl-2-inhibitors-work-and-where-should-we-use-them-in-the-clinic
#18
REVIEW
Joan Montero, Antony Letai
Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells' readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade...
October 27, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29061914/therapeutics-targeting-bcl-2-in-hematological-malignancies
#19
REVIEW
Astrid Ruefli-Brasse, John C Reed
Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications...
October 23, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29053589/structural-and-functional-insight-into-canarypox-virus-cnp058-mediated-regulation-of-apoptosis
#20
Mohd Ishtiaq Anasir, Amy A Baxter, Ivan K H Poon, Mark D Hulett, Marc Kvansakul
Programmed cell death or apoptosis is an important component of host defense systems against viral infection. The B-cell lymphoma 2 (Bcl-2) proteins family is the main arbiter of mitochondrially mediated apoptosis, and viruses have evolved sequence and structural mimics of Bcl-2 to subvert premature host cell apoptosis in response to viral infection. The sequencing of the canarypox virus genome identified a putative pro-survival Bcl-2 protein, CNP058. However, a role in apoptosis inhibition for CNP058 has not been identified to date...
October 20, 2017: Viruses
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