A5050805316- Cell death mechanisms and regulation
- Crystallization and Solubility Studies
- Synthetic Organic Chemistry Methods
- X-ray Diffraction in Crystallography
- Asymmetric Synthesis and Catalysis
- Computational Drug Discovery Methods
- Extraction and Separation Processes
- Ubiquitin and proteasome pathways
- Metal complexes synthesis and properties
- Cancer therapeutics and mechanisms
- Metal-Catalyzed Oxygenation Mechanisms
- Radioactive element chemistry and processing
- Lanthanide and Transition Metal Complexes
- Marine Sponges and Natural Products
- Oxidative Organic Chemistry Reactions
- Nitric Oxide and Endothelin Effects
- Microbial Natural Products and Biosynthesis
- Lubricants and Their Additives
- Advanced Synthetic Organic Chemistry
- Space exploration and regulation
- Acute Lymphoblastic Leukemia research
- Chronic Lymphocytic Leukemia Research
- Chemical synthesis and alkaloids
- Protein Structure and Dynamics
- Fluorine in Organic Chemistry
Waikato Institute of Technology
2024
Granta Design (United Kingdom)
2019-2023
University of Edinburgh
1925-2011
University of Cambridge
2000-2009
Hannah Research Foundation
2006
Edinburgh Cancer Research
2006
Western General Hospital
2006
University of Strathclyde
2005
Wokingham Hospital
2004
Purdue University West Lafayette
2003
We report structure−activity relationships for organometallic RuII complexes of the type [(η6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- β-diketonate) chelating ligand, arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z usually PF6. The X-ray structures 13 are reported. All have characteristic “piano-stool” geometry. most active toward A2780 human ovarian cancer cells contained = ethylenediamine (en) extended arenes....
Abstract The aqua adducts of the anticancer complexes [(η 6 ‐X)Ru(en)Cl][PF ] (X=biphenyl (Bip) 1, X=5,8,9,10‐tetrahydroanthracene (THA) 2, X=9,10‐dihydroanthracene (DHA) 3; en=ethylenediamime) were separated by HPLC and characterised mass spectrometry as products hydrolysis in water. X‐ray structures ‐X)Ru(en)Y][PF n , X=Bip, Y=0.5 H 2 O/0.5 OH, =1.5 ( 4 ), X=THA, 5 A Y=H O, =2 B X=DHA, are reported. In complex there is a large propeller twist 45° pendant phenyl ring with respect to...
Escape from apoptosis is one of the major hallmarks cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators apoptotic process. Overexpression pro-survival member BCL-2 a well-established mechanism contributing to oncogenesis chemoresistance in several cancers, including lymphoma leukemia. Thus, has become an attractive target for therapeutic strategy cancer, as demonstrated by recent approval ABT-199 (Venclexta™)...
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is antiapoptotic member of the Bcl-2 family proteins, whose upregulation in human cancers associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report discovery our clinical candidate S64315, a selective small molecule inhibitor Mcl-1. Starting from fragment derived lead compound, have conducted structure guided optimization that led significant (3 log) improvement...
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as attractive target for cancer therapy. Here, we report discovery selective small molecule inhibitors Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids promising but nonselective hits were optimized using nuclear...
We describe our work to establish structure- and fragment-based drug discovery identify small molecules that inhibit the anti-apoptotic activity of proteins Mcl-1 Bcl-2. This identified hit series compounds, some which were subsequently optimized clinical candidates in trials for treating various cancers. Many protein constructs designed with suitable properties different biophysical assays structural methods. Fragment screening using ligand-observed NMR experiments several compounds each...
// Patrick Casara 1, * , James Davidson 2, Audrey Claperon 3, Gaëtane Le Toumelin-Braizat 3 Meike Vogler 4 Alain Bruno 5 Maïa Chanrion Gaëlle Lysiak-Auvity Thierry Diguarher 1 Jérôme-Benoît Starck Ijen Chen 2 Neil Whitehead Christopher Graham Natalia Matassova Pawel Dokurno Pedder Youzhen Wang 6 Shumei Qiu Anne-Marie Girard Emilie Schneider Fabienne Gravé Aurélie Studeny Ghislaine Guasconi Francesca Rocchetti Sophie Maïga 7 Jean-Michel...
The reaction of [Mn3O(OAc)6(py)3] with 1,1,1-tris(hydroxymethyl)ethane (H3thme) gives the Mn(IV)3Mn(III)4Mn(II)2 complex [Mn9O7(OAc)11(thme)(py)3(H2O)2], which has an S = 17/2 ground state and displays strong out-of-phase signals in ac susceptibility studies that establish it as a new class single-molecule magnet.
Fragment merging is a promising approach to progressing fragments directly on-scale potency: each designed compound incorporates the structural motifs of overlapping in way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful quickly and cheaply identify such merges circumvents challenge synthetic accessibility, provided they can be readily identified. Here, we demonstrate Network, graph database novel explore chemical...
Atropisomersm is an emerging feature in recent drug candidates due to the increasing complexity of targeted protein surfaces. The developability requires that their atropisomer interconversion either fast or very slow at ambient temperature therefore understanding and predictability isomerization rate great importance. Through a series selective MCL‐1 inhibitors we studied how structural features influence atropisomers. Besides basic observations such as stability solution, also carried out...
3-Dialkylaminomethyl substituted salicylaldoximes are efficient metal salt extractants, and, in contrast to related "salen"-based reagents, sufficiently stable acid hydrolysis allow commercial application base recovery. Crystal structures show that salts bound by a zwitterionic form of the with copper(II) nitrate, tetrafluoroborate and trifluoroacetate forming [Cu()(2)X(2)] assemblies tritopic arrangement trans-disposition anions outwith coordination sphere. Copper(II) chloride, bromide...
Attaching dialkylaminomethyl arms to commercial phenolic oxime copper extractants yields reagents which transport base metal salts very efficiently by forming neutral 1 ∶ or 2 complexes with zwitterionic forms of the ligands.
Over the past decade intrinsically disordered proteins (IDPs) have emerged as a biologically important class of proteins, many which are therapeutic relevance. Here, we investigated interactions between model IDP system, tau K18, and nine literature compounds that been reported having an effect on in order to identify robust IDP–ligand system for optimization range biophysical methods. We used NMR, surface plasmon resonance (SPR) microscale thermophoresis (MST) methods investigate binding...
Hexadentate tris-salicylaldimine ligands bearing ortho-N-dialkylaminomethyl substituents have been shown to function as ditopic for NiSO4 or NiCl2. The incorporation of the Ni-ion into N3O33− site templates pendant alkylammonium groups allow them hydrogen bond attendant anion(s). Formulation complexes trianionic/tricationic ligand is supported by X-ray structure determinations solvated forms [Ni(L)SO4] and [Ni(L)Cl]Cl, where L =...
Abstract Mcl-1 is highly expressed in a variety of human cancers (including those hematopoietic and lymphoid origin) exploited by cancer cells to evade cell death develop resistance diverse chemotherapeutic agents. We disclose, for the first time, structure S64315 (also named MIK665) potent selective inhibitor with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 currently phase 1 AML (Acute Myeloid Leukemia) MDS (Myelodysplastic Syndrome) (EudraCT...
This paper reports the synthesis of sulphate extractants, N,N′-bis-(2-dibutylamino-ethyl)-isophthalamide (1), pyridine-2,6-dicarboxylic acid bis-[(2-dibutylamino-ethyl)-amide] (2) and 3,4-diphenyl-1H-pyrrole-2,5-dicarboxylic (3), demonstrates that, in combination with a commercially available oxime extractant 2-hydroxy-5-nonyl benzaldehyde (P50), these dual host systems are better extractants for nickel(II) than metal salt extractant, 5-nonyl-3-dihexylaminomethyl-2-hydroxy-benzaldehyde (4).
Abstract The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis chemoresistance in several cancers, including lymphoma leukemia. Venetoclax (Venclexta™), selective inhibitor, first new class anti-cancer drugs, called BH3 mimetics, be approved for CLL AML. Here, we describe identification novel potent...