Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Ultrastable Gold Nanoparticles Modified by Bidentate N-Heterocyclic Carbene Ligands.

Highly stable gold nanoparticles (Au NPs) functionalized by bidentate N-heterocyclic carbene (NHC) ligands have been synthesized by top-down and bottom-up approaches. A detailed study of the effect of alkylation, denticity, and method of synthesis has led to the production of NHC-stabilized nanoparticles with higher thermal stability than bi- and tridentate thiol-protected Au NPs and than monodentate NHC-stabilized NPs. Importantly, bidentate NHC-protected NPs also displayed unprecedented stability to external thiol, which has been an unsolved problem to date with all nanoparticles. Thus, multidentate NHC ligands are an important, and as yet unrecognized, step forward for the preparation of high stability nanomaterials.

Elucidation of the resting state of a rhodium NNN-pincer hydrogenation catalyst that features a remarkably upfield hydride (1)H NMR chemical shift.

Rhodium(I) alkene complexes of an NNN-pincer ligand catalyze the hydrogenation of alkenes, including ethylene. The terminal or resting state of the catalyst, which exhibits an unprecedentedly upfield Rh-hydride (1)H NMR chemical shift, has been isolated and a synthetic cycle for regenerating the catalytically active species has been established.

Differences in the cyclometalation reactivity of bisphosphinimine-supported organo-rare earth complexes.

The pyrrole-based ligand N,N'-((1H-pyrrole-2,5-diyl)bis(diphenylphosphoranylylidene))bis(4-isopropylaniline) (HL(B)) can be deprotonated and coordinated to yttrium and samarium ions upon reaction with their respective trialkyl precursors. In the case of yttrium, the resulting complex [L(B)Y(CH2SiMe3)2] (1) is a Lewis base-free monomer that is remarkably resistant to cyclometalation. Conversely, the analogous samarium complex [L(B)Sm(CH2SiMe3)2] is dramatically more reactive and undergoes rapid orthometalation of one phosphinimine aryl substituent, generating an unusual 4-membered azasamaracyclic THF adduct [κ(4)-L(B)Sm(CH2SiMe3)(THF)2] (2). This species undergoes further transformation in solution to generate a new dinuclear species that features unique carbon and nitrogen bridging units [κ(1):κ(2):µ(2)-L(B)Sm(THF)]2 (3). Alternatively, if 2 is intercepted by a second equivalent of HL(B), the doubly-ligated samarium complex [(κ(4)-L(B))L(B)Sm] (4) forms.

Carbene-anchored/pendent-imidazolium species as precursors to di-N-heterocyclic carbene-bridged mixed-metal complexes.

Reaction of a series of linked diimidazolium dibromide salts with one-half equivalent of [Rh(mu-OAc)(COD)](2) under reflux conditions generates a series of carbene-anchored/pendent-imidazolium complexes, [RhBr(COD)((R)C(H)-eta(1)-C(eth))][Br] ((Me)C(H)-eta(1)-C(eth) = ethylene[(N-methyl)imidazolium][(N-methyl)imidazole-2-ylidene] and (tBu)C(H)-eta(1)-C(eth) = ethylene[(N-tert-butyl)imidazolium][(N-tert-butyl)imidazole-2-ylidene]) via deprotonation of one end of the diimidazolium salt and coordination of the resulting carbene to Rh. Reaction of these complexes with carbon monoxide or the appropriate diphosphine yields either [RhBr(CO)(2)((R)C(H)-eta(1)-C(eth))][Br] (R = Me, (t)Bu) or [RhBr(P( intersection)P)((Me)C(H)-eta(1)-C(eth))][Br] (P( intersection)P = Ph(2)PCH(2)PPh(2), Ph(2)PCH(2)CH(2)PPh(2), Et(2)PCH(2)PEt(2)), respectively. The resulting diphosphine complexes readily decompose in solution. A series of palladium complexes [PdI(3-n)(PR(3))(n)(L)][I](n) (n = 1,2) and [PdI(P( intersection)P)(L)][I](2) (L = (tBu)C(H)-eta(1)-C(meth), (tBu)C(H)-eta(1)-C(eth); (tBu)C(H)-eta(1)-C(meth) = methylene[(N-tert-butyl)imidazolium][(N-tert-butyl)imidazole-2-ylidene]), containing the linked NHC-imidazolium moiety, have also been prepared by reacting the triiodo complexes, [PdI(3)((tBu)C(H)-eta(1)-C(meth))] and [PdI(3)((tBu)C(H)-eta(1)-C(eth))] with several mono- and diphosphines. Attempts to generate mixed Rh/Pd complexes using Pd(OAc)(2) to deprotonate the pendent arm of several of the above carbene-anchored/pendent-imidazolium complexes of Rh have proven unsuccessful. However, a targeted di-NHC-bridged heterobimetallic complex [PdI(2)(PEt(3))(mu-(tBu)CC(meth))RhI(COD)] ((tBu) CC(meth) = 1,1'-methylene-3,3'-di-tert-butyldiimidazol-2,2'-diylidene) can be generated by deprotonation of the imidazolium group in [PdI(2)(PEt(3))((tBu)C(H)-eta(1)-C(meth))][I] using half an equivalent of [Rh(mu-OAc)(COD)](2). The X-ray structure determination of this Pd/Rh complex confirms the dicarbene-bridged formulation and shows a metal-metal separation of approximately 6.2 A. Reaction of this Rh/Pd complex with CO yields the corresponding dicarbonyl product [PdI(2)(PEt(3))(mu-(tBu)CC(meth))RhI(CO)(2)] via replacement of the COD ligand. The related dicarbene-bridged Ir/Rh complex [IrBr(COD)(mu-(tBu)CC(meth))RhBr(COD)] can be generated by reaction of [IrBr(COD)((tBu)C(H)-eta(1)-C(meth) )][Br] with [Rh(mu-OAc)(COD)](2), while the Pd/Ir complexes [PdI(2)(PR(3))(mu-(tBu)CC(meth))IrI(COD)] (PR(3) = PPh(3), PMe(2)Ph) can be generated by reaction of the monometallic [PdI(2)(PR(3))((tBu)C(H)-eta(1)-C(meth))][I] species with K[N(SiMe(3))(2)] in the presence of [Ir(mu-Cl)(COD)](2). The carbonyl analogues, [PdI(2)(PR(3))(mu-(tBu)CC(meth))IrI(CO)(2)], can be generated via a gentle purge of CO gas. These di-NHC-bridged heterobimetallic species represent some of the first examples of this class and are the first involving palladium.

Ethyl 6-methyl-4-[2-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)thio-phen-3-yl]-2-thioxo-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate.

A new Biginelli compound, C(18)H(25)BN(2)O(4)S(2), containing a boronate ester group was synthesized from a lithium bromide-catalysed reaction. The compound crystallizes with two independent mol-ecules in the asymmetric unit that differ mainly in the conformation of the ester functionality. The crystal structure is stabilized by inter-molecular N-H⋯O and N-H⋯S hydrogen bonds involving the 3,4-dihydro-pyrimidine-2(1H)-thione NH groups as donors and the carbonyl O and thio-phene S atoms as acceptors.