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Let X, Y be Banach spaces, A : X ⟶ Y and B , C : Y ⟶ X be bounded linear operators satisfying operator equation A B A = A C A . In this paper, we show that the products AC and BA share the spectral properties such as Drazin invertibility, polaroidness and B-Fredholmness. As an application, we show that generalized Weyl's theorem holds for the Aluthge transform T ˜ of an algebraically ( n , k ) -quasiparanormal operator T. Also, Cline's formula for Drazin inverse in a ring with identity is established in the case when a b a = a c a , and in this case we establish Cline's formula for generalized Drazin inverse in the setting of Banach algebra.

For nonnegative integers \(n\) and \(k\), we introduce in this paper a new class of \((n,k)\)-quasi-\(*\)-paranormal operators satisfying $$\begin{aligned} ||T^{1+n}(T^{k}x)||^{1/(1+n)}||T^{k}x||^{n/(1+n)} \ge ||T^*(T^{k}x)|| \text { for all } x \in H. \end{aligned}$$ This class includes the class of \(n\)-\(*\)-paranormal operators and the class of \((1,k)\)-quasi-\(*\)-paranormal operators contains the class of \(k\)-quasi-\(*\)-class \(A\) operators. We study the basic properties of \((n,k)\)-quasi-\(*\)-paranormal operators, like relations of this new class of operators with other classes known in the literature, their matrix representation, and properties of their spectra.

A result due to Djordjevic shows that the accumulation points of the approximate point spectrum of an operator are invariant under commuting finite rank perturbations. In this paper, we extend it to power finite rank perturbations. Some applications to polaroid operators, a-polaroid operators, generalized Drazin spectrum, generalized Weyl’s theorem, generalized a-Weyl’s theorem, property and property are given.

In this note we obtain some characterizations of Banach spaces which are not isomorphic to any of their proper subspaces. In particular, we show that a Banach space X is not isomorphic to any of its proper subspaces if and only the equality σRD(LT) = σLD(T) holds for every bounded linear operator T on X if and only if int(σ(T)) ⊆ σLD(T) holds for every bounded linear operator T on X, where LT denotes the left multiplication operator by T.

Nanocomposites consisting of well-defined anatase TiO2 nanoparticles with an average diameter of 8 nm and multi-walled carbon nanotubes (MWCNTs) were fabricated by a facile two-step hydrothermal method using water as the main solvent, which is friendly to the environment and totally different from previous methods. The TiO2 nanoparticles were uniformly grafted on the surface of MWCNTs via intimate chemical bonds, which was beneficial for the enhancement of photocatalytic activity. The photocatalytic activities of as-prepared TiO2/MWCNT nanocomposites for degradation of rhodamine B under solar simulator illumination were investigated systemically. It was found that the photocatalytic activity of as-prepared TiO2/MWCNT nanocomposites was 7 times higher than that of pure TiO2 prepared via the same hydrothermal procedure. The enhancement was mainly due to the existence of MWCNTs, which could not only greatly improve the adsorption of rhodamine B, but also retard the recombination of photogenerated electron–hole pairs and absorb more light. The photocatalytic performance was further enhanced after being annealed at 400 °C and 500 °C for 1 h because of the improved crystallinity of anatase TiO2. Interestingly, the photocatalytic activities of samples annealed at 400 °C and 500 °C showed no difference, which was different from previous reports.

In this manuscript we present a novel, shape memory aerogel/epoxy composite structure composed of a reduced carbon nanotube and graphene compound aerogel as a scaffold and epoxy resin as a matrix. The composite was prepared via a vacuum infusion method and to the best of our knowledge it represents the first instance of a shape memory effect directly driven by an electrical field observable in polymer-infused conductive carbon scaffolds. Furthermore, the composite material obtained displays a high conductivity (i.e., up to 5.2 S m−1). In the manuscript it is shown that the composite's high conductivity can be attributed to the built-in 3D network of the thermally reduced graphene and carbon nanotube compound aerogel which displays high conductivity (16 S m−1) coupled with low density (6 mg mL−1). The composite material presented in this work is likely a suitable candidate for applications requiring polymer-infused conductive aerogels such as electromagnetic shielding, actuators and thermal sensors.

Thermally reduced graphene networks (TRGN) with low densities, less than 10 mg cm−3, were synthesized by thermal reduction of graphene oxide/poly(vinyl alcohol) networks. To evaluate the electromagnetic wave absorption properties of TRGN, TRGN were nondestructively backfilled with wax via a vacuum-assisted method. The as-prepared TRGN/wax composites, using integrated TRGN as fillers rather than directly dispersing graphene sheets in wax, exhibit better electromagnetic wave absorption capabilities because of the 3D conductive frameworks, which could generate more effective electrical loss in terms of dissipating the induced current in the TRGN/wax composites. Specifically, for the TRGN/wax composite with ∼1 wt% TRGN, the minimum reflection loss reaches −43.5 dB at 12.19 GHz with a thickness of 3.5 mm, and the bandwidth of reflection loss less than −10 dB (90% absorption) can reach up to 7.47 GHz. More importantly, our work provides a promising approach for constructing graphene-based composites with strong electromagnetic wave absorption ability at very low filler loadings.

A bounded linear operator $T$ acting on a Banach space $X$ satisfies property $(aBw)$, a strong version of a-Weyl's theorem, if the complement in the approximate point spectrum $\sigma_{a}(T)$ of the upper semi-B-Weyl spectrum $\sigma_{USBW}(T)$ is the set of all isolated points of approximate point spectrum which are eigenvalues of finite multiplicity. In this paper we investigate the property $(aBw)$ in connection with Weyl type theorems. In particular, we show that $T$ satisfies property $(aBw)$ if and only if $T$ satisfies a-Weyl's theorem and $\sigma_{USBW}(T)=\sigma_{USW}(T)$, where $\sigma_{USW}(T)$ is the upper semi-Weyl spectrum of $T$. The preservation of property $(aBw)$ is also studied under commuting nilpotent, quasi-nilpotent, power finite rank or Riesz perturbations. The theoretical results are illustrated by some concrete examples.

Utilization of oxygenated fuels has proven to be able to significantly control diesel engine exhaust emissions. Presented in this paper is a new oxygenated fuel di-(2-methoxypropyl) carbonate (DMPC), which was produced through transesterification reaction using dimethyl carbonate (DMC) and propylene glycol monomethyl ether (PGMME) as reactants as well as potassium hydroxide (KOH) as catalyst. Its structure characterization was completed through analyses with Fourier transform infrared (FT-IR), 1H nuclear magnetic resonance (NMR), and GC-MS analytical techniques. Further study was made about the effect of the oxygenate addition to diesel fuel on chemicophysical properties, combustion performances, and exhaust emissions characteristics. Experimental results displayed that the oxygenated fuel is mutually soluble with diesel fuel in any proportion at ambient temperature around 25 °C. With DMPC introduced to diesel fuel, kinematic viscosity decreases linearly, smoke point increases linearly, and flash point declines remarkably even under low content 5 vol %. Results of combustion test carried out on a single cylinder, DI diesel engine running at 1600 rpm and 2000 rpm showed that CO can be reduced by up to 60.0%, smoke can be lessened by up to 90.2%, while NOx increases by 4.4–14.0% as 15 vol % and 25 vol % of the oxygenate was added to a diesel fuel. Engine in-cylinder peak pressure increases somewhat and ignition delay duration becomes a little shorter. Both engine in-cylinder pressure rising rate and heat release rate increase noticeably during the premixed combustion.

The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Let X, Y be Banach spaces, A : X → Y and B , C : Y → X be bounded linear operators satisfying operator equation A B A = A C A . In this paper, we show that AC and BA share the local spectral properties such as Bishop's property (β), subscalarity and Dunford's property (C). Also, the quasi-nilpotent part and the analytic core for AC and BA are studied.

A MOSFET using a stress concentration (SC) structure to enhance the channel stress in strained MOSFETs is proposed. The nMOSFETs with gate length varying from 15 to 350 nm are simulated to investigate the effects of SC. For devices strained by tensile contact etching stop layer, over 12% driving current improvement better than that of conventional strained devices has been achieved. The method for introducing SC is effective for both short-and long-channel device.

Let X, Y be Banach spaces, and B, be bounded linear operators satisfying the operator equation . Recently, as extensions of Jacobson's lemma, Corach, Duggal and Harte studied common properties of and in algebraic viewpoint and also obtained some topological analogues. In this note, we continue to investigate common properties of AC and BA from the viewpoint of spectral theory. In particular, we give an affirmative answer to one question posed by Corach et al. by proving that has closed range if and only if has closed range.

In this note we give an answer to a question posed recently by Mecheri and Braha [Oper. Matrices 6 (2012), 725-734]. More precisely, we show that if T is n-perinormal, then the nonzero points λ of its approximate point spectrum and joint approximate point spectrum are identical; but this is not the case when λ = 0.

A three-space theorem for upper semi-Fredholmness (resp. lower semi-Fredholmness) is proved.

Motivated by a paper of Fang (2009), we study the Samuel multiplicity and the structure of essentially semi-regular operators on an infinite-dimensional complex Banach space. First, we generalize Fang’s results concerning Samuel multiplicity from semi-Fredholm operators to essentially semi-regular operators by elementary methods in operator theory. Second, we study the structure of essentially semi-regular operators. More precisely, we present a revised version of Fang’s 4 × 4 upper triangular model with a little modification, and prove it in detail after providing numerous preliminary results, some of which are inspired by Fang’s paper. At last, as some applications, we get the structure of semi-Fredholm operators which revised Fang’s 4 × 4 upper triangular model, from a different viewpoint, and characterize a semi-regular point λ ∈ ℂ in an essentially semi-regular domain.

Although the biosynthesis of artemisinin is unique to Artemisia annua L., the upstream pathway is ubiquitous among eukaryotes. Therefore, it should be possible to re-establish the downstream pathway for the de novo biosynthesis of artemisinin in eukaryotic microorganisms such as yeast. In the past decade, artemisinin biosynthetic genes have been cloned and introduced into yeast, resulting in the production of several artemisinin precursors including artemisinic acid and dihydroartemisinic acid. However, because of the lack of a suitable cellular environment, these artemisinin precursors failed to be converted into artemisinin. Consequently, A. annua remains the sole source of artemisinin and, therefore, there is a continuing need for research on the genetic improvement of A. annua germlines. Chinese scientists have obtained high-yielding transgenic A. annua plants or varieties using either the opening carbon flux strategy or the closing carbon flux strategy. These studies have shed light on the accelerated and sustainable production of artemisinin. In addition, the rate-limiting steps of artemisinin biosynthesis, particularly the final reaction mechanism, have been identified and characterized. This information is important to simulate the cellular environment in transgenic systems, to enable the successful production and accumulation of artemisinin. Together, these studies have paved the way towards a solution to the problem of limited artemisinin supply. Finally, we discuss the implications of patents for microorganisms that produce artemisinin precursors, and the ways in which China can avoid patent infringements.

In this paper we consider small essential spectral radius perturbations of operators with topological uniform descent—small essential spectral radius perturbations which cover compact, quasinilpotent and Riesz perturbations.

The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.

A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.

A 2-aminothiazole derivative 1 was developed as a potential inhibitor of the oncology target AKT, a serine/threonine kinase. When incubated in rat and human liver microsomes in the presence of NADPH, 1 underwent significant metabolic activation on its 2-aminothiazole ring, leading to substantial covalent protein binding. Upon addition of glutathione, covalent binding was reduced significantly, and multiple glutathione adducts were detected. Novel metabolites from the in vitro incubates were characterized by LC-MS and NMR to discern the mechanism of bioactivation. An in silico model was developed based on the proposed mechanism and was employed to predict bioactivation in 23 structural analogues. The predictions were confirmed empirically for the bioactivation liability, in vitro, by LC-MS methods screening for glutathione incorporation. New compounds were identified with a low propensity for bioactivation.

In this paper, new characterizations of the single valued extension property are given, for a bounded linear operator T acting on a Banach space and its adjoint T*, at Λ0 C in the case that Λ0 I - T is quasi-Fredholm. With the help of a classical perturbation result concerning operators with eventual topological uniform descent, we show the constancy of certain subspace valued mappings on the components of quasi-Fredholm resolvent set. As a consequence, we obtain a classification of these components.

Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

Quinobenzoxazine A-62176, developed from the antibacterial fluoroquinolones, is active in vitro andin vivo against murine and human tumors. It has been previously claimed that A-62176 is a catalytic inhibitor of mammalian topoisomerase II that does not stabilize the cleaved complex. However, at low drug concentrations and pH 6–7, we have found that A-62176 can enhance the formation of the cleaved complex at certain sites. Using a photocleavage assay, mismatched sequences, and competition experiments between psorospermin and A-62176, we pinpointed the drug binding site on the DNA base pairs between positions +1 and +2 relative to the cleaved phosphodiester bonds. A 2:2 quinobenzoxazine-Mg2+self-assembly model was previously proposed, in which one drug molecule intercalates into the DNA helix and the second drug molecule is externally bound, held to the first molecule and DNA by two Mg2+ bridges. The results of competition experiments between psorospermin and A-62176, as well as between psorospermin and A-62176 and norfloxacin, are consistent with this model and provide the first evidence that this 2:2 quinobenzoxazine-Mg2+ complex is assembled in the presence of topoisomerase II. These results also have parallel implications for the mode of binding of the quinolone antibiotics to the bacterial gyrase-DNA complex.

Psorospermin is a plant natural product that shows significant in vivo activity against P388 mouse leukemia. The molecular basis for this selectivity is unknown, although psorospermin has been demonstrated to intercalate into DNA and alkylate N7 of guanine. Significantly, the alkylation reactivity of psorospermin at specific sites on DNA increased 25-fold in the presence of topoisomerase II. In addition, psorospermin trapped the topoisomerase II-cleaved complex formation at the same site. These results imply that the efficacy of psorospermin is related to its interaction with the topoisomerase II–DNA complex. Because thermal treatment of (N7 guanine)–DNA adducts leads to DNA strand breakage, we were able to determine the site of alkylation of psorospermin within the topoisomerase II gate site and infer that intercalation takes place at the gate site between base pairs at the +1 and +2 positions. These results provide not only additional mechanistic information on the mode of action of the anticancer agent psorospermin but also structural insights into the design of an additional class of topoisomerase II poisons. Because the alkylation site for psorospermin in the presence of topoisomerase II can be assigned unambiguously and the intercalation site inferred, this drug is a useful probe for other topoisomerase poisons where the sites for interaction are less well defined.

Let $B(X, Y)$ denote the set of all bounded linear operators from Banach space $X$ to Banach space $Y$. In this paper, we introduce the concepts of left and right decomposably regular operators, left and right decomposably Fredholm operators in the setting of $B(X, Y)$, and the corresponding holomorphic versions in the setting of $B(X)$. By using Harte's techniques, we obtain various characterizations of these classes of operators. As the applications of these characterizations, we can compute the topological interiors and closures of them.

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.

An operator $T \in \mathcal{B}(X)$ defined on a Banach space $X$ satisfies property $(gb)$ if the complement in the approximate point spectrum $\sigma_{a}(T)$ of the upper semi-B-Weyl spectrum $\sigma_{SBF_{+}^{-}}(T)$ coincides with the set $\Pi(T)$ of all poles of the resolvent of $T$. In this note we continue to study property $(gb)$ and the stability of it, for a bounded linear operator $T$ acting on a Banach space, under perturbations by nilpotent operators, by finite rank operators, by quasi-nilpotent operators commuting with $T$. Two counterexamples show that property $(gb)$ in general is not preserved under commuting quasi-nilpotent perturbations or commuting finite rank perturbations., Comment: 10 pages

To try to find the ways to enhance the expression of ADS gene encoding amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis pathway catalyzing the formation of amorpha-4,11-diene from farnesyl diphosphate, and accelerate the artemisinin synthesis, the promoter of ADS was isolated and characterized.5' untranslated regions of ADS were isolated from Artemisia annua with PCR. For functional characterization, the isolated fragment was fused with GUS reporter gene and introduced into Nicotiana tabacum by Agrobacterium-mediated transformation. The GUS expression regulated by 5' untranslated regions of ADS in transgenic N. tabacum under the normal or stressed conditions were detected by histochemical staining and quantitative spectrophotometry assay.The 2 448 bp DNA fragment upstream of ADS coding sequence was isolated from A. annua and introduced into N. tabacum. Histochemical staining showed that the isolated fragment conferred stable GUS expression in transgenic plants. The quantitative results showed that the GUS activity in transgenic tobacco plants treated by low-temperature (4 degrees C) and ultraviolet irradiation were 1. 6 and 2.2 folds higher than that in the controls.It was suggested that the isolated fragment had promoter activity and maybe responsive to adverse environmental stresses.

Rhodium-catalyzed silylformylation and amidocarbonylation are applied to the syntheses of pyrrolizidine alkaloids, (±)-isoretronecanol and (±)-trachelanthamidine, from 5-ethynyl-2-pyrrolidinone.

Reactions of hydrosilanes with 1-hexyne catalyzed by Co 2 Rh 2 (CO) 12 , Rh 4 (CO) 12 , ( t BuNC) 4 RhCo(CO) 4 , and Rh(acac)(CO) 2 at 25°C and atmospheric pressure to 10 atm of carbon monoxide give (Z)-1-silyl-2-formyl-1-hexenes ( 1 ), which are the products of “silylformylation”, and/or ( E )-1-silyl-1-hexenes ( 2 ). The ratio of silylformylation vs. hydrosilylation products depends on the electronic nature of hydrosilane used, e.g., PhMe 2 SiH gives 1 almost exclusively whereas (MeO) 3 SiH favors the formation of 2 . When trialkylsilanes such as Et 3 SiH and EtMe 2 SiH are used, the reaction catalyzed by Co 2 Rh 2 (CO) 12 or ( t BuNC) 4 RhCo(CO) 4 gives 2,5-bis(n-butyl)-3-silylcyclopent-2-en-1-one ( 3 ) as a major product, which is a unique silylcarbocyclization product. Mechanism of the formation of 3 is discussed on the basis of deuterium-labeling experiments. Chemoselective silylformylations of alkenynes, a dialkyne, and an alkynyl nitrile proceed in high yields in which alkene and nitrile functionalities are inert for the reaction. Silylformylation is successfully applied to the syntheses of pyrrolizidine alkaloids, (±)-isoretronecanol and (±)-trachelanthamidine, from 5-ethynyl-2-pyrrolidinone ( 6 ) in combination with amidocarbonylation.

Rhodium-catalyzed silylformylation and amidocarbonylation are applied to the syntheses of pyrrolizidine alkaloids, (±)-isoretronecanol and (±)-trachelanthamidine, from 5-ethynyl-2-pyrrolidinone.

Reactions of hydrosilanes with 1-hexyne catalyzed by Co 2 Rh 2 (CO) 12 , Rh 4 (CO) 12 , ( t BuNC) 4 RhCo(CO) 4 , and Rh(acac)(CO) 2 at 25°C and atmospheric pressure to 10 atm of carbon monoxide give (Z)-1-silyl-2-formyl-1-hexenes ( 1 ), which are the products of “silylformylation”, and/or ( E )-1-silyl-1-hexenes ( 2 ). The ratio of silylformylation vs. hydrosilylation products depends on the electronic nature of hydrosilane used, e.g., PhMe 2 SiH gives 1 almost exclusively whereas (MeO) 3 SiH favors the formation of 2 . When trialkylsilanes such as Et 3 SiH and EtMe 2 SiH are used, the reaction catalyzed by Co 2 Rh 2 (CO) 12 or ( t BuNC) 4 RhCo(CO) 4 gives 2,5-bis(n-butyl)-3-silylcyclopent-2-en-1-one ( 3 ) as a major product, which is a unique silylcarbocyclization product. Mechanism of the formation of 3 is discussed on the basis of deuterium-labeling experiments. Chemoselective silylformylations of alkenynes, a dialkyne, and an alkynyl nitrile proceed in high yields in which alkene and nitrile functionalities are inert for the reaction. Silylformylation is successfully applied to the syntheses of pyrrolizidine alkaloids, (±)-isoretronecanol and (±)-trachelanthamidine, from 5-ethynyl-2-pyrrolidinone ( 6 ) in combination with amidocarbonylation.

The reactions of hydrosilane and/or alkyne as well as isonitriles with rhodium and rhodium cobalt mixed metal carbonyl clusters, e.g., Rh4(CO)12 and Co2Rh2(CO)12, are studied. Novel mixed metal complexes, e.g., CoRh(CO)5 (HC≡CBu n ), (R3Si)2Rh(CO) n Co(CO)4, Rh(R−N≡C)4Co(CO)4, Co2Rh2(CO)10(HC≡CR), and Co2Rh2(CO)9(HC≡CBu n ), are synthesized and identified. The catalytic activities of these rhodium and rhodium-cobalt mixed metal complexes are examined in hydrosilyation, silylformylation, and novel silylcarbocyclization reactions. Possible mechanisms for these reactions are proposed and discussed.

Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.

In vitro drug metabolism studies during the early drug discovery stage are becoming increasingly important. With the increasing demand for high throughput and quick turnaround time for in vitro metabolism studies, however, careful examination of the results and proper design of the experiments are still crucial. In this communication, we report the identification and mechanism of formation of a novel metabonate from incubations of a diamine-containing compound with liver microsomes. The metabonate appeared to be the major product, and its formation was NADPH- and microsomal protein-dependent. Liquid chromatography/mass spectrometry and NMR analysis of the metabonate indicated an extra carbon and unusual formation of an imidazolidine ring. Further studies revealed that this metabonate was not a true biotransformation product from the diamine compound itself in the microsomal incubation, but rather a product resulting from a condensation reaction between the compound and a metabolite of the solvent (alcohol) used in the incubation. When the microsomal incubations contained a small amount of methanol or ethanol as solvent, the alcohols were metabolized to formaldehyde or acetaldehyde, which then condensed with the diamine compound through an imine intermediate to form the metabonate. The compound itself was metabolically stable in vitro when acetonitrile or dimethyl sulfoxide was used as solvent. During the study of in vitro microsomal stability and metabolite identification of amine-containing compounds, the use of alcohol as solvent should be avoided.

A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitro benzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 percent over the 4-step sequence.

A new class of pyridobenzophenoxazine compounds has been developed as topoisomerase II inhibitors for anticancer chemotherapy. These compounds were designed based on a proposed model of a quinobenzoxazine self-assembly complex on DNA. They showed excellent inhibitory effects on several tumor cell lines with nanomolar IC50 values. Their cytotoxic potency correlates with their ability to unwind DNA and inhibit topoisomerase II.

Despite the recent advances made in the treatment and management of B cell malignancies, these diseases are not curable and overall survival is limited. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of intracellular kinases first identified for its signaling via the B-cell Receptor (BCR) and its role in the immune system. More recently, BTK was found to play an important role in B cell malignancies and select solid tumors. Preclinical and clinical results with selective irreversible BTK inhibitors provide validation for BTK as a therapeutic target in B cell malignancies. Aiming to leverage the contribution of the BTK signaling pathway to tumor growth, and its role in progression and drug resistance, we have developed a series of relatively selective, reversible, small molecule BTK inhibitors and evaluated their activity in enzyme, cell-based, and in vivo studies. Data obtained with the orally available MKC4659 compound illustrates our findings. In biochemical assays, compound MKC4659 demonstrated a relatively select targeting profile focused on a narrow group of PTKs including significant activity against BTK with IC50 less than 25 nM. In cellular assays the compound demonstrated significant in vitro potency against B cell lymphoma cell lines, inhibiting the growth of several B cell tumor cell lines including ones unresponsive to currently known BTK inhibitors. Importantly, MKC4659 showed a differential effect on B cell lymphoma, with no significant activity detected in control cells lacking detectable BTK expression. In vitro mode of action studies demonstrated that MKC4659 induces apoptosis and PARP cleavage in B cell lymphoma but not in control cells. Assays evaluating the in vitro on-target effect of compounds showed significant inhibition of the B cell receptor-mediated activation of the BTK pathway. In addition to inhibiting the phosphorylation of BTK, MKC4659 inhibited the phosphorylation of PLCγ in several B cell lymphoma cell lines. With in vitro potency demonstrated, and PK and ADMET profiles amenable to in vivo dosing, MKC4659 was evaluated for in vivo efficacy in a xenograft model of B cell lymphoma. In vivo dosing of MKC4659 inhibited growth of DOHH2 xenograft tumors in a dose dependent manner. In summary, our team has identified BTK pathway inhibitors with demonstrated on-target and anti-tumor activity in cellular assays, and efficacy in a preclinical model of B cell malignancy. This effort provides a platform for compound development and evaluation for the treatment of hematologic malignancies. Optimization efforts on the MKC4659 series are ongoing and have yielded potent and drug-like preclinical candidates that are now moving into advanced animal studies. Citation Format: Mary Faris, Uriel M. Malyankar, Victor Tam, Colleen Schweitzer, Diljeet Joea, Alexis Mollard, Bret Stephens, Steven L. Warner, David J. Bearss, Qingping Zeng. Small molecule inhibitor of the BTK pathway disrupts BCR signaling and demonstrates antitumor efficacy in a xenograft model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-303. doi:10.1158/1538-7445.AM2013-LB-303

Abstract 133 Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response (UPR). Therefore blockade of UPR could provide a novel therapeutic option in MM. Upon UPR, inositol-requiring enzyme 1α (IRE1α) is activated by auto-phosphorylation, resulting in activation of its endoribonuclease domain to cleave XBP1 mRNA from XBP1 unspliced form (XBP1u: inactive) to generate the XBP1 spliced form (XBP1s: active). XBP1s protein in turn regulates genes responsible for protein folding and degradation, playing a pro-survival signaling role in the UPR. In this study, we specifically examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM. We first examined the biologic significance of IRE1α by knockdown using lentiviral shRNA and observed significant growth inhibition in IRE1α knockdown cells. We next examined the impact of inhibition of XBP1 splicing using a novel small molecule IRE1α endoribonuclease domain inhibitor MKC-3946 (MannKind, Valencia CA). MKC-3946 blocked not only the basal level, but also inducible (by tunicamycin) XBP1s, evidenced by RT-PCR analysis in RPMI8226 cells, without affecting phosphorylation of IRE1α. Importantly, MKC-3946 also inhibited XBP1s in primary tumor cells from MM patients. We also confirmed functional inhibition of XBP1s, with target genes including SEC61A1, p58IPK, and ERdj4 downregulated by MKC-3946 treatment. Importantly, MKC-3946 triggered growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Furthermore, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG in RPMI8226 and INA6 cells, as well as primary tumor cells from MM patients. Both bortezomib and 17-AAG induced ER stress with XBP1s, which was markedly blocked by MKC-3946. Moreover, apoptosis induced by bortezomib or 17-AAG was enhanced by MKC-3946, associated with increased CHOP mRNA and protein, a proapoptotic factor triggered by ER stress. We next demonstrated that XBP1s was induced by bortezomib in INA6 cells co-cultured with bone marrow (BM) stromal cells, which was inhibited by MKC-3946, associated with enhanced cytotoxicity induced by the combination. Finally, MKC-3946 inhibited XBP1s in a model of in vivo ER stress induced by tunicamycin. To evaluate the anti-MM effect of MKC-3946, we used the subcutaneous RPMI8226 xenograft model in mice. MKC-3946 significantly reduced MM tumor growth in the treatment versus control group, associated with prolonged overall survival. We also confirmed that MKC-3946 treatment significantly inhibited XBP1s in excised tumors, assessed by RT-PCR. In order to examine the activity of MKC-3946 on MM cell growth in the context of the human BM microenvironment in vivo, we used the SCID-hu model, in which INA6 cells are directly injected into a human bone chip implanted subcutaneously in SCID-mice. MKC-3946 treatment significantly inhibited tumor growth compared with vehicle control. Moreover, XBP1s in excised tumor cells was inhibited, evidenced by RT-PCR. In conclusion, these data demonstrate that blockade of XBP1s by MKC-3946 triggers MM cell growth inhibition in vivo and prolongs host survival. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential novel therapeutic option in MM. Disclosures: Tam: MannKind Corporation: Employment, Equity Ownership. Zeng:MannKind Corporation: Employment, Equity Ownership. Patterson:MannKind Corporation: Employment, Equity Ownership. Richardson:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Munshi:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; MannKind: Membership on an entity's Board of Directors or advisory committees.

Abstract 4074 Aberrant protein folding results in the accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER), which in turn triggers ER stress followed by unfolded protein response (UPR), an adaptive response against ER stress. Since multiple myeloma (MM) cells have high protein synthesis, they are sensitive to ER stress and require strict ER quality control for cell survival. Upon UPR, IRE1α is activated by auto-phosphorylation resulting in activation of its endoribonuclease domain to splice XBP1 mRNA from XBP1 unspliced form (XBP1u: inactive) to XBP1 spliced form (XBP1s: active). Since XBP1 is a transcription factor regulating genes which are responsible for protein folding and ER associated degradation (ERAD), IRE1α-XBP1 pathway acts as a pro-survival signaling pathway under the UPR condition. In this study, we examined whether IRE1α-XBP1 pathway is a potential novel therapeutic option in MM. We first examined IRE1α expression and confirmed its expression in all MM cell lines. In contrast, XBP1s was not detected by RT-PCR in most cell lines except in for RPMI8226 cells. To assess biologic significance of IRE1α in MM cell, we knock-downed its expression using shRNA and found that downregulation of IRE1α inhibited MM cell growth, indicating that IRE1α has a crucial role in MM cell survival. We next examined the impact of inhibition of XBP1 splicing by a small molecule IRE1α endoribonuclease inhibitor MKC-3946 (Mannkind, Valencia CA) in MM cells in vitro. As expected, MKC-3946 significantly inhibited tunicamycin-induced XBP1s without affecting phosphorylation of IRE1α. MKC-3946 induced only modest cytotoxicity in MM cell lines without toxicity in normal mononuclear cells from healthy donors; however, it significantly enhanced cytotoxicity in combination with bortezomib or 17-AAG. Both bortezomib and 17-AAG induced ER stress evidenced by induction of XBP1s; conversely, MKC-3946 blocked XBP1s triggered by these agents. Furthermore, apoptosis induced by these agents was enhanced with MKC-3946 associated with increased CHOP, which is a known pro-apoptotic protein induced in uncompensated ER stress condition. Importantly, MKC-3946 enhanced the cytotoxicity of bortezomib or 17-AAG in INA6 cells, even in the presence of increased IL-6 or bone marrow stromal cells. Finally, MKC-3946 was active inhibiting XBP1 splicing in a model of ER stress and significantly inhibited growth of RPMI8226 plasmacytoma in a xenograft murine model when used in combination with a low dose of bortezomib. Taken together, our results demonstrate that inhibition of XBP1 splicing by blockade of IRE1α is a promising therapeutic option in MM. Disclosures: Blumenthal: Mannkind Corporation: Employment, Equity Ownership. Tam:Mannkind Corporation: Employment, Equity Ownership. Kertesz:Mannkind Corporation: Employment, Equity Ownership. Zeng:Mannkind Corporation: Employment, Equity Ownership. Patterson:Mannkind Corporation: Employment, Equity Ownership. Munshi:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.