Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 .     

The propagation of radiation through a medium containing a component that absorbs the radiation and is steadily destroyed by it

The Beer–Lambert law is inadequate to describe the absorption of radiation by a medium if the absorbing component is being simultaneously destroyed by the radiation. A replacement law is derived and solved in terms of a family of polynomials. The solution is confirmed numerically and by simulation.     

Hindered organoboron groups in organic synthesis. 17 [1]. Synthesis of 2,4,6-triisopropylphenylborane (TripBH2)2, a useful alternative to thexylborane

2,4,6-Triisopropylphenylborane (tripylborane, TripBH₂) resembles thexylborane in having a single, bulky organic group attached to boron, but the group is aromatic rather than aliphatic. The compound has been synthesized by two alternative routes, one involving direct reduction of dimethoxytripylborane and the other involving redistribution between ditripylborane and borane. It is a solid which is considerably more stable than thexylborane.     

An improved enzymatic assay for glucose determination in blood serum using a l,1′-dimethylferricinium dye

l,l′-dimethylferricinium (DMFe⁺),a stable and pH-insensitive blue dye, was prepared via enzymatic oxidation of a 1,1′-dimethylferrocene (DMFe):2-hydroxypropyl-β-cyclodextrin (HPCD) watersoluble inclusion complex, using bilirubin oxidase immobilized onto porous aminopropyl glass beads via glutaraldehyde activation. In the presence of glucose, DMFe⁺ was reduced to DMFe by reacting with the reduced glucose oxidase (FADH₂), and the absorbance decrease was followed at 650 nm. In acetate pH 5.2 buffer, the response to glucose in blood serum was nonlinear, especially in the low concentration range, because of a competition for the reduced glucose oxidase between the DMFe⁺ dye and oxygen. At this pH, endogenous ceruloplasmin was also observed to oxidize residual DMFe (16%) in the dye preparation, causing an increase in absorbance at 650 nm. An assay protocol was then developed using maleate buffer, pH 6.5, to overcome these interferences as well as mutarotation of α-D-glucose. The results obtained for glucose in the blood serum samples agreed well with those of the reference hexokinase/glucose-6-phosphate dehydrogenase method.     

Parametric excitation of beams moving over supports

Studied in this work are the formulation of equations of motion and the response to parametric excitation of a uniform cantilever beam moving longitudinally over a single bilateral support. The equations of motion are generated by using assumed modes to discretize the beam, by regarding the support as a kinematic constraint, and by employing an alternate form of Kane's method that is particularly well suited to systems subject to constraints. Instability information is developed using the results of perturbation analysis for harmonic longitudinal motions of small amplitude and with Floquet theory for general periodic motions of any amplitude. Results demonstrate that definitive instability information can be obtained for a beam moving longitudinally over supports based on the frequencies of free transverse vibration of a beam that is longitudinally fixed.     

Q parameter estimation using numerical simulations for linear and nonlinear transmission systems

We compare the Q parameter obtained from scalar, semi-analytical and full vector models for realistic transmission systems. One set of systems is operated in the linear regime, while another is using solitons at high peak power. We report in detail on the different results obtained for the same system using different models. Polarisation mode dispersion is also taken into account and a novel method to average Q parameters over several independent simulation runs is described.     

Stop coannihilation in the CMSSM and SubGUT models

Stop coannihilation may bring the relic density of heavy supersymmetric dark matter particles into the range allowed by cosmology. The efficiency of this process is enhanced by stop-antistop annihilations into the longitudinal (Goldstone) modes of the W and Z bosons, as well as by Sommerfeld enhancement of stop annihilations and the effects of bound states. Since the couplings of the stops to the Goldstone modes are proportional to the trilinear soft supersymmetry-breaking A-terms, these annihilations are enhanced when the A-terms are large. However, the Higgs mass may be reduced below the measured value if the A-terms are too large. Unfortunately, the interpretation of this constraint on the stop coannihilation strip is clouded by differences between the available Higgs mass calculators. For our study, we use as our default calculator FeynHiggs 2.13.0, the most recent publicly available version of this code. Exploring the CMSSM parameter space, we find that along the stop coannihilation strip the masses of the stops are severely split by the large A-terms. This suppresses the Higgs mass drastically for \(\mu \) and \(A_0 > 0\), whilst the extent of the stop coannihilation strip is limited for \(A_0 < 0\) and either sign of \(\mu \). However, in sub-GUT models, reduced renormalization-group running mitigates the effect of the large A-terms, allowing larger LSP masses to be consistent with the Higgs mass calculation. We give examples where the dark matter particle mass may reach \(\gtrsim 8\) TeV.     

Outdoor ground impedance models

Many models for the acoustical properties of rigid-porous media require knowledge of parameter values that are not available for outdoor ground surfaces. The relationship used between tortuosity and porosity for stacked spheres results in five characteristic impedance models that require not more than two adjustable parameters. These models and hard-backed-layer versions are considered further through numerical fitting of 42 short range level difference spectra measured over various ground surfaces. For all but eight sites, slit-pore, phenomenological and variable porosity models yield lower fitting errors than those given by the widely used one-parameter semi-empirical model. Data for 12 of 26 grassland sites and for three beech wood sites are fitted better by hard-backed-layer models. Parameter values obtained by fitting slit-pore and phenomenological models to data for relatively low flow resistivity grounds, such as forest floors, porous asphalt, and gravel, are consistent with values that have been obtained non-acoustically. Three impedance models yield reasonable fits to a narrow band excess attenuation spectrum measured at short range over railway ballast but, if extended reaction is taken into account, the hard-backed-layer version of the slit-pore model gives the most reasonable parameter values.