Synthesis and Crystal Structure of Dimorphic Dibenzo[cde,opq]rubicene.

Dibenzo[cde,opq]rubicene has been synthesized by an eight-step reaction sequence including an iron-mediated [2+2+1] cycloaddition and a flash vacuum pyrolysis as key steps. Two crystal modifications of the S-shaped, planar polycyclic aromatic hydrocarbon have been obtained and characterized by X-ray diffractometry.

Synthesis and Activity against Mycobacterium tuberculosis of Olivacine and Oxygenated Derivatives.

The tetracyclic pyrido[4,3-b]carbazole olivacine and four of its oxygenated derivatives have been synthesized by a late-stage palladium-catalyzed Heck-type cyclization of the pyrrole ring as a key step. In a test for the inhibition of the growth of Mycobacterium tuberculosis, 9-methoxyolivacine showed the most significant inhibitory activity against Mycobacterium tuberculosis, with an MIC90 value of 1.5 µM.

Iron-Catalyzed Oxidative C-C and N-N Coupling of Diarylamines and Synthesis of Spiroacridines.

We describe iron-catalyzed intermolecular oxidative coupling reactions of diarylamines to form substituted 2,2'-bis(arylamino)biaryl compounds, tetraarylhydrazines, and 5,6-dihydrobenzo[c]cinnolines with the same hexadecafluorinated iron-phthalocyanine catalyst. The mild formation of C-C or N-N bonds was controlled by the use of acidic or basic additives. In contrast to most iron-catalyzed dehydrogenative coupling reactions, ambient air could be used as the sole oxidant. Moreover, iron(III) chloride hexahydrate promoted a one-pot coupling and subsequent intramolecular dearomative coupling to give 10H-spiro[acridine-9,1'-cyclohexa-2',5'-dien-4'-ones].

Synthesis of Stable Diarylpalladium(II) Complexes: Detailed Study of the Aryl-Aryl Bond-Forming Reductive Elimination.

The synthesis of diarylpalladium(II) complexes by twofold aryl C-H bond activation was developed. These intermediates of oxidative cyclization reactions are stabilized by chelation with acetyl groups while still maintaining sufficient reactivity to study their reductive elimination. Four distinct triggers were found for the reductive elimination of these complexes to dibenzofurans and carbazoles. Thermal elimination occurs at very high temperatures, whereas ligand-promoted and oxidatively induced reductive eliminations proceed readily at room temperature. Under these conditions, no isomerization occurs. In contrast, weak Brønsted acids, such as acetic acid, lead to a sequence of proto-demetalation, isomerization to a κ(3) -diarylpalladium(II) complex, and reductive elimination to non-symmetrical cyclization products.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.

Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Inhibitory effect of oxygenated cholestan-3ß-ol derivatives on the growth of Mycobacterium tuberculosis.

A variety of cholestan-3ß-ol derivatives, which are oxygenated at different positions of the steroid ring system, were prepared and tested for their inhibition of the Mycobacterium tuberculosis H37Rv strain. Several compounds showed significant antitubercular activities with MIC90 values in the range 4-8 µM and low or non-detectable toxicity against mammalian cells.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.

Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing ß-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Spectroscopy of dibenzorubicene: experimental data for a search in interstellar spectra.

We report on the characterization of dibenzo[cde,opq]rubicene (C(30)H(14)). The molecule was studied in solution at room temperature with absorption spectroscopy in the visible (vis) and ultraviolet (UV) wavelength ranges, and with emission spectroscopy. The infrared (IR), visible, ultraviolet, and vacuum ultraviolet (VUV) absorption spectra of a thin film were measured also at room temperature. In addition, the UV/vis absorption spectrum was measured at cryogenic temperatures using the matrix isolation spectroscopy technique. The interpretation of spectra was supported by theoretical calculations based on semiempirical and ab initio models, as well as on density functional theory. Finally, the results of the laboratory study were compared with interstellar spectra.

Synthesis and biological activity of the (25R)-cholesten-26-oic acids--ligands for the hormonal receptor DAF-12 in Caenorhabditis elegans.

We describe the stereoselective transformation of diosgenin (4a) to (25R)-Delta(4)-dafachronic acid (1a),(25R)-Delta(7)-dafachronic acid (2a), and (25R)-cholestenoic acid (3a), which represent potential ligands forthe hormonal receptor DAF-12 in Caenorhabditis elegans. Key-steps of our synthetic approach are amodified Clemmensen reduction of diosgenin (4a) and a double bond shift from the 5,6- to the 7,8-position. In the 25R-series, the Delta(7)-dafachronic acid 2a exhibits the highest hormonal activity.

IR, Raman, and UV/Vis spectra of corannulene for use in possible interstellar identification.

The spectroscopic characterization of corannulene (C(20)H(10)) is carried out by several techniques. The high purity of the material synthesized for this study was confirmed by gas chromatography-mass spectrometry (GC-MS). During a high-performance liquid chromatography (HPLC) process, the absorption spectrum of corannulene in the ultraviolet (UV) and visible (vis) ranges is obtained. The infrared (IR) absorption spectrum is measured in CsI pellets, and the Raman scattering spectrum is recorded for pure crystal grains. In addition to room temperature measurements, absorption spectroscopy in an argon matrix at 12 K is also performed in the IR and UV/Vis ranges. The experimental spectra are compared with theoretical Raman and IR spectra and with calculated electronic transitions. All calculations are based on the density functional theory (DFT), either normal or time-dependent (TDDFT). Our results are discussed in view of their possible application in the search for corannulene in the interstellar medium.

Quantitative Structure-Retention Relationships for Polycyclic Aromatic Hydrocarbons and their Oligoalkynyl-Substituted Derivatives.

Reversed-phase high-performance liquid chromatography (RP-HPLC) has been carried out for a series of unsubstituted polycyclic aromatic hydrocarbons (PAHs) and the corresponding ethynyl, 1,3-butadiynyl, and 1,3,5-hexatriynyl derivatives. Theoretical values of the isotropic polarizability and several polarity descriptors have been computed for each compound by using semiempirical models and density functional theory (DFT), with the aim of evaluating linear functions as quantitative structure-retention relationships (QSRRs). The polarity has been described by using either the permanent electric dipole moment, the subpolarity, or a topological electronic index. Three types of partial atomic charges have been used to calculate the subpolarity and a topological index. The choice of the theoretical model, of the polarity descriptor, and of the partial atomic charges is discussed and the resulting QSRRs are compared. Calculating the retention times from the polarizability and the topological electronic index (AM1, PM3, or DFT-B3LYP/6-31+G(d,p)) gives the best agreement with the experimental values.

Determination of 4-nonylphenol in water samples using 4-(2,6-dimethylhept-3-yl)phenol as new internal standard.

A new method for determining the endocrine disrupting substance 4-nonylphenol (technical grade=mixture of isomers, 4-NP) from water samples has been developed by using 4-(2,6-dimethylhept-3-yl)phenol (4-sec-NP) as model compound. This branched monoalkylphenol is shown to serve as internal standard (IS) for the determination of technical 4-nonylphenol. To the best of our knowledge, 4-(2,6-dimethylhept-3-yl)phenol (racemic mixture) is a newly synthesized 4-nonylphenol isomer and has not been described elsewhere. Recoveries have been determined by analyzing spiked water samples from distilled water, river water and wastewater. Following acetylation, the compounds were enriched via solid phase extraction (SPE). Analyses of the compounds were performed by capillary column gas chromatography/mass spectrometry (GC/MS), operating in selected ion-monitoring (SIM) mode. The recovery of technical 4-NP using either the newly prepared 4-sec-NP or 4-n-nonylphenol (4-n-NP) as IS have been compared. 4-sec-NP showed slightly better results. However, in the first series of experiments using wastewater, the yields for the derivatization of the two standard compounds were remarkably different. The yield for derivatization of 4-n-NP was approximately 20%, probably due to the difficult matrix of the wastewater. In contrast, the yield for the derivatization of 4-sec-NP was considerably higher (approximately 63%). This problem can be solved by increasing the concentration of the reagent used for derivatization. For better control of the clean-up process, we recommend application of 4-sec-NP as internal standard, at least in water samples with complex matrices (e.g., high content of hydroxylated compounds).

Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.

In response to pheromone(s), Caenorhabditis elegans interrupts its reproductive life cycle and enters diapause as a stress-resistant dauer larva. This decision is governed by a complex system of neuronal and hormonal regulation. All the signals converge onto the nuclear hormone receptor DAF-12. A sterol-derived hormone, dafachronic acid (DA), supports reproductive development by binding to DAF-12 and inhibiting its dauer-promoting activity. Here, we identify a methyltransferase, STRM-1, that modulates DA levels and thus dauer formation. By modifying the substrates that are used for the synthesis of DA, STRM-1 can reduce the amount of hormone produced. Loss of STRM-1 function leads to elevated levels of DA and inefficient dauer formation. Sterol methylation was not previously recognized as a mechanism for regulating hormone activity. Moreover, the C-4 sterol nucleus methylation catalyzed by STRM-1 is unique to nematodes and thus could be a target for therapeutic strategies against parasitic nematode infections.