Desymmetrization of 3,3′‐Bis(acylamino)‐2,2′‐bipyridine‐Based Discotics: The High Fidelity of Their Self‐Assembly Behavior in the Liquid‐Crystalline State and in Solution

Two novel nonsymmetrical disc‐shaped molecules 1 and 2 based on 3,3′‐bis(acylamino)‐2,2′‐bipyridine units were synthesized by means of a statistical approach. Discotic 1 possesses six chiral dihydrocitronellyl tails and one peripheral phenyl group, whereas discotic 2 possesses six linear dodecyloxy tails and one peripheral pyridyl group. Preorganization by strong intramolecular hydrogen bonding and subsequent aromatic interactions induce self‐assembly of the discotics. Liquid crystallinity of 1 and 2 was determined with the aid of polarized optical microscopy, differential scanning calorimetry, and X‐ray diffraction. Two columnar rectangular mesophases (Col_r) have been identified, whereas for C₃‐symmetrical derivatives only one Col_r mesophase has been found. 1 In solution, the molecularly dissolved state in chloroform was studied with ¹H NMR spectroscopy, whereas the self‐assembled state in apolar solution was examined with optical spectroscopy. Remarkably, these desymmetrized discotics, which lack one aliphatic wedge, behave similar to the symmetric parent compound. To prove that the stacking behavior of discotics 1 and 2 is similar to that of reported C₃‐symmetrical derivatives, a mixing experiment of chiral 1 with C₃‐symmetrical 13 has been undertaken; it has shown that they indeed belong to one type of self‐assembly. This helical J‐type self‐assembly was further confirmed with UV/Vis and photoluminescence (PL) spectroscopy. Eventually, disc 2 , functionalized with a hydrogen‐bonding acceptor moiety, might perform secondary interactions with molecules such as acids.     

Chiral poly(ureidophthalimide) foldamers in water

Poly(ureidophthalimide)s decorated with hydrophilic side chains, that ensure solubility in aqueous media, have been synthesized and characterized by UV/Vis and circular dichroism (CD) spectroscopy. Temperature and concentration dependent CD measurements in water have revealed an almost temperature and concentration independent Cotton effect, indicative for a strong intramolecular organization. Similar studies in THF demonstrate the dynamic nature of the secondary architecture, a characteristic of foldamers. In addition, the bisignated Cotton effect in water is opposite in sign to that in THF, suggestive for a solvent-dependent preference for one helical handedness. Mixing experiments prove the dominance of water in determining the handedness of the helical architecture. The solvent allows for control over the helical architecture and thus governs the supramolecular synthesis.     

Radical cation formation in characterization of novel C3-symmetric disks and their precursors by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Four C3-symmetrical tris(dipeptide) disks and their precursors were characterized using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS). The C3-symmetrical disks were based on a benzene-1,3,5-triscarboxamide core extended by oligopeptides with trialkoxyanilide tails. The results indicate that MALDI TOF MS is a powerful and straightforward analytical technique for characterizing C3-symmetrical disks and their precursors. Clear (pseudo)-molecular ion peaks could readily be identified. It is remarkable that strong radical ion signals were observed for all the compounds, including the anilines that were expected to be protonated prior to laser irradiation using acidic MALDI matrixes. Possible mechanisms for radical ion formation were investigated with the employment of radical scavengers, with various matrixes and with direct laser desorption/ionization (LDI). Most likely the radicals are formed by losing one electron from the aniline nitrogen and stabilized by conjugation through the phenyl ring. It appears that direct photo/thermal ionization of analytes is an important route for the radical ion formation of the compounds with trialkoxy aniline/anilide groups.     

Synthesis and Properties of Oligonucleotides Containing 2,4‐Dihydroxycyclohexyl Nucleosides

Cyclohexyl nucleosides with an adenine and uracil base have been synthesized from 2‐azidocyclohexane‐1,5‐diol. The obtained racemic nucleosides were resolved using (R)‐O‐methylmandelic acid. Short oligonucleotides were synthesized using phorphoramidite chemistry. However, these oligonucleotides do not show self‐hybridization, and duplexes are less stable than those of ribopyranosyl‐(4′ → 2′)‐oligonucleotides.     

"Majority-rules" operative in chiral columnar stacks of C3-symmetrical molecules

C(3)-symmetrical disks 1, preorganized by acylated 2,2'-bipyridine-3,3'-diamine moieties and decorated with nine identical chiral, lipophilic tails, aggregate into a dynamic helix in apolar solvents. The aggregates, previously shown to be governed by the "sergeants-and-soldiers" principle when mixed with achiral analogues, are now also revealed to obey the "majority-rules" effect, a phenomenon not earlier observed in nonpolymers. Our experimental circular dichroism data can be accurately described with a recently developed theory. A fit of the theory to the experimental results shows that the mismatch penalty, i.e., the free energy of a monomer present in a helix of its nonpreferred screw sense (0.94 kJ/mol), is about 8 times lower than the penalty for a helix reversal (7.8 kJ/mol). This corresponds well to our vision of the supramolecular architecture of the disks.     

Alfaxalone: Effect of Temperature on Complexation with 2-Hydroxypropyl-β-cyclodextrin

Phase solubility analysis is used to investigate the complex formation of alfaxalone with various cyclodextrins(2-hydroxypropyl--cyclodextrine [HPBCD],-cyclodextrin [BCD] and2-hydroxypropyl--cyclodextrin [HPGCD]).The complexationwith HPBCD was studied in more detail by looking at the effect of temperature on the stability constants using phase solubility analysis. HPLC-analysis was used to measure the dissolved amount of alfaxalone.The solubility of alfaxalone increases linearly with increasing concentration of cyclodextrin, suggesting the formation of a 1 : 1 complex. For the parent BCD the complex starts precipitating out of solution when the solubilizer concentration exceeds 0.25% making the unsubstituted BCD less useful for the preparation of solutions of alfaxalone. Substituted cyclodextrins do not form insoluble complexes with alfaxalone. The complexation constant for BCD and HPBCD are comparable in magnitude, but for HPGCD, the constant is substantially lower.The effect of temperature on thecomplexation constant was also studied at elevated temperature. Increasing the temperature results in an increased S₀ (solubility without HPBCD) and a decrease in the value of the complexation constant. The net effect results in minor changes of the solubility of alfaxalone as a function of temperature. Based on regression analysis, the change in enthalpy for complex formation between alfaxalone and HPBCD is calculated as -4610 cal/mol.The results indicate that substitutedcyclodextrins are useful in the preparation of solutions of alfaxalone. Since 1 : 1 complexes are formed there is no theoretical danger for precipitation on dilution, e.g., after injection.     

A Novel Cyclodextrin-containing Glass Thermoplastic System (GTS) for Formulating Poorly Water Soluble Drug Candidates: Preclinical and Clinical Results

We present a novel solid solution/dispersion technology with glass thermoplastic properties that provide good dissolution rates and oral bioavailabilities for poorly water-soluble weak bases. In this process, a thermoplastic gum was prepared by mixing a polyhydroxy acid such as citric acid or tartaric acid with a weakly basic drug, hydroxypropyl--cyclodextrin (HP--CD) and a cellulose polymer such as hydroxypropylmethylcellulose (HPMC) in a protic solvent. Removal of the solvent gave a material which could be loaded into hard gelatin capsules. Several model compounds were processed in this manner including methylene blue and itraconazole. The resulting data indicated that dissolution properties of GTS's based on methylene blue was pH independent and rapid with 80% dissolved within 30 min. Three GTS formulations of itraconazole containing 100 mg of the drug and 500 mg of citric acid as well as various concentrations of HP--CD and HMPC were found to dissolve rapidly (100% in 45 min). One of these formulations was selected for human pharmacokinetic evaluation and demonstrated significant oral bioavailability relative to unmanipulated drug.The studies suggest that the components of the GTS provide for solubilization through complexation and reduced pH and that the cellulose polymer acts to inhibit recrystallization of the supersaturated solution formed. The rationaldevelopment of the GTS dosage form can be useful for generating acceptable formulations for poorly water-soluble drug candidates.     

Strong disorder fixed point in absorbing-state phase transitions

The effect of quenched disorder on nonequilibrium phase transitions in the directed percolation universality class is studied by a strong disorder renormalization group approach and by density matrix renormalization group calculations. We show that for sufficiently strong disorder the critical behavior is controlled by a strong disorder fixed point and in one dimension the critical exponents are conjectured to be exact: beta=(3-sqrt[5])/2 and nu( perpendicular )=2. For disorder strengths outside the attractive region of this fixed point, disorder dependent critical exponents are detected. Existing numerical results in two dimensions can be interpreted within a similar scenario.     

Divergent strategy for the synthesis of alpha-aryl-substituted fosmidomycin analogues

Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin.