Novel fragmentation reaction of correolide

[reaction: see text] Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolide-type E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.     

Estrogen receptor ligands. 12. Synthesis of the major metabolites of an ERalpha-selective, dihydrobenzoxathiin antagonist for osteoporosis

[reaction: see text] During the course of drug metabolism studies, a major metabolite of compound 1 was detected in rhesus monkeys and assigned structure 4. The intriguing biotransformation of 1 leading to 4 was confirmed by a 19-step total synthesis starting from resorcinol (11), the key feature of which was the construction of the oxygen bridge utilizing a phenolic oxidation and trapping sequence. In addition, the synthesis of a related metabolite (5) is described.     

Photolithographic Patterning and Doping of Silica Xerogel Films

This study shows that conventional photolithography can be applied for patterning native or organic dye-doped silica films (0.5 m thick) obtained via a base-catalyzed sol-gel process. Photoresist was spin-coated onto high optical quality xerogel films, soft-baked, exposed to UV irradiation through a photomask, and developed with a commercial photoresist developing solution. Etching away of the photoresist-unprotected areas of the silica films was carried out with a dilute HF solution, while the remaining unexposed photoresist was removed with acetone. Interdigitated array patterns with features as small as 0.5 mm show a smooth surface and extremely sharp interfaces. Densification of the films at 550°C for 2 h decreases the film thickness by 11%, increases the refractive index from 1.420 to 1.456, and allows for well-defined patterning down to length scales of 10 m. Since the densification conditions are incompatible with organic dopants, it is demonstrated that sol-gel films can be doped after pattering (post-doping) by adsorption of cationic dyes from solution. Scanning electron microscopy reveals that the microstructure of patterned sol-gel films is similar to that of bulk monoliths, indicating that the photolithographic procedure is not harmful to the film quality. All patterned films demonstrate highly regular light diffraction patterns.     

Comparisom of electron impact and field desorption mass spectra I : Substituted sultams

The low and the high resolution electron impact (EI) and field desorption (FD) mass spectra (MS) of substituted 5- or 6-membered ring sultams are given and the main fragmentation pathways are interpreted. Sultams carrying polar substituents, such as dicarboxylic acids and their mono- and di-amides show either small or no molecular ions with EI-MS. Their existence, however, can be indirectly inferred by metastable defocusing. In contrast to these findings FD-MS display in all our examples the quasimolecular ions (M + 1)⁺ as the base peaks of the spectra. While the pattern for the EI fragmentations follows the generally known rules very closely, five general aspects for the fragmentation pathway of FD mass spectra have been established which demonstrate the characteristics of this modern analytical method. The use of high temperature activated emitters enables a choice to be made between obtaining only molecular peaks and producing significant fragments via a controlled thermal degradation. This is the first time that the complementary and different characters of the information obtained with the two ionization modes EI and FD have been demonstrated on a homologous series of compounds.     

Synthesis and stereochemical assignment of 7-arylidene and 7-heteroarylidene morphinan-6-ones

A number of (E)-7-arylidenenaltrexones were synthesized by azeotropic distillation of water from a benzene solution of naltrexone and an aromatic aldehyde (benzaldehyde, 4-chloro- and 4-fluorobenzaldehyde, 3-and 4-pyridinecarboxaldehyde and 1-methyl-2-imidazolecarboxaldehyde) using piperidine as a catalyst. In addition, (E)-7-benzylidenenaloxone was prepared by the previously published Claisen-Schmidt condensation using sodium hydroxide in methanol. The stereochemistry of these arylidene derivatives 3–9 was determined to be (E) by means of nuclear Overhauser enhancement experiments. The ¹³C nmr spectra of (E)- 3–9 are recorded in deuteriochloroform and those of the hydrochlorides in deuteriodimethyl sulfoxide.     

Disease-Causing Mutation in Extracellular and Intracellular Domain of FGFR1 Protein: Computational Approach

In-depth computationally based structural analysis of human fibroblast growth factor type 1 (FGFR1) protein carrying disease-causing mutation was performed in this study. Gain or loss of function due to missense mutations in FGFR1 is responsible for a variety of disorders including Kallmann syndrome, Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, etc. The mutant model of the human FGFR1 protein was subjected to various in silico analysis, and most deleterious SNPs were screened out. Furthermore, docking and long molecular dynamics simulations were carried out with an intention of studying the possible impact of these mutations on the protein structure and hence its function. Analysis of various structural properties—especially of those of the functionally important regions: the extracellular immunoglobulin domain and intracellular Tyrosine kinase domain—gave some insights into the possible structural characteristics of the disease mutant and the wild-type forms of the protein. In a nutshell, compared to the wild-type protein, the mutant structures V273M and S685F are associated with significant changes, and the functionally important regions seem to adopt such structures that are not conducive for the wild-type-like functionality.     

Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome,Boomerang Dysplasia,and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1–242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.     

X-ray determination of the mean amplitudes of vibration and debye temperatures of some rare earth monochalcogenides

The x-ray diffraction intensities of Bragg reflections have been measured at room temperature for thulium selenide, samarium sulphide, samarium selenide and samarium telluride. On the basis of a common amplitude approximation, the Debye-Waller factor, the mean amplitude of vibration and the Debye temperature have been evaluated. The values of the Debye temperatures and mean amplitudes of vibration are 176±16°K, 0·185 ± 0·017 Å (TmSe), 155 ± 7°K, 0·244 ± 0·012 Å (SmS), 153 ± 14°K, 0·221 ± 0·020 Å (SmSe) and 151 ± 20°K, 0·204 ± 0·027 Å (SmTe).