Ab initio calculations of vibronic activity in phosphorescence microwave double resonance spectra of p-dichlorobenzene

The phosphorescence spectrum of p-dichlorobenzene has been calculated using multiconfiguration self-consistent-field wave functions and the quadratic response technique. Attention has been paid to the intensity distribution of the singlet–triplet (³B_1u¹A_g) transition through a number of vibronic subbands. The second order spin–orbit coupling (SOC) contribution to the spin splitting of the ³B_1u (^3*) state is found to be almost negligible, and the calculations therefore provide a good estimate for the zero-field splitting (ZFS) parameters based only on the electron spin–spin coupling expectation values. Nuclear quadrupole resonance constants for the different Cl isotopes are also calculated to accomplish the ZFS assignment. The electric dipole activity of the spin sublevels in the triplet–singlet transitions to the ground-state vibrational levels is estimated by calculations of derivatives using distorted geometries which are shifted from the equilibrium position along different vibrational modes. A vibrational analysis of the phosphorescence spectrum, based on the SOC-induced mixing of the singlet and triplet states calculated along different vibrational modes, provides reasonable agreement with experimental data.Acknowledgment O. R.-P. would like to thank the European MOLPROP network for support. The authors thank Alexander Baev for fruitful discussions. This work was supported by the Swedish Royal Academy of Science (KVA).     

Modified AutoDock for accurate docking of protein kinase inhibitors

Protein kinases are an important class of enzymes controlling virtually all cellular signaling pathways. Consequently, selective inhibitors of protein kinases have attracted significant interest as potential new drugs for many diseases. Computational methods, including molecular docking, have increasingly been used in the inhibitor design process [1]. We have considered several docking packages in order to strengthen our kinase inhibitor work with computational capabilities. In our experience, AutoDock offered a reasonable combination of accuracy and speed, as opposed to methods that specialize either in fast database searches or detailed and computationally intensive calculations.However, AutoDock did not perform well in cases where extensive hydrophobic contacts were involved, such as docking of SB203580 to its target protein kinase p38. Another shortcoming was a hydrogen bonding energy function, which underestimated the attraction component and, thus, did not allow for sufficiently accurate modeling of the key hydrogen bonds in the kinase-inhibitor complexes.We have modified the parameter set used to model hydrogen bonds, which increased the accuracy of AutoDock and appeared to be generally applicable to many kinase-inhibitor pairs without customization. Binding to largely hydrophobic sites, such as the active site of p38, was significantly improved by introducing a correction factor selectively affecting only carbon and hydrogen energy grids, thus, providing an effective, although approximate, treatment of solvation.     

Elastic Light Tunable Tissue Adhesive Dendrimers

Development of bioadhesive formulations for tissue fixation remains a challenge. The major drawbacks of available bioadhesives are low adhesion strength, toxic byproducts, and complexity of application onto affected tissues. In order to address these problems, this study has developed a hydrogel bioadhesive system based on poly amido amine (PAMAM) dendrimer, grafted (conjugated) with UV‐sensitive, 4‐[3‐(trifluoromethyl)‐3H‐diazirin‐3‐yl] benzyl bromide (PAMAM‐g‐diazirine). This particular diazirine molecule can be grafted to the surface amine groups of PAMAM in a one‐pot synthesis. Diazirine functionalities are carbene precursors that form covalent crosslinks with hydrated tissues after low‐power UV activation without necessity of free‐radical initiators. The rheological properties and adhesion strength to ex vivo tissues are highly controllable depending on diazirine grafting, hydrogel concentration, and UV dose intensity fitting variety types of tissues. Covalent bonds at the tissue/bioadhesive interface provide robust adhesive and mechanical strength in a highly hydrated environment. The free flowing hydrogel conversion to elastic adhesive after UV activation allows intimate contact with the ex vivo swine tissue surfaces with low in vitro cytotoxicity observed, making it a promising bioadhesive formulation toward clinical applications.

     

Synthesis,Anticancer, and QSAR Studies of 2‐Alkyl(aryl,hetaryl)quinazolin‐4(3H)‐thione's and [1,2,4]Triazolo[1,5‐c]quinazoline‐2‐thione's Thioderivatives

Considering the frightening high level of mortality from cancer, studies of anticancer agents are vital nowadays. The 24 thioderivatives of 2‐alkyl(aryl)‐quinazolin‐4(3H)‐thiones and 20 thioderivatives of [1,2,4]triazolo[1,5‐c]quinazoline‐2‐thiones were synthesized and evaluated for preliminary in vitro anticancer activity with subsequent in silico QSAR analysis. The substance 18 had the best results inhibiting growth of eight cancer cell lines: CCRF‐CEM of leukemia; SF‐539, SNB‐75, and U251 of CNS cancer; 786, RXF393, and UO‐31 of renal cancer; and MDA‐MB‐231/ATCC of breast cancer (?31.50 – 47.41% of cell growth) with low procancer effect. Calculated QSAR‐models for CCRF‐CEM of leukemia, T‐47D and HS 578T of breast cancer, and mean cell growth demonstrated good rate of anticancer activity prediction (r² = 0.7 – 0.8,  = 0.5 – 0.7).     

Synthesis and Characterization of 2‐Pyridylsulfur Pentafluorides

Current approaches to prepare SF₅‐substituted heterocycles during the synthesis of targeted heterocyclic compounds require the use of SF₅‐functionalized aryl or alkyne reagents or SF₅Cl as a source of the SF₅ functional group. Herein we report that excess oxidative fluorination of 2,2′‐dipyridyl disulfide with a KF/Cl₂/MeCN system leads to the formation of thirteen new 2‐pyridylsulfur chlorotetrafluorides (2‐SF₄Cl‐pyridines). These molecules are found to undergo further chlorine–fluorine exchange reactions by treatment with silver(I) fluoride enabling ready access to a series of ten new substituted 2‐pyridylsulfur pentafluorides (2‐SF₅‐pyridines). This is the first preparatively simple and readily scalable example of the transformation of an existing heterocyclic sulfur functionality to prepare SF₅‐substituted heterocycles.     

Synthesis of a novel Boc-protected cyclopropane-modified proline analogue

The synthesis of the Boc derivative of a novel member of the cyclopropane-modified proline library, Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid, is reported. The synthesis was performed in six steps starting from (2S,4R)-4-hydroxyproline using a modified Simmons-Smith reaction as the key step. The reaction conditions for all the steps were carefully selected to avoid racemization at the chiral centers in the intermediates and the final product.     

Generation of new landomycins by combinatorial biosynthetic manipulation of the LndGT4 gene of the landomycin E cluster in S. globisporus

A 3 kb DNA fragment from the Streptomyces globisporus 1912 landomycin E (LaE) biosynthetic gene cluster (lnd) was completely sequenced. Three open reading frames were identified, lndGT4, lndZ4, and lndZ5, whose probable translation products resemble a glycosyltransferase, a reductase, and a hydroxylase, respectively. Studies of generated mutants from disruption and complementation experiments involving the lndGT4 gene allowed us to determine that LndGT4 controls the terminal L-rhodinose sugar attachment during LaE biosynthesis and that LndZ4/LndZ5 are responsible for the unique C11-hydroxylation of the landomycins. Generation of the novel landomycins F, G, and H in the course of these studies provided evidence for the flexibility of lnd glycosyltransferases toward their acceptor substrates and a basis for initial structure-activity relationships within the landomycin family of antibiotics.     

Saturated Boronic Acids,Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

This review discusses recent advances in the chemistry of saturated boronic acids, boronates, and trifluoroborates. Applications of the title compounds in the design of boron-containing drugs are surveyed, with special emphasis on α-amino boronic derivatives. A general overview of saturated boronic compounds as modern tools to construct C(sp³)−C and C(sp³)-heteroatom bonds is given, including recent developments in the Suzuki-Miyaura and Chan-Lam cross-couplings, single-electron-transfer processes including metallo- and organocatalytic photoredox reactions, and transformations of boron “ate” complexes. Finally, an attempt to summarize the current state of the art in the synthesis of saturated boronic acids, boronates, and trifluoroborates is made, with a brief mention of the “classical” methods (transmetallation of organolithium/magnesium reagents with boron species, anti-Markovnikov hydroboration of alkenes, and the modification of alkenyl boron compounds) and a special focus on recent methodologies (boronation of alkyl (pseudo)halides, derivatives of carboxylic acids, alcohols, and primary amines, boronative C−H activation, novel approaches to alkene hydroboration, and 1,2-metallate-type rearrangements).     

Multigram Synthesis of α- and γ-((Hetera)cyclo)alkylpyridines through α-Arylation of (Hetero)aliphatic Nitriles

A systematic study on the S_nAr reaction of halogenated fluoropyridines and (hetero)aliphatic nitrile anions as an approach to the synthesis of functionalized pyridines bearing a (cyclo)alkyl or saturated heterocyclic substituent by is described. The scope of the method was demonstrated on a wide range of (hetero)aliphatic nitriles (including three- to six-membered cycloalkane derivatives and N-, O-, S-containing saturated heterocycles) and all isomeric halogenated 2-and 4-fluoropyridines. High chemo- and regioselectivity (i. e., exclusive substitution of the fluorine atom), as well as excellent scalability of the proposed reaction sequence were demonstrated (up to 450 g for the arylation step or up to 77 g of cycloalkylpyridine over two steps in a single run). The utility of the synthesized products was illustrated in the additional functional group transformations resulting in synthetically valuable pyridine-containing building blocks.