Organic & Biomolecular Chemistry (v.13, #40)

Front cover (10077-10078).

Contents list (10079-10085).

Production of chiral compounds using immobilized cells as a source of biocatalysts by Camila M. Kisukuri; Leandro H. Andrade (10086-10107).
The importance of chiral compounds in all fields of technology and life sciences is shown. Small chiral molecules are mainly used as building blocks in the synthesis of more complex and functionalized compounds. Nature creates and imposes stereoselectivity by means of enzymes, which are highly efficient biocatalysts. The use of whole cells as a biocatalyst source is a promising strategy for avoiding some drawbacks associated with the use of pure enzymes, especially their high cost. The use of free cells is also challenging, since cell lysis can also occur under the reaction conditions. However, cell immobilization has been employed to increase the catalytic potential of enzymes by extending their lifetimes in organic solvents and non-natural environments. Besides, immobilized cells maintain their biocatalytic performance for several reaction cycles. Considering the above-mentioned arguments, several authors have synthesized different classes of chiral compounds such as alcohols, amines, carboxylic acids, amides, sulfides and lactones by means of immobilized cells. Our aim was to discuss the main aspects of the production of chiral compounds using immobilized cells as a source of biocatalysts, except under fermentation conditions.

The first o-iodoxybenzoic acid (IBX) mediated oxidation of unactivated amines to imines is described. A range of meso-pyrrolidines were shown to be suitable substrates. The chemical space was further explored with one-pot oxidative Ugi-type and aza-Friedel–Crafts reactions, which proved to be highly diastereoselective.

Copper-catalyzed C(sp3)–H functionalization of ketones with vinyl azides: synthesis of substituted-1H-pyrroles by Ramachandra Reddy Donthiri; Supravat Samanta; Subbarayappa Adimurthy (10113-10116).
Copper-catalyzed C(sp3)–H functionalization of ketones with vinyl azides for the synthesis of substituted pyrroles has been developed. The method is a straightforward and efficient way to access a series of 2,3,5-trisubstituted-1H-pyrroles in modest to excellent yields with broad functional group tolerance under mild conditions.

A hybridisation-dependent membrane-insertable amphiphilic DNA by C. Dohno; K. Matsuzaki; H. Yamaguchi; T. Shibata; K. Nakatani (10117-10121).
We synthesised a novel membrane-insertable amphiphilic DNA. The amphiphilic DNA had a nine-nucleotide hydrophobic region at one end consisting of octyl phosphotriester linkages. The amphiphilic DNA bound to the lipid membrane by inserting the hydrophobic region; this process was facilitated by the presence of the complementary DNA strand.

Efficient Pd-catalyzed domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives by Min Jiang; Haoyue Xiang; Fangxia Zhu; Xing Xu; Lianfu Deng; Chunhao Yang (10122-10126).
An efficient and practical one-pot domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives from readily available 2-(2-bromophenyl)acetonitriles was developed. The overall protocol involves a Buchwald–Hartwig type coupling and a base-promoted intramolecular nucleophilic reaction. The reaction scope, advantages and limitations are discussed.

Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B by Rodolfo Tello-Aburto; Liam P. Hallada; Doleshwar Niroula; Snezna Rogelj (10127-10130).
The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (−)-10 and (−)-15 were found to be about 100 times more potent, and to selectively kill MCF-7 cancerous cells.

Efficient methods for enol phosphate synthesis using carbon-centred magnesium bases by William J. Kerr; David M. Lindsay; Vipulkumar K. Patel; Muralikrishnan Rajamanickam (10131-10135).
Efficient conversion of ketones into kinetic enol phosphates under mild and accessible conditions has been realised using the developed methods with di-tert-butylmagnesium and bismesitylmagnesium. Optimisation of the quench protocol resulted in high yields of enol phosphates from a range of cyclohexanones and aryl methyl ketones, with tolerance of a range of additional functional units.

Synthesis and biological evaluation of pyrazolo–triazole hybrids as cytotoxic and apoptosis inducing agents by T. Srinivasa Reddy; Hitesh Kulhari; V. Ganga Reddy; A. V. Subba Rao; Vipul Bansal; Ahmed Kamal; Ravi Shukla (10136-10149).
A series of pyrazolo–triazole hybrids were designed and synthesized by combining the 1,3-diphenyl pyrazole and triazole scaffolds to obtain (1-benzyl-1H-1,2,3-triazol-4-yl)(1,3-diphenyl-1H-pyrazol-4-yl)methanones. All the synthesized compounds were screened for their anticancer activity against four tumor cell lines, viz. HT-29 (colon), PC-3 (prostate), A549 (lung), and U87MG (glioblastoma) cells. Most of the tested compounds showed moderate to potent cell growth inhibition on different cancer cells, in particular, the compounds 17, 23, and 29 exhibited promising cytotoxicity against these cell lines with the IC50 values in the range of 0.86–3.72 μM. In addition, the potential mechanism of cell growth inhibition and apoptotic induction by these compounds was investigated in U87MG cancer cells using cell-based assays, including wound healing assay, flow cytometry, Hoechst staining, acridine orange/ethidium bromide staining, Annexin V-FITC/propidium Iodide dual staining, Rhodamine 123 staining, and carboxy-DCFDA staining. The results indicate that the compounds induce apoptosis in U87MG cells via mitochondrial pathway through up-regulation of pro-apoptotic (Bax) and down-regulation of anti-apoptotic (Bcl-2) genes. Based on these studies, three compounds 17, 23 and 29 have been identified as promising new molecules that have the potential to be developed as leads.

Enhanced immunogenicity of multivalent MUC1 glycopeptide antitumour vaccines based on hyperbranched polymers by M. Glaffig; B. Palitzsch; N. Stergiou; C. Schüll; D. Straßburger; E. Schmitt; H. Frey; H. Kunz (10150-10154).
Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in mice and elicited IgG antibodies of distinctly higher affinity to epithelial tumour cells.

Dual-mode chemodosimetric response of dibromo-BODIPY with anions by Adiki Raja Sekhar; Masood Ayoub Kaloo; Jeyaraman Sankar (10155-10161).
Aromatic nucleophilic substitution (Ar-SN) reaction of 3,5-dibromopentafluorophenyl-BODIPY has been explored as a remarkable basis for selective discrimination of anions. The efficient and characteristic ability of anions to modulate the absorption and emission properties of the dye provides an instantaneous distinction through dual-modes. For the first time, a novel platform to achieve dual-modal and promising recognition with discrimination of a series of anions differing in the nucleophilic atoms (F, O, C and N) has been taken into consideration. The behaviour of various anions with dibromo-BODIPY and vivid signal transduction has been fully established with absorption and emission spectroscopy. In addition to this, recognition events have been unambiguously characterized by 1H, 19F-NMR and single-crystal XRD.

Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents by Ahmed Kamal; Anver Basha Shaik; Bala Bhaskara Rao; Irfan Khan; G. Bharath Kumar; Nishant Jain (10162-10178).
As pyrazole and isoxazole based derivatives are well-known for displaying a considerable biological profile, an attempt has been made to unravel their cytotoxic potential. In this context, a number of pyrazole/isoxazole linked arylcinnamide conjugates (15a–o and 21a–n) have been synthesized by employing a straight forward route. The basic structure comprised three ring scaffolds (A, B and C): methoxyphenyl rings as A and C rings and a five membered heterocyclic ring (pyrazole or isoxazole) as the B-ring. To achieve clear understanding, these derivatives are categorized as pyrazole-phenylcinnamides (PP) and isoxazole-phenylcinnamides (IP). These compounds have been evaluated for their ability to inhibit the growth of various human cancer cell lines such as HeLa, DU-145, A549 and MDA-MB231 and most of them exhibit considerable cytotoxic effects. Some of them like 15a, 15b, 15e, 15i and 15l exhibit promising cytotoxicity in HeLa cells (IC50 = 0.4, 1.8, 1.2, 2.7 and 1.7 μM). Amongst them 15a, 15b and 15e were taken up for detailed biological studies, they were found to arrest the cells in the G2/M phase of the cell cycle. Moreover, they were investigated for their effect on the microtubular cytoskeletal system by using a tubulin polymerization assay, immunofluroscence and molecular docking studies; interestingly they demonstrate a significant inhibition of tubulin polymerization.

A computational study of the phosphoryl transfer reaction between ATP and Dha in aqueous solution by I. Bordes; J. J. Ruiz-Pernía; R. Castillo; V. Moliner (10179-10190).
Phosphoryl transfer reactions are ubiquitous in biology, being involved in processes ranging from energy and signal transduction to the replication genetic material. Dihydroxyacetone phosphate (Dha-P), an intermediate of the synthesis of pyruvate and a very important building block in nature, can be generated by converting free dihydroxyacetone (Dha) through the action of the dihydroxyacetone kinase enzyme. In this paper the reference uncatalyzed reaction in solution has been studied in order to define the foundations of the chemical reaction and to determine the most adequate computational method to describe this electronically complex reaction. In particular, the phosphorylation reaction mechanism between adenosine triphosphate (ATP) and Dha in aqueous solution has been studied by means of quantum mechanics/molecular mechanics (QM/MM) Molecular Dynamics (MD) simulations with the QM subset of atoms described with semi-empirical and DFT methods. The results appear to be strongly dependent on the level of calculation, which will have to be taken into account for future studies of the reaction catalyzed by enzymes. In particular, PM3/MM renders lower free energy barriers and a less endergonic process than AM1d/MM and PM6/MM methods. Nevertheless, the concerted pathway was not located with the former combination of potentials.

Synthesis of 2- and 6-thienylazulenes by palladium-catalyzed direct arylation of 2- and 6-haloazulenes with thiophene derivatives by Taku Shoji; Akifumi Maruyama; Takanori Araki; Shunji Ito; Tetsuo Okujima (10191-10197).
Preparation of 2- and 6-thienylazulene derivatives was established by the palladium-catalyzed direct cross-coupling reaction of 2- and 6-haloazulenes with the corresponding thiophene derivatives in good yield. Several thienylazulene derivatives were also used in the reaction with 2-chloroazulene derivatives in the presence of the palladium-catalyst to afford the thiophene derivatives with two azulene functions in good yield.

Synthesis and electronic properties of π-extended flavins by L. N. Mataranga-Popa; I. Torje; T. Ghosh; M. J. Leitl; A. Späth; M. L. Novianti; R. D. Webster; B. König (10198-10204).
Flavin derivatives with an extended π-conjugation were synthesized in moderate to good yields from aryl bromides via a Buchwald–Hartwig palladium catalyzed amination protocol, followed by condensation of the corresponding aromatic amines with violuric acid. The electronic properties of the new compounds were investigated by absorption and emission spectroscopy, cyclic voltammetry, density functional theory (DFT) and time dependent density functional theory (TDDFT). The compounds absorb up to 550 nm and show strong luminescence. The photoluminescence quantum yields ϕPL measured in dichloromethane reach 80% and in PMMA (poly(methyl methacrylate)) 77%, respectively, at ambient temperature. The electrochemical redox behaviour of π-extended flavins follows the mechanism previously described for the parent flavin.

Benzyl anion transfer in the fragmentation of N-(phenylsulfonyl)-benzeneacetamides: a gas-phase intramolecular SNAr reaction by Shanshan Shen; Yunfeng Chai; Yaqin Liu; Chang Li; Yuanjiang Pan (10205-10211).
In this study, we report a gas-phase benzyl anion transfer via intramolecular aromatic nucleophilic substitution (SNAr) during the course of tandem mass spectrometry of deprotonated N-(phenylsulfonyl)-benzeneacetamide. Upon collisional activation, the formation of the initial ion/neutral complex ([C6H5CH2/C6H5SO2NCO]), which was generated by heterolytic cleavage of the CH2–CO bond, is proposed as the key step. Subsequently, the anionic counterpart, benzyl anion, is transferred to conduct the intra-complex SNAr reaction. After losing neutral HNCO, the intermediate gives rise to product ion B at m/z 231, whose structure is confirmed by comparing the multistage spectra with those of deprotonated 2-benzylbenzenesulfinic acid and (benzylsulfonyl)benzene. In addition, intra-complex proton transfer is also observed within the complex [C6H5CH2/C6H5SO2NCO] to generate product ion C at m/z 182. The INC-mediated mechanism was corroborated by theoretical calculations, isotope experiments, breakdown curve, substituent experiments, etc. This work may provide further understanding of the physicochemical properties of the gaseous benzyl anion.

Stereoselective synthesis of octahydrocyclohepta[c]pyran-6(1H)-one scaffolds through a Prins/alkynylation/hydration sequence by A. Venkateswarlu; M. Kanakaraju; Ajit C. Kunwar; B. V. Subba Reddy (10212-10215).
Aldehydes undergo a smooth coupling with (E/Z)-non-3-en-8-yn-1-ol in the presence of 10 mol% of CuX and BF3·OEt2 under mild conditions to produce a novel class of octahydrocyclohepta[c]pyran-6(1H)-one derivatives in good yields with excellent diastereoselectivity through a sequential Prins/alkynylation/hydration. This is the first report on the termination of Prins cyclization with a tethered alkyne.

New pentaerythritol tetrabromide-based chiral quaternary ammonium salts acting as organocatalysts (7a and 7b) have been prepared and used as organocatalysts for enantioselective Michael addition reactions between various nitroolefins and Michael donors (malonates) under mild reaction conditions, such as lower concentration of base and catalyst and room temperature, with very good chemical yields (up to 97%) and ee's (up to 99%).

Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells by Yi-Min Liu; Hsueh-Yun Lee; Mei-Jung Lai; Shiow-Lin Pan; Hsiang-Ling Huang; Fei-Chiao Kuo; Mei-Chuan Chen; Jing-Ping Liou (10226-10235).
We synthesized a series of pyrimidinedione derivatives and evaluated their activities. The results indicate that compound 6, 4-[5-fluoro-2,6-dioxo-3-(tetrahydro-furan-2-yl)-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-N-hydroxy-benzamide, exhibits potent antiproliferative activity, apoptosis induction with cleavage of caspase and PARP, and enhanced tendency to inhibit HDAC6 (IC50 = 12.4 nM) activity over HDAC1 (IC50 = 1710 nM) and HDAC2 (IC50 = 5500 nM). Compound 6 also inhibits tumor growth and is less toxic than parent 4in vivo. These data provide compelling evidence that compound 6 is a potential antitumor compound with HDAC6 targeted inhibitory activity and may be tested for preclinical investigation for cancer treatment.

Palladium-catalyzed direct and regioselective C–H acyloxylation of indolizines by Jinwei Sun; Fuyao Wang; Yongmiao Shen; Huizhen Zhi; Hui Wu; Yun Liu (10236-10243).
A direct and regioselective C1-acyloxylation of indolizines was developed via palladium-catalyzed C–H functionalization. A series of indolizines were successfully acyloxylated at the C1 position with the tolerance of a broad range of functional groups. In this reaction, high regioselectivity was achieved in the absence of a directing group. This work represents the first example of indolizine acyloxylation via C–H activation.

Superoxide dismutase (SOD) is a 32 kDa dimeric enzyme that actively removes a toxic oxygen species within red cells. The acellular protein itself does not survive circulation as it is filtered through the kidney. Conjugating the protein to another SOD should increase the size of the dual protein above the threshold for filtration by the kidney, making the material a potential therapeutic in circulation. Site-selective chemical cross-linking of SOD introduces a bioorthogonal azide group on the cross-link so that two SODs react efficiently with a bis-alkyne through phase-directed copper-catalyzed azide–alkyne cycloaddition (PDCuAAC). The modification has a negligible effect on the catalytic activity of the constituent proteins. Consistent with the retained activity, circular dichroism (CD) spectroscopy indicates that the secondary structures of the proteins are similar to that of the native protein.

Back cover (10251-10252).