Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin αvß3.

Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvß3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were constructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.

Donor-acceptor biomorphs from the ionic self-assembly of porphyrins.

Microscale four-leaf clover-shaped structures are formed by self-assembly of anionic and cationic porphyrins. Depending on the metal complexed in the porphyrin macrocycle (Zn or Sn), the porphyrin cores are either electron donors or electron acceptors. All four combinations of these two metals in cationic tetra(N-ethanol-4-pyridinium)porphyrin and anionic tetra(sulfonatophenyl)porphyrin result in related cloverlike structures with similar crystalline packing indicated by X-ray diffraction patterns. The clover morphology transforms as the ionic strength and temperature of the self-assembly reaction are increased, but the structures maintain 4-fold symmetry. The ability to alter the electronic and photophysical properties of these solids (e.g., by altering the metals in the porphyrins) and to vary cooperative interactions between the porphyrin subunits raises the possibility of producing binary solids with tunable functionality. For example, we show that the clovers derived from anionic Zn porphyrins (electron donors) and cationic Sn porphyrins (electron acceptors) are photoconductors, but when the metals are reversed in the two porphyrins, the resulting clovers are insulators.

Molecular organization in self-assembled binary porphyrin nanotubes revealed by resonance Raman spectroscopy.

Porphyrin nanotubes were formed by the ionic self-assembly of tetrakis(4-sulfonatophenyl) porphyrin diacid (H(4)TPPS(4)(2-)) and Sn(IV) tetra(4-pyridyl) porphyrin (Sn(OH(-))(X)TPyP(4+/5+) [X = OH(-) or H(2)O]) at pH 2.0. As reported previously, the tubes are hollow as revealed by transmission electron microscopy, approximately 60 nm in diameter, and can be up to several micrometres long. The absorption spectrum of the porphyrin nanotubes presents monomer-like Soret bands, as well as two additional red-shifted bands characteristic of porphyrin J-aggregates (offset face-to-face stacks). To elucidate the origin of the J-aggregate bands and the internal interactions of the porphyrins, the resonance Raman spectra have been obtained for the porphyrin nanotubes with excitations near resonance with the Soret J-aggregate band and the monomer-like bands. The resonance Raman data reveal that the Sn porphyrins are not electronically coupled to the J-aggregates within the tubes, which are formed exclusively by H(4)TPPS(4)(2-). This suggests that the internal structure of the nanotubes has H(4)TPPS(4)(2-) in aggregates that are similar to the widely studied H(4)TPPS(4)(2-) self-aggregates and that are segregated from the Sn porphyrins. Possible internal structures of the nanotubes and mechanisms for their formation are discussed.

Catalytically active, recyclable zirconocene supported at cross-links within porous polymer disks.

[reaction: see text] Copolymerization of bis(4-vinylbenzylcyclopentadienyl)zirconium dichloride and styrene in a test tube, followed by extraction of the bulk polymer and slicing into "disks" 1 mm thick and 5 mm in diameter, gives a supported zirconocene species that exhibits both stoichiometric and catalytic chemical activity. The disks catalyze reaction of trimethylaluminum and phenylacetylene to give alpha-methylstyrene with modest turnover numbers and are active over at least six recyclings.

Synthesis of 2-arylcycloalka-2,4-dienones using sulfone-based methodology.

Addition of the anion derived from (phenylthiomethyl)phenyl sulfone to a selection of aryl omega-alkenyl ketones gives adducts that via a sequence of Lewis acid catalyzed rearrangement, alpha-allylation, and metathesis give rise to 2-thio-4-cycloalkenones. These in turn give cycloalkadienones upon oxidation and elimination. An attempt to develop a polymer-supported variant fails because of the reversibility of sulfone anion addition.

Comparison of solid-phase and solution-phase chiral auxiliaries in the alkylation/iodolactonization sequence to gamma-butyrolactones.

Five prolinol-based chiral auxilaries have been compared for the stereoselective synthesis of gamma-butyrolactones via the sequence of N-acylation, C(alpha)()-allylation, and iodolactonization under both solution-phase and solid-phase conditions. Comparisons of stereoselectivity of both the C(alpha)()-allylation and iodolactonization processes indicate that incorporation of a non-C(2)-symmetric auxiliary as a polymer cross-link gives results superior to those obtained either in solution or with other non-C(2)-symmetric auxiliaries and comparable to those observed using a polymer-supported pseudo-C(2)-symmetric auxiliary.

Oxazaborolidines as functional monomers: ketone reduction using polymer-supported Corey, Bakshi, and Shibata catalysts.

The first two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst have been prepared. Functional monomers based structurally upon the original B-methylated catalyst have been used to prepare catalytic polymers containing the CBS moiety bound both in a pendant fashion and in the form of a cross-link. Enantioselective reductions of two prochiral ketones have been carried out using the original catalyst in the solution phase as well as the two solid-state systems. While the pendant-bound system shows reduced stereoselectivity, the cross-linked version affords enantioselectivities almost identical to those of the solution-phase model.