The textures and the growth kinetics of the hexagons were analyzed using a polarizing microscope equipped with a Mettler hot stage and a Leica image analyzing system. AFM investigations were performed with a Digital Instruments setup and fluorescence microscopy investigations were performed on the discotic host materials containing fluorescent dyes as guest molecules.Poly((3-substituted)thiophenes) (PTs) represent a class of polymer that are environmentally stable, highly processable, and exhibit high electrical conductivity. These materials are promising candidates for field-effect transistors, optical and electronic sensors, light-emitting diodes (LEDs), and nonlinear optical materials, to name a few. [1] However, the polymerization of the non-symmetrical 3substituted thiophene leads to a mixture of PT structures containing three regiochemical linkages between repeat units (2,2¢, 2,5¢, 5,5¢). The 2,2¢ and 5,5¢ couplings are considered defects in the polymer structure since they diminish conjugation and prevent ideal solid-state packing, thus impairing these materials' electronic and photonic properties. However, the synthesis of the pure 2,5¢ (or head-to-tail (HT) coupled) regioregular PTs was first accomplished by our group by employing Kumada cross-coupling methods to regiospecifically polymerize 2-bromo-3-alkyl-5-magnesiobromothiophene. [2] Other methods have employed organozinc [3] reagents with nickel(II) catalysts. We have also shown that regioregular PTs can be made using Stille crosscoupling procedures, [4,5] while others have employed Suzuki cross-coupling. [6] Despite these new advances, the above synthetic procedures have some drawbacks. The method developed in our laboratory [2] requires highly purified starting materials, most important of which is the monomer, 2-bromo-3-alkylthiophene. In addition, this method requires cryogenic temperatures and long polymerization times ranging from 12 to 24 h or longer. The Rieke method starts with the easy-to-purify 2,5-dibromo-3-alkylthiophene (since the compound is the highest boiling fraction in the crude mixture in its preparation), however, it requires the non-trivial preparation of Rieke zinc via alkali metal reduction of zinc halides, employs cryogenic temperatures, and necessitates long reaction times. Both Suzuki and Stille coupling methods also suffer from many of the above drawbacks. In addition, there have been no reports of using the above methods for the large-scale synthesis of HT-PTs. This communication will describe a new method for the preparation of HT-poly(3-alkylthiophenes) (HT-PATs) that is simple, efficient, fast, and economical.[**] We are grateful to the NSF (CHE-9509959) for financial support. We also thank Lubrizol for providing a research fellowship for RSL and Eric van Inwegen for help with syntheses.See page 187 for ordering details.

An improved forward chemical genetics approach was successfully demonstrated using a tagged library concept. A small-molecule triazine library with linkers was used to screen for brain/eye developmental phenotypes in a zebrafish embryo system. This approach enabled the rapid isolation of the target proteins by facile affinity matrix preparation and elucidated the first small-molecule inhibitors for several ribosomal accessory proteins or their complex as the target.

Presented here is the synthesis and unique physical properties for a new class of highly processable regioregular poly(3-alkoxy-functionalized thiophenes). These polymers exhibit high electrical conductivities with very good stabilities (over 3 years) when doped with iodine vapor followed by exposure to ambient conditions.

Phosphorylation of translation initiation factor 2alpha (eIF2alpha) coordinates a translational and transcriptional program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. A screen for small molecule activators of the ISR identified two related compounds that also activated sterol-regulated genes by blocking cholesterol biosynthesis at the level of CYP51. Ketoconazole, a known CYP51 inhibitor, had similar effects, establishing that perturbed flux of precursors to cholesterol activates the ISR. Surprisingly, compound-mediated activation of sterol-regulated genes was enhanced in cells with an ISR-blocking mutation in the regulatory phosphorylation site of eIF2alpha. Furthermore, induction of the ISR by an artificial drug-activated eIF2alpha kinase reduced the level of active sterol regulatory element binding protein (SREBP) and sterol-regulated mRNAs. These findings suggest a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress.

The first orthogonal combinatorial synthesis of a high-purity triazine library was demonstrated. Novel triazine-based microtubule inhibitors were discovered by an efficient zebrafish embryo screening and in vitro microtubule polymerization assay.

Insulin and insulin-like growth factor have an essential role in growth, development and the maintenance of metabolic homeostasis, including glucose uptake from the bloodstream. Researchers have identified mutations in insulin receptors that cause severe insulin resistance, and a temperature-sensitive daf-2 (a gene encoding an insulin receptor-like protein) mutant in Caenorhabditis elegans has served as an insulin resistance model. Here we report a forward chemical genetic approach with a tagged library that we used to identify a small molecule, GAPDH segregator (GAPDS), that suppresses the dauer formation induced by the daf-2 mutant. Like insulin, GAPDS increased both glucose uptake and the concentration of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) in mammalian preadipocytes. Using affinity matrices and RNA interference, we identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a GAPDS target. We discovered that GAPDH stimulates phosphatase activity against not only PtdIns(3,4,5)P(3) but also PtdIns(4,5)P(2). These results suggest that GAPDH is both an active regulator in the phosphoinositide-mediated signaling pathway and a potential new target for insulin resistance treatment.

Bioactive compounds can be used to selectively modulate gene function. We utilized a chemical genetic approach to dissect the mammalian pigmentation pathway and identify protein regulators. We screened a tagged library of 1170 small molecules in a cell-based assay and discovered a class of pigment-enhancing chemicals. From this class we characterized the small molecule melanogenin. Using melanogenin bound to an affinity matrix and amino acid sequencing, we identified the mitochondrial protein, prohibitin, as an intracellular binding target. Studies employing siRNA demonstrate that prohibitin is required for melanogenin to exert its propigmentary effects and reveal an unsuspected functional role for this protein in melanin induction. This represents a mechanism by which propigmentary signals are transduced and ultimately provides a potential target for the treatment of pigmentary disorders.

A triazine-based combinatorial library of small molecules was screened in albino murine melanocytes to identify compounds that induce pigmentation. Six compounds (of 1536 screened) produced at least 3-fold increases in pigmentation. Immunohistochemical studies demonstrated that the compounds conferred correct routing of the mistrafficked enzyme tyrosinase, which is critical to normal melanogenesis. Affinity matrices of the immobilized compounds allowed the cellular target to be identified as the mitochondrial F1F0-ATP synthase. Oligomycin and aurovertin B, small molecules known to inhibit the mitochondrial ATP synthase, were shown to compete with the triazine-based compounds for their cellular target in albino melanocytes and confer similar effects on pigmentation and tyrosinase rerouting. This is the first demonstration of the mitochondrial ATP synthase as a potential therapeutic target for restoring pigmentation in albino melanocytes.