- An Efficient Method for the Programmed Synthesis of Multifunctional Diketopyrrolopyrroles
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A new, transformative methodology for the preparation of diketopyrrolopyrroles from aldehydes, primary amines, nitriles, and diethyl oxalacetate has been developed. It is now possible to prepare diketopyrrolopyrroles bearing an ordered arrangement of three different substituents from abundant and commercially available materials, allowing the independent regulation of all desired physicochemical properties. For the first time very electron-rich (carbazol-3-yl, dimethylaminophenyl, pyrrolo[3,2-b]pyrrolyl), and sterically hindered substituents (naphthalen-1-yl, quinolin-4-yl, acridin-9-yl, imidazo[1,5-a]pyridin-1-yl, 2-bromophenyl etc.) can be appended to the diketopyrrolopyrrole core by condensation of an appropriate nitrile with a pyrrolidin-2-one intermediate. Even greater synthetic possibilities are related to the fact that such demanding substituents as 4-dimethylaminophenyl, indol-3-yl, and 2-methoxyphenyl can be incorporated from aldehyde precursors, bypassing problems with the nitriles reactivity.
- Gryko, Daniel T.,Pieczykolan, Micha?,Sadowski, Bart?omiej
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- Multicomponent Bioluminescence Imaging with a π-Extended Luciferin
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Bioluminescence imaging with luciferase-luciferin pairs is commonly used for monitoring biological processes in cells and whole organisms. Traditional bioluminescent probes are limited in scope, though, as they cannot be easily distinguished in biological environments, precluding efforts to visualize multicellular processes. Additionally, many luciferase-luciferin pairs emit light that is poorly tissue penetrant, hindering efforts to visualize targets in deep tissues. To address these issues, we synthesized a set of π-extended luciferins that were predicted to be red-shifted luminophores. The scaffolds were designed to be rotationally labile such that they produced light only when paired with luciferases capable of enforcing planarity. A luciferin comprising an intramolecular "lock"was identified as a viable light-emitting probe. Native luciferases were unable to efficiently process the analog, but a complementary luciferase was identified via Rosetta-guided enzyme design. The unique enzyme-substrate pair is red-shifted compared to well-known bioluminescent tools. The probe set is also orthogonal to other luciferase-luciferin probes and can be used for multicomponent imaging. Four substrate-resolved luciferases were imaged in a single session. Collectively, this work provides the first example of Rosetta-guided design in engineering bioluminescent tools and expands the scope of orthogonal imaging probes.
- Yao, Zi,Zhang, Brendan S.,Steinhardt, Rachel C.,Mills, Jeremy H.,Prescher, Jennifer A.
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supporting information
p. 14080 - 14089
(2020/09/02)
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- A novel anti-Alzheimer agent inhibiting oligomerization and fibriliation of beta-amyloid protects neuronal cell from Aβ-induced cytotoxicity
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The present invention relates to development of a novel treatment agent for Alzheimerandprime;s disease, having ability of protecting neural cells and inhibiting fibrosis and oligomerization of beta-amyloid. A compound of the present invention is capable of, while maintaining therapeutic effects on Alzheimerandprime;s disease, recovering ability of directly inhibiting oligomerized and fibrous amyloid beta, which is inherent activities of existing curcumin, thereby being useful as a novel inhibitor.COPYRIGHT KIPO 2017
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Paragraph 0076; 0077
(2017/04/25)
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- Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity
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A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42 oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.
- Kim, Kyoungdo,Park, Kwang-Su,Kim, Mi Kyoung,Choo, Hyunah,Chong, Youhoon
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supporting information
p. 9564 - 9569
(2015/09/28)
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- INDOLE SULFONAMIDE MODULATORS OF PROGESTERONE RECEPTORS
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Compounds of Formula (I), wherein n is 1 or 2, and R1, R2, R3, R4, R5, R6, R7, and R8 are as defined herein, their preparation, pharmaceutical compositions, and methods of use are disclosed.
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Page/Page column 27
(2008/06/13)
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