- ESTER COMPOUND
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This ester compound is represented by formula (1) [wherein R1 to R24 are each independently a hydrogen atom, a halogen atom, a hydrocarbon group, or a heteroatom-containing hydrocarbon group; R1 to R10, R23, and R24 may be bonded to each other to form a ring, and adjacent substituents may be directly bonded to form a multiple bond; R11 to R24 may be bonded to each other to form a ring, and adjacent substituents may be bonded to each other to form a multiple bond; at least two, as a pair, of R1 to R24 are bonded to each other to form a ring structure; n2 to n5 each independently indicate an integer of 0-2; n1 and n6 each independently indicate 0 or 1; and L1 and L2 are each independently a hydrocarbon group or a heteroatom-containing hydrocarbon group].
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Paragraph 0575-0577; 0582-0584; 0736-0738
(2022/04/06)
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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supporting information
p. 17887 - 17896
(2020/08/19)
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- Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain
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Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3‘,5‘-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain.
- Kaur, Jatinder,Soto-Velasquez, Monica,Ding, Zhong,Ghanbarpour, Ahmadreza,Lill, Markus A.,van Rijn, Richard M.,Watts, Val J.,Flaherty, Daniel P.
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p. 568 - 585
(2018/11/26)
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