- Switching Lysophosphatidylserine G Protein-Coupled Receptor Agonists to Antagonists by Acylation of the Hydrophilic Serine Amine
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Three human G protein-coupled receptors (GPCRs)—GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3—are activated specifically by lysophosphatidylserine (LysoPS), an endogenous hydrolysis product of a cell membrane component, phosphatidylserine (PS). LysoPS consists of-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages. We previously generated potent and selective GPCR agonists by modification of the three modules and the ester linkage. Here, we show that a novel modification of the hydrophilic serine moiety, that is, N-acylations of the serine amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural exploration of the amide functionality provided access to a range of activities from agonist to partial agonist to antagonist. The present study would provide a new strategy for the development of lysophospholipid receptor antagonists.
- Sayama, Misa,Uwamizu, Akiharu,Ikubo, Masaya,Chen, Luying,Yan, Ge,Otani, Yuko,Inoue, Asuka,Aoki, Junken,Ohwada, Tomohiko
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p. 10059 - 10101
(2021/07/28)
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- Synthesis method and application of 1-aza -5-germanium-5-alkyl bicyclic [3.3.3] undecane compound.
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The invention provides a 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound having a structure shown in the formula I, and the types of the 1-aza-5-germanium hetero-5-alkyl bicyclic[3.3.3] hendecane compound are expanded. The provided compound can serve as a nucleophilic reagent, the air and humidity conditions of the nucleophilic reagent are stable, and the efficiency of the Ge-Stille coupling reaction of aryl halogen and the 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound is high.
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- Toward aplyronine payloads for antibody-drug conjugates: Total synthesis of aplyronines A and D
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The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.
- An?i?ek, Nika,Williams, Simon,Housden, Michael P.,Paterson, Ian
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p. 1343 - 1350
(2018/03/06)
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- NOVEL COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (formula 1) wherein R1,R2, R3, R4, R5, X, m and n are defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.
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Page/Page column 49-50
(2016/02/26)
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- A practical decarboxylative hydroxylation of carboxylic acids
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Irradiation of esters of N-hydroxy-2-thiazolinethione under air or oxygen at room temperature in the presence of tert-dodecanethiol affords the corresponding nor-alcohols after a reductive work-up.
- Barton, Derek H. R.,Gero, Stephane D.,Holliday, Pascale,Quiclet-Sire, Beatrice,Zard, Samir Z.
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p. 6751 - 6756
(2007/10/03)
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