128924-04-9Relevant academic research and scientific papers
Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin
Shang, Changhui,Kang, Yulong,Yang, Qingyun,Zhu, Qibin,Yao, Chunsuo
, p. 3768 - 3776 (2019)
A versatile and efficient enantioselective total synthesis of natural isorhapontigenin dimers (?)-gnetulin, (+)-gnetulin, and (±)-gentulin was proposed. By using this method, we were able to synthesize the dimers from commercial available achiral materials in 13 steps, and achieve a 7%–9% overall yield with >98% enantiomeric excess. The key features of the method include the stereocontrolled enantioselective conjugate reduction of 3-arylindenone catalyzed by methyloxazaborolidine (Me-CBS) and the α-arylation of 3-aryl-1-indanones. Benzylic sulfide was accessed in excellent yield through the InCl3-catalyzed thio-etherification reaction between 2,3-diarylindanol and bezylic thiol. The method is practical and might thus be useful in the enantioselective synthesis of the optical antipodes of natural indane derivatives with or without methoxy groups at aromatic rings. (Figure presented.).
Facile and divergent optimization of chromazonarol enabled the identification of simplified drimane meroterpenoids as novel pharmaceutical leads
Hu, Nvdan,Kong, Wenlong,Li, Shengkun,Song, Baoan,Wang, Xia
supporting information, (2021/10/16)
The diversity of drimane hydroquinones was significantly expanded by the facile construction of (+)-chromazonarol relevant natural products, isomers, and analogues for the discovery of new pharmaceutical leads. The structure-activity relationship of (+)-c
CONJUGATED CHEMICAL INDUCERS OF DEGRADATION AND METHODS OF USE
-
Page/Page column 442; 462, (2020/05/28)
The subject matter described herein is directed to antibody-CIDE conjugates (Ab-CIDEs), to pharmaceutical compositions containing them, and to their use in treating diseases and conditions where targeted protein degradation is beneficial.
Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer
Crowley, Vincent M.,Huard, Dustin J. E.,Lieberman, Raquel L.,Blagg, Brian S. J.
supporting information, p. 15775 - 15782 (2017/11/14)
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure–activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.
SHIP1 MODULATORS AND RELATED METHODS
-
Paragraph 0137; 0138, (2016/08/23)
Compounds of structure (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2 and A are as defined herein are disclosed. Such compounds have enhanced water solubility and have activity as SHIP1 modulators, and thus may be used to treat any of a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. Enantioselective methods for preparation of compounds of structure (I), compositions comprising a compound of structure (I) in combination with a pharmaceutically acceptable carrier or diluents and methods of SHIP1 modulation by administration of such compounds to an animal in need thereof are also disclosed.
Two novel tetracycles, cassibiphenols A and B from the flowers of Cassia siamea
Deguchi, Jun,Sasaki, Tadahiro,Hirasawa, Yusuke,Kaneda, Toshio,Kusumawati, Idha,Shirota, Osamu,Morita, Hiroshi
supporting information, p. 1362 - 1365 (2014/03/21)
Chemical investigation of the flowers of Cassia siamea (Leguminosae), resulted in the isolation of two novel tetracycles connecting 5-(2-hydroxypropyl)benzene-1,3-diol, cassibiphenols A (1) and B (2). The structures were elucidated by analysis of the 1D, 2D NMR, and HRMS spectra. Synthesis of a tetracyclic core of 1 and 2 led to determine the absolute configuration of 1 and C-12 of 2.
META-SUBSTITUTED BIPHENYL PERIPHERALLY RESTRICTED FAAH INHIBITORS
-
Paragraph 0154; 0155, (2013/03/26)
The present invention provides methods of making and using peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH). The present invention provides compounds and compositions that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). The present invention also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the invention also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit.
Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors
Moreno-Sanz, Guillermo,Duranti, Andrea,Melzig, Laurin,Fiorelli, Claudio,Ruda, Gian Filippo,Colombano, Giampiero,Mestichelli, Paola,Sanchini, Silvano,Tontini, Andrea,Mor, Marco,Bandiera, Tiziano,Scarpelli, Rita,Tarzia, Giorgio,Piomelli, Daniele
, p. 5917 - 5930 (2013/08/23)
The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3′-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3′-carbamoyl-5- hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.
Total synthesis of (+)-korupensamine B via an atropselective intermolecular biaryl coupling
Huang, Shenlin,Petersen, Tue B.,Lipshutz, Bruce H.
supporting information; experimental part, p. 14021 - 14023 (2011/01/04)
The asymmetric total synthesis of nonracemic korupensamine B is reported. It includes a newly designed and highly trans-diastereoselective (>20:1 dr) route to the tetrahydroisoquinoline ring and an unprecedented atropdiastereoselective Suzuki-Miyaura coupling for construction of the fully fashioned naphthylisoquinoline framework that invokes π stacking as a possible source of stereocontrol.
Total synthesis of berkelic acid
Snaddon, Thomas N.,Buchgraber, Philipp,Schulthoff, Saskia,Wirtz, Conny,Mynott, Richard,Fuerstner, Alois
supporting information; experimental part, p. 12133 - 12140 (2011/02/25)
A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route. Queue up: Three deprotection and three bond-forming reactions, all of which are effected just by a trace of HCl, zip an easily attained enone to the polycyclic core of berkelic acid in diastereomerically pure form and essentially quantitative yield. This cascade process paves the way to a concise and effective total synthesis of this alleged metalloproteinase-3 inhibitor and cytotoxic metabolite derived from an extremophilic fungus.
