114144-17-1Relevant articles and documents
Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes
Cummings, David F.,Canseco, Diana C.,Sheth, Pratikkumar,Johnson, James E.,Schetz, John A.
, p. 4783 - 4792 (2010)
Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)- 2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1,R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore.
Structural Diversification of Hapalindole and Fischerindole Natural Products via Cascade Biocatalysis
Hohlman, Robert M.,Newmister, Sean A.,Sanders, Jacob N.,Khatri, Yogan,Li, Shasha,Keramati, Nikki R.,Lowell, Andrew N.,Houk,Sherman, David H.
, p. 4670 - 4681 (2021)
Hapalindoles and related compounds (ambiguines, fischerindoles, welwitindolinones) are a diverse class of indole alkaloid natural products. They are typically isolated from the Stigonematales order of cyanobacteria and possess a broad scope of biological activities. Recently the biosynthetic pathway for assembly of these metabolites has been elucidated. In order to generate the core ring system, l-tryptophan is converted into the cis-indole isonitrile subunit before being prenylated with geranyl pyrophosphate at the C-3 position. A class of cyclases (Stig) catalyzes a three-step process, including a Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution, to create a polycyclic core. The formation of the initial alkaloid is followed by diverse late-stage tailoring reactions mediated by additional biosynthetic enzymes to give rise to a wide array of structural variations observed in this compound class. Herein, we demonstrate the versatility and utility of the Fam prenyltransferase and Stig cyclases toward the core structural diversification of this family of indole alkaloids. Through the synthesis of cis-indole isonitrile subunit derivatives, and with the aid of protein engineering and computational analysis, we have employed cascade biocatalysis to generate a range of derivatives and gained insights into the basis for substrate flexibility in this system.
Triphenylphosphine/1,2-Diiodoethane-Promoted Formylation of Indoles with N, N -Dimethylformamide
Zhu, Yu-Rong,Lin, Jin-Hong,Xiao, Ji-Chang
supporting information, p. 259 - 263 (2021/11/22)
Despite intensive studies on the synthesis of 3-formylindoles, it is still highly desirable to develop efficient methods for the formylation of indoles, due to the shortcomings of the reported methods, such as inconvenient operations and/or harsh reaction conditions. Here, we describe a Ph3P/ICH2CH2I-promoted formylation of indoles with DMF under mild conditions. A Vilsmeier-type intermediate is readily formed from DMF promoted by the Ph3P/ICH2CH2I system. A onestep formylation process can be applied to various electron-rich indoles, but a hydrolysis needs to be carried out as a second step in the case of electron-deficient indoles. Convenient operations make this protocol attractive.
Synthesis method of 5-iodoindole compound
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Paragraph 0014-0015, (2021/03/13)
The invention discloses a synthesis method of a 5-iodo indole compound, and the method comprises the following steps: by using an indole compound as a starting raw material and Niodo succinimide or iodine as an iodine source, carrying out free radical reaction in a halogenated organic solvent at normal temperature and normal pressure in the presence of Lewis acid to synthesize the 5-iodo indole compound. The synthesis method is mild in condition, wide in substrate application range, good in functional group tolerance and free of metal participation, and has the advantages of being easy to operate, environmentally friendly, high in specific regioselectivity and the like.
N-skatyltryptamines-dual 5-ht6r/d2r ligands with antipsychotic and procognitive potential
Bojarski, Andrzej J.,Bugno, Ryszard,Cie?lik, Paulina,Duszyńska, Beata,Handzlik, Jadwiga,Hogendorf, Adam S.,Hogendorf, Agata,Kaczorowska, Katarzyna,Kurczab, Rafa?,Latacz, Gniewomir,Lenda, Tomasz,Sata?a, Grzegorz,Staroń, Jakub,Szewczyk, Bernadeta
, (2021/08/17)
A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study
Sigalapalli, Dilep Kumar,Pooladanda, Venkatesh,Singh, Priti,Kadagathur, Manasa,Guggilapu, Sravanthi Devi,Uppu, Jaya Lakshmi,Tangellamudi, Neelima D.,Gangireddy, Pavan Kumar,Godugu, Chandraiah,Bathini, Nagendra Babu
supporting information, (2019/08/26)
A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ± 0.12 μM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ± 0.23 μM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/β-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies.
IMIDAZOLYL-SUBSTITUTED INDOLE DERIVATIVES BINDING 5-HT7 SEROTONIN RECEPTOR AND PHARMACEUTICAL COMPOSITIONS THEREOF
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Page/Page column 15; 29; 30, (2018/02/28)
The invention relates to a new class of substituted indole derivatives that are able to activate 5-HT7 serotonin receptor. These compounds bind 5-HT7 serotonin receptor with high affinity and selectivity, while possessing favourable physicochemical properties. The compounds of the invention are the first described low-basicity 5-HT7 receptor agonists. The invention also relates to use of such compounds in the treatment or prevention of 5-HT7 receptor-related disorders, especially of the central nervous system. The invention also relates to the isotopically labelled compounds for use in the in vivo diagnostics or imaging of a 5-HT7 serotonin receptor.
SELECTIVE ALPHA-7 NICOTINIC RECEPTOR AGONISTS AND METHODS FOR MAKING AND USING THEM
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Paragraph 0212, (2018/09/16)
In alternative embodiments, provided are selective agonists having a high affinity for the alpha7 nicotinic acetylcholine receptor (α7 nAChR), assays for selectivity of nicotinic receptor subtype and ligand-gated ion channel subtype based on receptor occupation and response, behavioral assessments for reversing cognitive impairment after scopolamine treatment, enhancing memory retention over time, pharmaceutical compositions and formulations and devices comprising them, and methods for making and using them, including characterizing and efficiently assaying them for receptor subtype selectivity. In alternative embodiments, provided are substituted anti 1,2,3-triazoles compounds with high affinity, and selective binding, for the alpha7 nicotine acetylcholine receptor (α7 nAChR), as exemplified by 5-(1-(2-(Piperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)-1H-indole (“IND1”), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (“IND8”) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (“QND8”). In alternative embodiments, provided are products of manufacture such as pumps, devices, syringes and the like comprising a compound, pharmaceutical composition or formulation as provided herein.
Organocatalytic enantioselective synthesis of C3 functionalized indole derivatives
Kaur, Jasneet,Islam, Nasarul,Kumar, Akshay,Bhardwaj, Vimal K.,Chimni, Swapandeep Singh
, p. 8042 - 8049 (2016/11/22)
A highly enantioselective Michael addition reaction of indolylnitroalkenes with 1,3-dicarbonyl compounds has been developed to obtain enantiomerically enriched 3-(2-nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)pentane-2,4-dione derivatives in up to 98% ee using BnCPN as an organocatalyst. The transition state structure has been predicted using DFT calculation.
Synthesis and anti-tuberculosis activity of the marine natural product caulerpin and its analogues
Canche Chay, Cristina I.,Cansino, Rocio Gomez,Espitia Pinzon, Clara I.,Torres-Ochoa, Ruben O.,Martinez, Roberto
, p. 1757 - 1772 (2014/06/09)
Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b-1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a-4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 μM).
