- Rationally designed N-phenylsulfonylindoles as a tool for the analysis of the non-basic 5-HT6R ligands binding mode
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Among all of the monoaminergic receptors, the 5-HT6R has the highest number of non-basic ligands (approximately 5% of compounds stored in 25th version of ChEMBL database have the strongest basic pKa below 5, calculated using the Instant JChem c
- Staroń, Jakub,Bugno, Ryszard,Pietru?, Wojciech,Sata?a, Grzegorz,Mordalski, Stefan,Warszycki, Dawid,Hogendorf, Agata,Hogendorf, Adam S.,Kalinowska-T?u?cik, Justyna,Lenda, Tomasz,Pilarski, Bogus?aw,Bojarski, Andrzej J.
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- Rational Design of Original Fused-Cycle Selective Inhibitors of Tryptophan 2,3-Dioxygenase
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Tryptophan 2,3-dioxygenase (TDO2) is a heme-containing enzyme constitutively expressed at high concentrations in the liver and responsible for l-tryptophan (l-Trp) homeostasis. Expression of TDO2 in cancer cells results in the inhibition of immune-mediated tumor rejection due to an enhancement of l-Trp catabolism via the kynurenine pathway. In the study herein, we disclose a new 6-(1H-indol-3-yl)-benzotriazole scaffold of TDO2 inhibitors developed through rational design, starting from existing inhibitors. Rigidification of the initial scaffold led to the synthesis of stable compounds displaying a nanomolar cellular potency and a better understanding of the structural modulations that can be accommodated inside the active site of hTDO2.
- Kozlova, Arina,Thabault, Léopold,Liberelle, Maxime,Klaessens, Simon,Prévost, Julien R. C.,Mathieu, Caroline,Pilotte, Luc,Stroobant, Vincent,Van Den Eynde, Beno?t,Frédérick, Rapha?l
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p. 10967 - 10980
(2021/08/24)
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- Synthesis and DNA binding of 6-(alkylamino)indolo[1,2-b][2,7]naphthyridine-5,12-quinones
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We describe the synthesis of eight novel putative mono– and bis–DNA intercalators from a common precursor, 6-bromoindolo[1,2-b][2,7]naphthyridine-5,12-dione. Of these new indoloquinones, our data indicate that two are most likely DNA mono–intercalators, but weaker than ethidium bromide, and two others are DNA bis–intercalators. Our indoloquinones are inactive against mammalian topoisomerase II.
- Davis, Deborah A.,Cory, Michael,Fairley, Terri A.,Gribble, Gordon W.
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- Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues
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In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.
- Verschueren, Klaas,Cobbaut, Mathias,Demaerel, Joachim,Saadah, Lina,Voet, Arnout R. D.,Van Lint, Johan,De Borggraeve, Wim M.
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p. 640 - 646
(2017/03/30)
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- Decarboxylative halogenation of indolecarboxylic acids using hypervalent iodine(III) reagent and its application to the synthesis of polybromoindoles
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Hypervalent iodine mediated decarboxylative halogenation of indoledicarboxylic acid derivatives was studied. The treatment of 1-methylindole-2,3-dicarboxylic acid with phenyliodine diacetate (PIDA) in the presence of lithium bromide gave 1-methyl-3,3-brom
- Hamamoto, Hiromi,Umemoto, Hideaki,Umemoto, Misako,Ohta, Chiaki,Fujita, Emi,Nakamura, Akira,Maegawa, Tomohiro,Miki, Yasuyoshi
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p. 561 - 572
(2015/05/20)
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- A Palladium(II)-Catalyzed C-H Activation Cascade Sequence for Polyheterocycle Formation
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Polyheterocycles are found in many natural products and are useful moieties in functional materials and drug design. As part of a program towards the synthesis of Stemona alkaloids, a novel palladium(II)-catalyzed C-H activation strategy for the construction of such systems has been developed. Starting from simple 1,3-dienyl-substituted heterocycles, a large range of polycyclic systems containing pyrrole, indole, furan and thiophene moieties can be synthesized in a single step. Don't overdo it: A palladium(II)-catalyzed C-H activation cascade sequence for the synthesis of polyheterocycles is reported. Aromatization of the initially formed dihydro species occurred with a quinone oxidant. In some cases the use of one equivalent of the oxidant enabled isolation of the dihydro species as a single isomer (see scheme; X=NMe, O, S).
- Cooper, Stephen P.,Booker-Milburn, Kevin I.
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p. 6496 - 6500
(2015/06/02)
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- FUNCTIONALISED AND SUBSTITUTED INDOLES AS ANTI-CANCER AGENTS
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The present invention relates to anti-tropomyosin compounds, processes for their preparation, and methods for treating or preventing a proliferative disease, preferably cancer, using compounds of the invention.
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Page/Page column 43; 44
(2015/06/08)
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- Synthesis of a pentalene centered polycyclic fused system
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A novel pentalene-centered polycyclic 24π-electron system, IB1, was synthesized via a Pd-catalyzed homocoupling reaction. The geometry structure was studied by X-ray diffraction and theoretical method. The HOMO level of IB1 was studied by electrochemical
- Li, Yuliang,Yin, Xiaodong,Li, Yongjun,Zhu, Yulan,Kan, Yuhe,Zhu, Daoben
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p. 1520 - 1523
(2011/05/02)
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- The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity
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A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)2 and NaBH4 afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.
- Leboho, Tlabo C.,Michael, Joseph P.,van Otterlo, Willem A.L.,van Vuuren, Sandy F.,de Koning, Charles B.
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body text
p. 4948 - 4951
(2009/12/24)
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- Computer-aided rational drug design: A novel agent (SR13668) designed to mimic the unique anticancer mechanisms of dietary indole-3-carbinol to block Akt signaling
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Indole-3-carbinol (I3C) is a naturally occurring anticancer agent and has entered clinical trials for cancer prevention. However, the clinical development of I3C has been impeded by its poor metabolic profile. The active components of I3C were used to develop a novel class of indole analogs to optimize I3C's anticancer actions, including blocking growth factor-stimulated Akt activation. The most promising of these analogs, SRI3668, exhibited potent oral anticancer activity against various cancers and no significant toxicity.
- Chao, Wan-Ru,Yean, Dawn,Amin, Khalid,Green, Carol,Jong, Ling
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p. 3412 - 3415
(2008/02/11)
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- A simple iodination protocol via in situ generated ICl using NaI/FeCl 3
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A novel iodination of silyl-enol ethers using hitherto unexplored NaI/FeCl3 system is reported. The procedure has been extended to the iodination of aromatic and hetero aromatic compounds.
- Mohanakrishnan, Arasambattu K.,Prakash, Chandran,Ramesh, Neelamegam
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p. 3242 - 3247
(2007/10/03)
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- A concise synthesis of novel naphtho[a]carbazoles and benzo[c]carbazoles
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Starting from simple indole precursors the synthesis of naphtho[a]carbazoles and benzo[c]carbazoles is described. Key steps include the use of the Suzuki-Miyaura reaction to afford 2- or 3-aryl substituted indoles, as well as a potassium t-butoxide and light assisted aromatic ring-forming reaction.
- Pathak, Rakhi,Nhlapo, Johanna M.,Govender, Sameshnee,Michael, Joseph P.,Van Otterlo, Willem A. L.,De Koning, Charles B.
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p. 2820 - 2830
(2007/10/03)
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- Bis-Suzuki reactions of 2,3-dihaloindoles. A convenient synthesis of 2,3-diarylindoles
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A convenient, one-pot synthesis of 2,3-diarylindoles 4 is described via a bis-Suzuki palladium-catalyzed cross coupling of 2,3-dihalo-1-(phenylsulfonyl)indoles 1 with arylboronic acids 2, followed by cleavage of the N-protecting group to give 4. The anti-inflammatory drug indoxole (4c) is prepared in high yield. (C) 2000 Elsevier Science Ltd.
- Liu,Gribble
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p. 8717 - 8721
(2007/10/03)
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- HETEROARYL SUBSTITUTED PHENYL ISOXAZOLE SULFONAMIDE ENDOTHELIN ANTAGONISTS
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Compounds of the formula STR1 inhibit the activity of endothelin.
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- DIMERIZATION OF INDOLONAPHTHYRIDINE-5,12-QUINONE
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Attempts to isomerize indolonaphthyridine-5,12-quinone (5) to ellipticine quinone (7) with various nucleophiles (cyanide, methoxide, halide, thiophenoxide) lead instead to 6,6'-bis(indolonaphthyridine-5,12-quinone) (8), the dimer of 5.
- Davis, Deborah A.,Gribble, Gordon W.
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p. 1613 - 1621
(2007/10/02)
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- APPROACHES TO THE GENERATION OF 2,3-INDOLYNE
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Several unsuccessful attempts to generate and trap 1-phenylsulfonyl2,3-indolyne (4) from lithio-3-bromo-1-phenylsulfonylindole (9) and 2-lithio-3-iodo-1-phenylsulfonylindole (12), generated by different methods, are described.The remarkable stability of 9
- Conway, Samuel C.,Gribble, Gordon W.
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p. 2095 - 2108
(2007/10/02)
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- SYNTHESIS OF 1-(PHENYLSULFONYL)INDOL-3-YL TRIFLUOROMETHANESULFONATE
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The synthesis of the potentially useful intermediate 1-(phenylsulfonyl)indol-3-yl trifluoromethanesulfonate (triflate) (1), via several approaches to the corresponding indoxyl 6, is decsribed.Of these, the direct oxidation of 1-(phenylsulfonyl)indole (2)
- Conway, Samuel C.,Gribble, Gordon W.
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p. 627 - 633
(2007/10/02)
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- Synthesis of Prenylated Indoles
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Interaction of magnesium indolates and allyl oxides in the presence of bis(triphenylphosphine)nickel dichloride results in indole β-allylation, except in cases involving highly substituted indoles and allyl alcohols.This method permits the β-prenylation of indole and α-prenylation of ketones (by way of their magnesium enaminates).Base-induced interaction of ethynyldimethylcarbinyl chloride and indole under a variety of conditions yields β-(β,β-dimethylvinyl)quinoline as well as variously dehydroprenylated indoles. α-Lithiation of N-(benzenesulfonyl)indole followed by treatmentwith prenyl bromide or β,β-dimethylacrylyl chloride produces α-prenyl- or α-oxoprenylidole derivatives, the sodium amalgam reduction of the former of which yields α-prenylidole.Interaction of β-cuprated N-(benzenesulfonyl)indole with the same halides followed by reduction affords β-prenylindole and β-oxoprenylindole, the latter also being the product of the reaction of magnesium indolate and the acid chloride.Lithium aluminum hydride reduction of 1-(benzenesulfonyl)-3-oxoprenylindole affords an alcohol, whose base hydrolysis produces β-dehydroprenylindole, a compound whose dimerization has led previously to naturally occuring yuehchukene.
- Wenkert, Ernest,Angell, E. Charles,Ferreira, Vitor F.,Michelotti, Enrique L.,Piettre, Serge R.,et al.
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p. 2343 - 2351
(2007/10/02)
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- Stereocontrolled Total Syntheses of (-)-Hobartine and (+)-Aristoteline via an Intramolecular Nitrone-Olefin Cycloaddition
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The Aristotelia alkaloids (-)-hobartine and (+)-aristoteline have been synthesized from indole and (S)-1-p-menthen-8-ylamine (7) in 11 steps (19percent) via an intramolecular nitrone-olefin 1,3-dipolar cycloaddition.
- Gribble, Gordon W.,Barden, Timothy C.
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p. 5900 - 5902
(2007/10/02)
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