- Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
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To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.
- An, Jianxiong,Cao, Zhuoxian,Gu, Zhicheng,He, Bin,Li, Yan,Li, Yongjun,Lin, Hening,Lin, Shuxian,Liu, Ting,Wang, Jie,Wang, Pan,Yang, Fenfen,Zhao, Yonglong
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p. 15280 - 15296
(2021/10/25)
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- Construction of Oxepino[3,2-b]indoles via [4+3] Annulation of 2-Ylideneoxindoles with Crotonate-Derived Sulfur Ylides
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A [4+3] annulation of 2-ylideneoxindoles with crotonate-derived sulfur ylides has been developed. A series of oxepino[3,2-b]indoles were prepared in moderate to excellent yields (62-93%) under mild conditions. Moreover, the synthetic oxepino[3,2-b] indoles can be further transformed into more complex cyclopropa[5,6]oxepino[3,2-b]indoles via a [2+1] cyclopropanation. In addition, the synthetic compounds show certain antiproliferative activity against K562 and MCF-7 cells, and its IC50 values for these two kinds of tumor cells up to 5.40±0.88 μM and 18.41±0.50 μM, respectively. (Figure presented.).
- Fei, Xing-Hai,Guan, Xiang,He, Bin,Li, Zong-Qin,Wang, Da-Peng,Yang, Fen-Fen,Yang, Yuan-Yong,Zhao, Yong-Long,Zhou, Meng
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supporting information
p. 3018 - 3024
(2021/06/26)
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- Synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine and its bromo-derivative as dual cholinesterase inhibitors
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Alkaloids have always been a great source of cholinesterase inhibitors. Numerous studies have shown that inhibiting acetylcholinesterase as well as butyrylcholinetserase is advantageous, and have better chances of success in preclinical/ clinical settings. With the objective to discover dual cholinesterase inhibitors, herein we report synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine (1) and its bromo-derivative 2. Our study has shown that cryptolepine (1) and its 2-bromo-derivative 2 are dual inhibitors of acetylcholinesterase and butyrylcholinesterase, the enzymes which are involved in blocking the process of neurotransmission. Cryptolepine inhibits Electrophorus electricus acetylcholinesterase, recombinant human acetylcholinesterase and equine serum butyrylcholinesterase with IC50 values of 267, 485 and 699 nM, respectively. The 2-bromo-derivative of cryptolepine also showed inhibition of these enzymes, with IC50 values of 415, 868 and 770 nM, respectively. The kinetic studies revealed that cryptolepine inhibits human acetylcholinesterase in a non-competitive manner, with ki value of 0.88 μM. Additionally, these alkaloids were also tested against two other important pathological events of Alzheimer's disease viz. stopping the formation of toxic amyloid-β oligomers (via inhibition of BACE-1), and increasing the amyloid-β clearance (via P-gp induction). Cryptolepine displayed potent P-gp induction activity at 100 nM, in P-gp overexpressing adenocarcinoma LS-180 cells and excellent toxicity window in LS-180 as well as in human neuroblastoma SH-SY5Y cell line. The molecular modeling studies with AChE and BChE have shown that both alkaloids were tightly packed inside the active site gorge (site 1) via multiple π-π and cation-π interactions. Both inhibitors have shown interaction with the allosteric “peripheral anionic site” via hydrophobic interactions. The ADME properties including the BBB permeability were computed for these alkaloids, and were found within the acceptable range.
- Nuthakki, Vijay K.,Mudududdla, Ramesh,Sharma, Ankita,Kumar, Ajay,Bharate, Sandip B.
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- Pharmacological evaluation of novel PKR inhibitor indirubin-3-hydrazone in-vitro in cardiac myocytes and in-vivo in wistar rats
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Aims: Double stranded protein kinase R cellular response is associated with various stress signals such as nutrients, endoplasmic stress, cytokines and mechanical stress. Increased PKR activity has been observed under diabetic and cardiovascular disease conditions. Most of the currently available PKR inhibitors are non-specific and have other effects as well. Thus, the aim of the present study was to examine the effect of novel PKR inhibitor indirubin-3-hydrazone (IHZ) in cultured rat H9C2 cardiomyocytes and wistar rats. Materials and methods: PKR expression was determined by Q-PCR, immunofluorescence and immunoblotting. The expression of different gene markers for apoptosis was measured by RT-PCR. Apoptosis and oxidative stress were determined by flow cytometry. KEY FINDINGS: High glucose (HG) treated H9C2 cardiomyocytes and high fructose (HF) treated wistar rats developed a significant increase in PKR expression. A significant increase in apoptosis and generation of reactive oxygen species was also observed in HG treated H9C2 cells and HF treated rats. Reduced vacuole formation and prominent nuclei were also observed in high glucose treated cells. Cardiac hypertrophy and increased fibrosis were observed in HF treated rats. All these effects of HG and HF were attenuated by novel PKR inhibitor, indirubin-3-hydrazone. Significance: Our results indicate IHZ as an effective inhibitor of PKR in vitro and in-vivo, thus it may prove very useful in blocking the multiple harmful effects of PKR.
- Udumula, Mary Priyanka,Bhat, Audesh,Mangali, Sureshbabu,Kalra, Jaspreet,Dhar, Indu,Sriram, Dharamrajan,Dhar, Arti
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- A General Way to Construct Arene-Fused Seven-Membered Nitrogen Heterocycles
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Imines react with seven-membered cyclic anhydrides (prepared from the corresponding dicarboxylic acids by a recently discovered in-situ cyclodehydration protocol) by the Castagnoli–Cushman reaction pathway to give privileged seven-membered arene-fused nitrogen-heterocyclic compounds with reagent-controlled diversity of the skeleton and peripheral groups.
- Bakulina, Olga,Chizhova, Maria,Dar'in, Dmitry,Krasavin, Mikhail
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supporting information
p. 362 - 371
(2018/01/27)
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- Orally Effective Aminoalkyl 10H-Indolo[3,2-b]quinoline-11-carboxamide Kills the Malaria Parasite by Inhibiting Host Hemoglobin Uptake
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A series of indolo[3,2-b]quinoline-C11-carboxamides were synthesized by incorporation of aminoalkyl side chains into the core of indolo[3,2-b]quinoline-C11-carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum led to the identification of a 2-(piperidin-1-yl)ethanamine-linked analogue {2-bromo-N-[2-(piperidin-1-yl)ethyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (3 g)} (IC50=1.3 μm) as the most promising compound exhibiting good selectivity indices against mammalian cell lines. The kill kinetics on erythrocytic-stage parasites revealed that 3 g caused complete killing of only the trophozoite-stage parasites. Mechanistic studies showed that 3 g targets the food vacuole of the parasite and inhibits hemoglobin uptake, β-hematin formation, and the basic endocytic processes of the parasite. Analogue 3 g was found to be orally bioavailable, and its curative antimalarial studies at 50 mg per kg p.o. against a Plasmodium berghei (ANKA)-infected mouse model revealed that mice treated with 3 g showed 27–35 % suppression of parasitemia with an increase in life span relative to untreated, control mice. Thus, the present work demonstrated a proof of concept for the oral efficacy of indolo[3,2-b]quinoline-C11-carboxamides.
- Mudududdla, Ramesh,Mohanakrishnan, Dinesh,Bharate, Sonali S.,Vishwakarma, Ram A.,Sahal, Dinkar,Bharate, Sandip B.
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p. 2581 - 2598
(2018/11/23)
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- The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains
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Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ~200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
- Unzue, Andrea,Zhao, Hongtao,Lolli, Graziano,Dong, Jing,Zhu, Jian,Zechner, Melanie,Dolbois, Aymeric,Caflisch, Amedeo,Nevado, Cristina
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p. 3087 - 3097
(2016/05/19)
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- Efficient synthesis of some new antiproliferative N-fused indoles and isoquinolines via 1,3-dipolar cycloaddition reaction in an ionic liquid
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Syntheses of some new pyrrolo-fused pyrrolo[1,2-a] indole derivatives have been achieved by combining N-allyl-indole-2-carbaldehyde with a variety of N-alkyl-glycine esters as well as tetrahydroisoquinolines in an ionic liquid, triethylammonium acetate (TEAA), a recyclable reaction medium, via intramolecular [3+2] cycloaddition reaction. This new method is highly efficient, and the ionic liquid employed is recyclable. The stereochemistry of all the compounds was confirmed by 2D NMR NOESY and in some cases single crystal X-ray diffraction data. The in vitro screening of all new candidates against various bacterial strains and representative human solid tumor cell lines, A549 (lung), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), revealed that many of them have good antibacterial, antifungal and antitubercular and antiproliferative activities.
- Sutariya, Tushar R.,Labana, Balvantsingh M.,Parmar, Narsidas J.,Kant, Rajni,Gupta, Vivek K.,Plata, Gabriela B.,Padrón, José M.
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supporting information
p. 2657 - 2668
(2015/04/14)
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- CYCLIC AMIDE DERIVATIVES AS INHIBITORS OF 11 - BETA - HYDROXYSTEROID DEHYDROGENASE AND USES THEREOF
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The present invention relates to certain amide derivatives that have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.
- -
-
Paragraph 0354
(2015/06/17)
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- N-heterocyclic carbene-catalyzed enantioselective annulation of indolin-3-ones with bromoenals
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N-Heterocyclic carbene-catalyzed reactions of indolin-3-ones with 2-bromoenals opened an asymmetric access to 3,4-dihydropyrano[3,2-b]indol-2(5 H)-ones in good yields and with good to excellent enantioselectivities. This protocol tolerates a broad substrate scope. In addition, a possible mechanism for the annulation reaction is presented. More NHC-organocatalysis: N-Heterocyclic carbene-catalyzed reactions of indolin-3-ones with 2-bromoenals opened an asymmetric access to 3,4-dihydropyrano[3,2-b]indol-2(5 H)-ones in good yields and with good to excellent enantioselectivities. This protocol tolerates a broad substrate scope. In addition, a possible mechanism for the annulation reaction is presented.
- Ni, Qijian,Song, Xiaoxiao,Raabe, Gerhard,Enders, Dieter
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supporting information
p. 1535 - 1538
(2014/06/09)
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- CYCLIC AMIDE DERIVATIVES AS INHIBITORS OF 11 - BETA - HYDROXYSTEROID DEHYDROGENASE AND USES THEREOF
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The present invention relates to certain amide derivatives that have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.
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Page/Page column 101
(2013/09/12)
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- Design, synthesis and pharmacological evaluation of conformationally restricted N-arylsulfonyl-3-aminoalkoxy indoles as a potential 5-HT6 receptor ligands
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A series of novel conformationally restricted N1-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized as 5-HT6 receptor (5-HT6R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities at 5-HT6R. The lead compound 8b (% inhibition=97.2 at 1 μM) from this series has good pharmacokinetic profile in male Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR, pharmacokinetics and pharmacological data constitute the subject matter of this report.
- Nirogia, Ramakrishna V.S.,Kambhampati, Ramasastri,Daulatabad, Anand V.,Gudla, Parandhama,Shaikh, Mohammad,Achanta, Pramod Kumar,Shinde, Anil K.,Dubey, Pramod Kumar
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scheme or table
p. 341 - 349
(2012/01/06)
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- Synthesis and physical properties of various organic dyes derived from a single core skeleton, 1,2-dihydroindol-3-one
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Various organic dyes were synthesized from 1,2-dihydroindol-3-one analogue via Robinson ring annulation, which proceeded efficiently using DBU as a base to give the π-expanded compounds. These compounds exhibited longer Stokes shifts (over 100 nm) than the 1,2-dihydroindol-3-ones (50-80 nm). Emission peaks of the obtained materials covered the 440-640 nm range.
- Matsumoto, Shoji,Samata, Daisuke,Akazome, Motohiro,Ogura, Katsuyuki
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supporting information; body text
p. 111 - 114
(2009/04/14)
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- Polymeric colorants: Statistical copolymers of indigo building blocks with defined structures
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Statistical copolymers of indigo (1a) and N-acetylindigo (1b) building blocks with defined structures were studied. They belong to the class of polymeric colorants. The polymers consist of 5,5′-connected indigo units with keto structure and N-acetylindigo units with uncommon tautomeric indoxyl/indolone (=1H-indol-3-ol/3H-indol-3-one) structure (see 2a and 2b in Fig. 1). They formed amorphous salts of elongated monomer lengths as compared to monomeric indigo. The polymers were studied by various spectroscopic and physico-chemical methods in solid state and in solution. As shown by small-angleneutron scattering (SANS) and transmission-electron microscopy (TEM), disk-like polymeric aggregates were present in concentrated solutions (DMSO and aq. NaOH soln.). Their thickness and radii were determined to be ca. 0.4 and ca. 80 nm, respectively. From the disk volumes and by a Guinier analysis, the molecular masses of the aggregates were calculated, which were in good agreement with each other. Defined structural changes of the polymer chains were observed during several-weeks storage in concentrated DMSO solutions. The original keto structure of the unsubstituted indigo building blocks reverted to the more flexible indoxyl/indolone structure. The new polymers were simultaneously stabilized by intermolecular H-bonds to give aggregates, preferentially dimers. Both aggregation and tautomerization were reversible upon dissolution. The polymers were synthesized by repeated oxidative coupling of 1,1′-diacetyl- 3,3′-dihydroxybis-indoles 5 (from 1,1′-diacetyl-3,3′- bis(acetyloxy)bis-indoles 6) followed by gradual hydrolysis of the primarily formed poly(N,N′-diacetylindigos) 7 (Scheme). N,N′-Diacetylbis- anthranilic acids 9 were isolated as by-products.
- Voss, Gundula,Drechsler, Markus,Eller, Steffen,Gradzielski, Michael,Gunzelmann, Daniel,Mondal, Svastik,Van Smaalen, Sander,Voertler, Claus S.
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experimental part
p. 2675 - 2697
(2010/04/02)
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- A concise synthesis of the DNA-intercalating and antimalarial alkaloid cryptolepine and its fluorescence behaviour in solvents of different polarities
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A microwave-induced rapid and facile synthesis of the DNA-intercalating and antimalarial drug cryptolepine is described. The key step in this synthesis involves the aqueous-phase base-catalyzed condensation of isatin and 1-acetyl-1H-indol-3-yl acetate which has been simplified and expedited by dielectric heating, employing an ordinary domestic microwave oven. The method transforms the synthesis of an important drug molecule from a prohibitively lengthy process to a matter of a few minutes with a much improved yield. Dual absorption and fluorescence is observed from the molecular system in solvents of different polarity thus providing valuable insight into its binding modes toward protein or DNA.
- Lai, Tapan Kumar,Chatterjee, Asima,Banerji, Julie,Sarkar, Deboleena,Chattopadhyay, Nitin
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experimental part
p. 1975 - 1983
(2009/02/07)
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- Ultrasound-promoted reaction of 2-chlorobenzoic acids and aliphatic amines
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An improvement to the use of DMF as a solvent for the condensation of 2-chlorobenzoic acids with aliphatic primary or secondary amines was described. A number of alkylaminobenzoic acids and dialkylaminobenzoic acids were synthesized in acceptable-to-good yield. The advantages of this procedure include readily available substrates, the use of an inexpensive copper powder without taking any precautions to exclude moisture under mild conditions and experimental ease. Furthermore, this condensation could also be achieved under nonclassical conditions by using ultrasonic irradiation at room temperature. We demonstrated that ultrasound-promoted condensation of 2-chlorobenzoic acid with aliphatic amines with the use of DMF as the solvent, especially in the case of secondary amines, affords products in high yields and reduces the reaction time to minutes. The results proved to be highly reproducible because the relevant sonochemical parameters were rigorously controlled. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Docampo, Maite L.,Pellon, Rolando F.,Estevez-Braun, Ana,Ravelo, Angel G.
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p. 4111 - 4115
(2008/02/13)
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- An improved synthesis of 1-acetyl-1H-indol-3-yl acetates
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(Chemical Equation Presented) An efficient two steps procedure for the synthesis of 1-acetyl-1H-indol-3-yl acetates, starting from 2-chlorobenzoic acids, was developed and in general, moderate to good yields were obtained.
- Rodriguez-Dominguez, Juan C.,Balbuzano-Deus, Alexander,Lopez-Lopez, Miguel A.,Kirsch, Gilbert
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p. 273 - 275
(2008/03/14)
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- Synthesis and evaluation of phenyl substituted sydnones as potential DPPH-radical scavengers
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A series of phenyl substituted sydnones has been synthesized and their radical-scavenging activity has been studied on DPPH free radical. Out of eighteen compounds screened, nine compounds show interesting activity. A mechanism is presented whereby sydnones scavenge DPPH radical through donating H-atom at 4th-position. Its strong radical-scavenging activity mainly arises from 1, 2, 3-oxadiazolium-5-olate ring. Different substituents and their positions on the phenyl ring differently influence DPPH scavenging activity and therefore, may provide clues to design and develop better free-radical scavenging sydnones with multiple activities.
- Mallur, Shanta G.,Tiwari,Raju, B. China,Babu, K. Suresh,Ali, A. Zehra,Sastry,Rao, J. Madhusudana
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p. 1686 - 1689
(2008/09/19)
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- Use of ultrasound in the synthesis of 2-(alkylamino)benzoic acids in water
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The synthesis of substituted 2-(alkylamino)benzoic acids using the Ullmann condensation with water as the solvent and utilizing ultrasound irradiation was achieved with high yields in a short reaction time. Georg Thieme Verlag Stuttgart.
- Pellón, Rolando F.,Estévez-Braun, Ana,Docampo, Maite L.,Martín, Ana,Ravelo, Angel G.
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p. 1606 - 1608
(2007/10/03)
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- Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action
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A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC50 values of several compounds (11a, 11k-m, 11o, 13) against Plasmodium falciparum (strain K1) were 90% at doses of 25 mg kg-1 day -1 with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED90 = 21.6 mg kg-1 day -1). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of β-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r2 = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.
- Onyeibor, Onyeka,Croft, Simon L.,Dodson, Hilary I.,Feiz-Haddad, Mohammad,Kendrick, Howard,Millington, Nicola J.,Parapini, Silvia,Phillips, Roger M.,Seville, Scott,Shnyder, Steven D.,Taramelli, Donatella,Wright, Colin W.
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p. 2701 - 2709
(2007/10/03)
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