- A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism
-
By docking 126 derivatives of β-carboline-3-carboxylic acid, tetrahydro-β-carboline-3-carboxylic acid and indoloquinolizine into the active pocket of P-selectin (2-(3-(hydroxymethyl)-9H-pyrido[3,4-b]indol-1-yl)ethyl)-L-phenylalanine (HMCEF) was assigned a novel inhibitor. ELISA and flow cytometry experiments showed that HMCEF effectively down-regulated P-selectin expression and supported the rationality of the computer assistant screening, while UV spectrum experiments demonstrated that HMCEF directly bound to P-selectin. In vivo HMCEF dose dependently inhibited the rats and mice to form thrombus and had a minimal effective dose of 20?nmol/kg, dose dependently inhibited inflammatory response of mice and had a minimal effective dose of 20?nmol/kg. The decrease of serum TNFα and IL-8 of the treated mice was proposed to be the action mechanism of HMCEF inhibiting thrombosis and inflammation. All data imply that HMCEF is a novel lead of P-selectin inhibitor.
- Wu, Jianhui,Zhao, Ming,Wang, Yuji,Wang, Yaonan,Zhu, Haimei,Zhao, Shurui,Peng, Shiqi
-
-
Read Online
- Experimental and theoretical investigation of stable diastereomeric conformations of biscarboline amides in solution
-
Stable axial conformations generally exist only when the single bond's (axis’) rotation was sterically hindered in solution. Herein, we firstly show that two stable conformations could be observed in solution by 1H and 13C NMR experiments when the single bond rotates freely. Its coalescence temperature was measured up to 120 °C when we took compound 13 as an example. The ratio of the two stable conformations was computed using quantum methods. The predicted results matched with the experimental results well. The conversion barrier between two conformers was estimated by potential energy scan (PES) and transition state (TS) calculations at the B3LYP/6-311 + G(d) level. Furthermore, its stereochemistry was also well studied by comparing theoretical electronic circular dichroism (ECD) spectra with the experimental one.
- Liang, Miao-Miao,Ma, Yang-Yang,Zhu, Liang,Jia, Yun-Jing,Zhu, Hua-Jie,Li, Wan,Zhou, Bei-Dou
-
-
Read Online
- Stereoselective Synthesis of Functionalized Tetrahydro-β-Carbolines via Pictet-Spengler Reaction
-
A TFA-catalyzed Pictet-Spengler reaction of synthesized tryptophan propargyl ester with aromatic and heteroaromatic aldehydes resulted in cis-tetrahydro-β-carbolines with remarkably high stereocontrol under kinetically controlled conditions. In another approach, a diastereomeric mixture of tetrahydro-β-carboline hydrazides was synthesized. The tetrahydro-β-carboline hydrazides were prepared through the reaction of tryptophan hydrazide with carbonyl compounds via Pictet-Spengler reaction.
- Vavsari, Vaezeh Fathi,Dianati, Vahid,Ramezanpour, Sorour,Balalaie, Saeed
-
-
Read Online
- Synthesis of pseudellone analogs and characterization as novel T-type calcium channel blockers
-
T-type calcium channel (Cav3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson's disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved Cav3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual Cav3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two Cav3.2 (2, IC50 = 18.24 μM; 3, IC50 = 6.59 μM) and Cav3.3 (2, IC50 = 7.71 μM; 3, IC50 = 3.81 μM) selective blockers using a FLIPR cell-based assay measuring Cav3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of Cav3.1 activated current (2, IC50 = 5.60 μM; 3, IC50 = 9.91 μM), suggesting their state-dependent block is subtype specific.
- Wang, Dan,Neupane, Pratik,Ragnarsson, Lotten,Capon, Robert J.,Lewis, Richard J.
-
-
Read Online
- Efficient photosensitized splitting of thymine dimer by a covalently linked tryptophan in solvents of high polarity
-
Tryptophan-thymine dimer model compounds used to mimic the repair reaction of DNA photolyase have been synthesized. The photosensitized cleavage of the dimer by the covalently linked tryptophan is strongly solvent-dependent with the reaction rates increasing in increasingly polar solvents, for example, the quantum yield π = 0.004 in THF/hexane (5:95) and 0.093 in water. The fluorescence of the tryptophan residue is quenched by the dimer moiety by electron transfer from the excited tryptophan to the dimer. Fluorescence- quenching studies indicated that the electron transfer was efficient in polar solvents. The splitting efficiency of the dimer radical anion within the tryptophan.+-dimer.- species is also remarkably solvent-dependent and increases with the polarity of the solvents. The back-electron-transfer reaction in the charge-separated species, which competes with cleavage, was suppressed in polar solvents. These results are in contrast to those of earlier solvent-dependent studies of indole-dimer systems, but they can be rationalized in terms of the differences in the distances between the chromophore unit and the attached dimer. The pH-dependent measurements of the splitting reaction and the deuterium isotope effect showed that the tryptophan radical cation within the charge-separated species does not deprotonate prior to the cleavage of the dimer radical anion. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Song, Qin-Hua,Tang, Wen-Jian,Hei, Xiao-Ming,Wang, Hong-Bo,Guo, Qing-Xiang,Yu, Shu-Qin
-
-
Read Online
- Synthesis of novel 1,2,3-triazole tethered 1,3-disubstituted β-carboline derivatives and their cytotoxic and antibacterial activities
-
In this paper new β-carboline derivatives possessing the 1,2,3-triazole ring at C-1 substituent were synthesized from L-tryptophan by Pictet–Spengler reaction followed by a Huisgen 1,3-dipolar addition. In vitro cytotoxicity and antibacterial activity of synthetic compounds were investigated. Methyl 1-(3-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-β-carboline-3-carboxylate (7f) showed the highest cytotoxic activity with IC50 values of 46 and 32 μM against Hela and HepG2 cell lines, respectively. Compounds 7d and 7i (possessing 4-bromophenyl substituent) and 5c showed excellent inhibition activity for Enterococcus faecium with MIC of 8 μg/mL. The results demonstrated that the presence of 1,2,3-triazole rings in β-carboline derivatives improve their biological activities.
- Salehi, Peyman,Babanezhad-Harikandei, Kosar,Bararjanian, Morteza,Al-Harrasi, Ahmed,Esmaeili, Mohammad-Ali,Aliahmadi, Atousa
-
-
Read Online
- 1H NMR and theoretical studies on the conformational equilibrium of tryptophan methyl ester
-
Selected 3JHH coupling constants and theoretical calculations were used to explain the conformational equilibrium of L-tryptophan methyl ester (Trp-OMe) in several solvents. The obtained 3J HαHβ values did not exhibit any significant variability and thus indicate that there are no conformational population variations for the side chain of the Trp-O-Me depending on the solvent. Moreover, the potential energy surfaces obtained at the B3LYP/cc-pVDZ theoretical level produced eight energy minima that were analysed by QTAIM and NBO methods. It was possible to conclude that the Trp-OMe conformational preferences were due to hyperconjugative effects involving the nonbonding electron pairs of the main chain nitrogen atom and certain antibonding orbitals (σC4-C13a?? -, σC1-C4a?? - and σC4-H12a?? -) and also to the steric effects from the nonbonding electron pairs of oxygen atoms and the main and side chain of this system.
- Duarte, Claudimar J.,Cormanich, Rodrigo A.,Ducati, Lucas C.,Rittner, Roberto
-
-
Read Online
- In Vitro Stepwise Reconstitution of Amino Acid Derived Vinyl Isocyanide Biosynthesis: Detection of an Elusive Intermediate
-
In vitro reconstitution of a newly discovered isonitrile synthase (AmbI1 and AmbI2) and the detection of an elusive intermediate (S)-3-(1H-indol-3-yl)-2-isocyanopropanoic acid 1 in indolyl vinyl isocyanide biogenesis are reported. The characterization of iron/2-oxoglutarate (Fe/2OG) dependent desaturases IsnB and AmbI3 sheds light on the possible mechanism underlying stereoselective alkene installation to complete the biosynthesis of (E)- and (Z)-3-(2-isocyanovinyl)-1H-indole 2 and 5. Establishment of a tractable isonitrile synthase system (AmbI1 and AmbI2) paves the way to elucidate the enigmatic enzyme mechanism for isocyanide formation.
- Chang, Wei-chen,Sanyal, Dev,Huang, Jhih-Liang,Ittiamornkul, Kuljira,Zhu, Qin,Liu, Xinyu
-
-
Read Online
- Boron Accumulation in Brain Tumor Cells through Boc-Protected Tryptophan as a Carrier for Boron Neutron Capture Therapy
-
Boron neutron capture therapy (BNCT) is a binary therapeutic approach. Nonradioactive boron-10 atoms accumulated in tumor cells combining with the neutron beams produce two highly energetic particles that could eradicate the cell that takes it and the neighboring cells. Small molecules that carry boron atom, e.g. 5- and 6-boronated and 2,7-diboronated tryptophans, were assessed for their boron accumulation in U87-MG, LN229, and 3T3 for BNCT. TriBoc tryptophan, TB-6-BT, shows boron-10 at 300 ppm in both types of tumor cells with a tumor to normal ratio (T/N) of 5.19-5.25 (4 h). TB-5-BT and DBA-5-BT show boron-10 at 300 ppm (2 h) in U87-MG cells. TB-5-BT exerts a T/N of >9.66 (1 h) in LN229 compared with the current clinical boronophenyl alanine with a highest T/N of 2.3 (1 h) and accumulation concentration of 50 ppm. TB-5-BT and TB-6-BT warrant further animal study.
- Chio, Chun-Ming,Chou, You-Cheng,Hsu, Fu-Chun,Huang, Ying-Cheng,Lai, Yen-Buo,Yu, Chung-Shan
-
-
Read Online
- Synthesis and fungicidal activity of tryptophan analogues–the unexpected calycanthaceous alkaloid derivatives
-
A series of 21?N-protected tryptophan derivatives were synthesised from tryptophan in good yields. Their structures were characterised by IR,1H NMR,13C NMR, DEPT (90° and 135°) and MS analysis. The synthesised compounds were evaluated against a wide variety of plant pathogen fungi. Compounds a19 and a21 displayed activity against Fusarium oxysporum (F. oxysporum), and compound a21 showed high activity against F. oxysporum and Eggplant Verticillium, with EC50values of 58.27 and 77.39?μg?mL?1, respectively. Considering that the bioassay of the title compounds was evaluated, effects of the chain alkyl substituents may contribute to the significant variations in fungicidal potency. Their structure–antifungal activity relationships were also discussed. These results will pave the way for further design, structural modification and development of calycanthaceous alkaloids as antimicrobial agents.
- Zheng, Shaojun,Gu, Yongdong,Li, Longbo,Zhu, Rui,Cai, Xingwei,Bai, Hongjin,Zhang, Jiwen
-
-
Read Online
- Design, synthesis of novel tryptophan derivatives for antiplatelet aggregation activity based on tripeptide pENW (pGlu-Asn-Trp)
-
pENW, a three mer peptide derived from Agkistrodon acutus Guenther venom, has been found to be an antagonist of the GPIIb/IIIa receptor and shows antiplatelet aggregation activity. Based on pENW and a GPIIb/IIIa inhibitor Tirofiban, a series of tryptophan derivatives were designed, synthesized and evaluated for their antiplatelet aggregation activity induced by ADP. The most potent compound 87 was also tested for the bleeding time and antithrombotic activity in vivo in comparison with Tirofiban. The results indicated that 87 shows similar antiplatelet aggregation activity as Tirofiban to the aggregation of platelet induced by all of the four agonists, but has lower bleeding risk than Tirofiban, representing a promising lead compound for further study.
- Xie, Zhouling,Feng, Sen,Wang, Ying,Cao, Chen,Huang, Jing,Chen, Yahui,Kong, Yi,Li, Zhiyu
-
-
Read Online
- Synthesis and Antibacterial Activity of Calycanthaceous Alkaloid Derivatives
-
A series of 45 calycanthaceous alkaloid derivatives with the tetrahydropyrroloindole core structure was synthesized from tryptophan in good yields. The synthesized compounds were evaluated against five strains of bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coil, Ralstonia solanacearum, and Pseudomonas aeruginosa). The bioassays indicated that among the synthesized compounds, compounds b3 and b4 exhibited a high degree of activity towards Gram positive B. subtilis. Compounds a14 and a18 displayed a high degree of activity towards R. solanacearum. These results will pave the way for further design, structural modification, and development of calycanthaceous alkaloids as antibacterial agents.
- Zheng, Shaojun,Gu, Yongdong,Zhu, Rui,Li, Longbo,Bai, Hongjin,Zhang, Jiwen
-
-
Read Online
- TOTAL SYNTHESIS OF Na-METHYL-Δ18-ISOKOUMIDINE, A POSSIBLE PRECURSOR OF THE KOUMINE TYPE INDOLE ALKALOIDS
-
A novel total synthesis of title compound 3 is described.
- LIU, Zhujin,XU, Feng
-
-
Read Online
- Preparation of chiral amino acid materials and the study of their interactions with 1,1-Bi-2-naphthol
-
The amino acid tryptophan has been converted into acrylamide monomers using L/D-tryptophan methyl ester forming the enantiopure chiral monomers. Attempts were made to polymerize these monomers via reversible addition fragmentation chain transfer (RAFT) polymerization to form poly(tryptophan). Unfortunately, this proved difficult, and instead, a postpolymerization modification route was used by first synthesizing poly(pentafluorophenyl acrylate) via RAFT, which was then substituted with L-tryptophan methyl ester to give poly(L-tryptophan). The interactions of the newly synthesized tryptophan monomers, as well as previously reported phenylalanine monomers, were studied in the presence of rac-BINOL. It has been shown that the enantiomers of tryptophan have a stronger interaction with BINOL than phenylalanine and this has been attributed to the larger π system on the side chain. By monitoring the shifts and splitting of the phenolic protons of BINOL, it has been observed that S-BINOL interacts more favorably with L-monomer enantiomers and R-BINOL with D-monomer enantiomers. Similar interactions have also been seen with poly(phenylalanine) and the newly synthesized poly(tryptophan) materials. Copyright
- Moore, Beth L.,O'Reilly, Rachel K.
-
-
Read Online
- Indole Alkaloids from a Soil-Derived Clonostachys rosea
-
Clonorosins A ( 1 ) and B ( 2 ), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids ( 3 - 9 ), were isolated from the soil-derived fungusClonostachys roseaYRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i - 3iv were synthesized and analyzed. 1 was active againstFusarium oxysporumwith an MIC value of 50 μg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50values of 0.12-0.60 μM.
- Fang, Jianguo,Jiang, Chun-Xiao,Miao, Ya-Mei,Ren, Hao,Tian, Li-Li,Wang, Xiaolei,Wu, Quan-Xiang,Xu, Qianhe,Yu, Bo,Yu, Zhen-Qing,Zhang, Jin Z.,Zhang, Jiwen,Zhao, Chun,Zhou, Pan-Pan
-
supporting information
p. 2468 - 2474
(2021/09/13)
-
- Total Synthesis of Homo-and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products
-
Total synthesis and structural confirmation of homo-and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N′-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-Tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-Triazepan-6-one heterocycle.
- álvarez, Rosana,Alvarez, Susana,Areal, Andrea,De Lera, ángel R.,Domínguez, Marta,Vendrig, Pim
-
supporting information
p. 1725 - 1737
(2021/06/28)
-
- Method for preparing pharmaceutical intermediate of tryptophan derivative
-
The synthesis method comprises the following steps: L - tryptophan derivatives are taken as starting materials, and esterification is carried out in sequence. The amidation, Boc protection, hydrolysis, amidation or sequential esterification, amidation, Boc protection, hydrogenation, hydrolysis, amidation yields a target product, a tryptophan derivative pharmaceutical intermediate. The preparation method has the advantages of cheap and easily available raw materials, environment friendliness, less process three wastes, accords with the idea of green pharmacy, mild reaction conditions, simple process, simple and convenient operation, high yield and purity and easy amplification and production.
- -
-
Paragraph 0043-0051; 0086-0090
(2021/09/21)
-
- Development of β-carboline-benzothiazole hybrids via carboxamide formation as cytotoxic agents: DNA intercalative topoisomerase IIα inhibition and apoptosis induction
-
In quest of promising anticancer agents, the pharmacophores of natural (β-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 μM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 μM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.
- Tokala, Ramya,Mahajan, Surbhi,Kiranmai, Gaddam,Sigalapalli, Dilep Kumar,Sana, Sravani,John, Stephy Elza,Nagesh, Narayana,Shankaraiah, Nagula
-
-
- Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation**
-
A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic β-carboline alkaloid peganumine A. The latter synthesis features a protecting-group-free assembly and an asymmetric disulfonimide-catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10-desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.
- Christmann, Mathias,He, Guoli,List, Benjamin
-
supporting information
p. 13591 - 13596
(2021/05/07)
-
- The benzyl can be selectively removed by visible light or near visible light. Method for protecting allyl and propargyl group
-
The invention provides a method for selectively removing benzyl, allyl and propargyl protecting groups by visible light or near visible light, namely a substrate containing benzyl, allyl or propargyl protecting groups. The method has the advantages of simple operation, safe and clean visible light or near visible light as excitation conditions, cheap and easily available reagents, high reaction yield, high reaction chemistry and regional selectivity, and is suitable for selective removal of benzyl, allyl and propargyl protecting groups in various substrates.
- -
-
Paragraph 0034
(2021/10/16)
-
- Preparation and application of medium-ring-containing tetrahydrocarboline-tetrahydroisoquinoline compound
-
The invention belongs to the technical field of medicines, and discloses preparation and application of a medium-ring-containing tetrahydrocarboline-tetrahydroisoquinoline compound. The invention specifically relates to a compound shown in a general formula I and pharmaceutically acceptable salts thereof, a preparation method of the compound, a pharmaceutical composition containing the compound shown in the general formula I, a preparation method of the pharmaceutical composition and application of the compound and the pharmaceutical composition in the anti-tumor aspect.
- -
-
-
- Production process of tadalafil bulk drug
-
The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
- -
-
Paragraph 0014-0015
(2020/07/02)
-
- An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4
-
Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).
- Samuels, Eric R.,Sevrioukova, Irina F.
-
-
- Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors
-
Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity over PDE11, the most common off–target for tadalafil. Modifying the stereochemistry into 6S, 12aS configuration and adopting the hydroxamic acid moiety as a terminal group gave rise to compounds that only inhibited HDAC. Dual PDE5/HDAC inhibition could be achieved with compounds having 6R, 12aR configuration and hydroxamic acid moiety as a terminal group. The anticancer activity of the synthesized compounds was evaluated against a diverse number of cell lines of different origin. The compounds elicited anticancer activity against cell lines belonging to lymphoproliferative cancer as well as solid tumors. Despite the previous reports suggesting anticancer activity of PDE5 inhibitors, the growth inhibitory activity of the compounds seemed to be solely dependent on HDAC inhibition. Compound 26 (pan HDAC IC50 = 14 nM, PDE5 IC50 = 46 nM) displayed the most potent anticancer activity in the present series and was shown to induce apoptosis in Molt-4 cells. HDAC isoform selectivity testing for compound 26 showed that it is more selective for HDAC6 and 8 over HDAC1 by more than 20-fold.
- Abadi, Ashraf H.,Abdel-Halim, Mohammad,Ahmed, Nermin S.,Chen, Yu-Cheng,ElHady, Ahmed K.,Engel, Matthias,Keeton, Adam B.,Liu, Yi-Chang,Piazza, Gary A.,Shih, Shou-Ping
-
-
- Solvent free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type Compounds from L-tryptophan: DFT-B3LYP calculations for the reaction mechanism and 3H-pyrrol-3-one?1H-pyrrol-3-ol tautomeric equilibrium
-
In this paper, we describe the solvent-free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds from L-tryptophan. The first step of the synthetic methodology involved the esterification of L-tryptophan in excellent yields (93–98%). Equimolar mixtures of alkyl 2-aminoesters, 1,3-dicarbonyl compounds, and potassium hydroxide (0.1 eq.) were heated under solvent-free conditions. The title compounds were obtained in moderate to good yields (45%–81%). Density functional theory using “Becke, 3-parameter, Lee–Yang–Parr” correlational functional (DFT-B3LYP) calculations were performed to understand the molecular stability of the synthesized compounds and the tautomeric equilibrium from 3H-pyrrol-3-one type intermediates to 1H-pyrrol-3-ol type aromatized rings.
- Becerra, Lili Dahiana,Coy-Barrera, Ericsson,Quiroga, Diego
-
-
- Indolylhydrazone derivative as well as preparation method and application thereof to prevention and control of plant viruses, sterilization and disinsection
-
The invention relates to a tetrahydroaza [4,5-b] indolylhydrazone derivative as well as a preparation method and application thereof to prevention and control of plant virtuses, sterilization and disinsection, and the meaning of each group in a general formula is shown as a specification. The tetrahydroaza [4,5-b] indolylhydrazone derivative disclosed by the invention has excellent anti-plant-virus activity and further has broad-spectrum bactericidal activity and insecticidal activity.
- -
-
Paragraph 0081-0084
(2020/02/17)
-
- Design and synthesis of β-carboline linked aryl sulfonyl piperazine derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability
-
A series of new β-carboline linked aryl sulfonyl piperazine congeners have been synthesized by coupling various β-carboline acids with substituted aryl sulfonyl piperazines. Evaluation of their anticancer activity against a panel of human cancer cell lines such as colon (HT-29), breast (MDA-MB-231), bone osteosarcoma (MG-63), brain (U87 MG), prostate (PC- 3) and normal monkey kidney (Vero) cell line has been done. Among the series, compound 8ec and 8ed has shown most potent cytotoxicity with an IC50 values of 2.80 ± 0.10 μM and 0.59 ± 0.28 μM respectively against MG-63 cell line and also potent on other cell lines tested. Compounds 8ec and 8ed was found to inhibit Topo II that is confirmed by specific Topo II inhibition assay. DNA binding studies, cell cycle analysis, Annexin V study indicate that these compounds has potential anticancer activity. Molecular docking studies for compound 8ec and 8ed are incorporated to understand the nature of interaction with topoisomerase IIα and dsDNA.
- Alvala, Mallika,Godugu, Chandraiah,Kalle, Arunasree M.,Kiranmai, Gaddam,Lakshmi Manasa, Kesari,Nagendra Babu, Bathini,Nagesh, Narayana,Sagar, Arpita,Sigalapalli, Dilep Kumar,Thatikonda, Sowjanya
-
-
- Diketopiperazine acylhydrazone derivatives, preparation method thereof and application of diketopiperazine acylhydrazone derivatives in prevention and treatment of plant viruses, sterilization and insect killing
-
The invention relates to diketopiperazine acylhydrazone derivatives, a preparation method thereof and application of the diketopiperazine acylhydrazone derivatives in prevention and treatment of plantviruses, insect killing and sterilization. The meanings of groups in the general formula of the derivatives are shown in the description. The diketopiperazine acylhydrazone derivatives has excellentactivity of plant virus resistance, and also has broad-spectrum bactericidal activity and insecticidal activity.
- -
-
Paragraph 0056-0059
(2020/02/17)
-
- Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
-
The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
- Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
-
-
- Tetrahydro-beta-carboline dimer as well as preparation method and application thereof
-
The invention discloses an application of a tetrahydro-beta-carboline dimer derivative in the preparation of a medicine for preventing or treating Alzheimer's disease. The tetrahydro-beta-carboline dimer derivative is as shown in a structural formula I, which is described in the specification, L-tryptophan and tryptamine are used as raw materials; a tetrahydro-beta-carboline monomer is generated through a Picet-Spengler reaction and aldehyde cyclization, then a tetrahydro-beta-carboline dimer is generated through acyl chloride connection and a click chemical reaction, the synthesis steps are simple, the raw materials are easy to obtain, the yield is high, and the tetrahydro-beta-carboline dimer has remarkable inhibitory activity on butyrylcholine esterase and A[beta]1-42 aggregation. According to the neural protective effect under three AD models on cells, after the cells are independently treated by A[beta]1-42, H2O2 and OA, the survival rate of the cells is low, and apoptosis or necrosis of the cells occurs. The compounds 11, 12, 13, 17 and 19 are used for co-treatment, the compounds 11, 12, 13, 17 and 19 successfully block A[beta]1-42, H2O2 and OA induced cell death, and it is proved that the compounds 11, 12, 13, 17 and 19 have a remarkable neural protective effect.
- -
-
Paragraph 0067-0071
(2020/09/30)
-
- Synthesis and anti-Mycobacterium tuberculosis activity of imide-β-carboline and carbomethoxy-β-carboline derivatives
-
A series of methyl β-carboline carboxylates (2a-g) and of imide-β-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active β-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of β-carboline activity in M. tuberculosis. All 19 β-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 μg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 μg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from 1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 β-carboline derivatives showed the importance of steric effects for the synthesized β-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.
- Lopes-Ortiz, Mariana Aparecida,Panice, Manuela Ribeiro,Borges de Melo, Eduardo,Ataide Martins, Jo?o Paulo,Baldin, Vanessa Pietrowski,Agostinho Pires, Cláudia Terêncio,Caleffi-Ferracioli, Katiany Rizzieri,Dias Siqueira, Vera Lúcia,Bertin de Lima Scodro, Regiane,Sarragiotto, Maria Helena,Cardoso, Rosilene Fressatti
-
-
- Synthesis, Antileishmanial Activity and Spin Labeling EPR Studies of Novel β-Carboline-Oxazoline and β-Carboline-Dihydrooxazine Derivatives
-
A series of novel 1-(substituted-phenyl)-3-(4,5-dihydro-1,3-oxazol-2-yl)-9H-β-carboline (8a-8i) and 1-(substituted-phenyl)-3-(5,6-dihydro-4H-1,3-oxazin-2-yl)-9H-β-carboline (9a-9h) derivatives, as well as their respective N-(chloroalkyl)-1-(substituted-phenyl)-9H-β-carboline-3-carboxamide precursors (6a-6i and 7a-7h), were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. Compounds 8d, 8i, 9e and 9h exhibited significant activity for both promastigote and amastigote forms, with IC50 (50% inhibitory concentration) values ranging from 2.9 to 23.0 μM. In addition, spin label electron paramagnetic resonance (EPR) spectroscopy studies were carried out for the most active compounds against L. amazonensis promastigotes. The studies indicated that the tested compounds cause strong stiffness in the parasite plasma membrane and are capable of inducing internal metalloproteins oxidation of the parasite, resulting in their cross-linking to skeletal proteins. Compounds 8d and 8i produced the largest effect, showing that the presence of oxazoline group at C-3 of β-carboline nucleus is important for antileishmanial activity.
- Alonso, Antonio,Alonso, Laís,Baréa, Paula,Nakamura, Celso V.,Sarragiotto, Maria H.,da Costa, Willian F.,de Oliveira, Aline R.,de Paula, Jéssica C.
-
p. 1170 - 1185
(2020/10/14)
-
- Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A
-
Human histidine triad nucleotide-binding protein 2 (hHINT2) is an important player in human mitochondrial bioenergetics, but little is known about its catalytic capabilities or its nucleotide phosphoramidate prodrug (proTide)-activating activity akin to the cytosolic isozyme hHINT1. Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1?=?6.76?±?0.16, pK2?=?8.41?±?0.07). In addition, the known hHINT1-microphthalmia-inducing transcription factor-regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. These results demonstrate that despite differences in their sequence and localization, HINT1 and HINT2 have similar nucleotide substrate specificities, which should be considered in future proTide design and in studies of their natural function.
- Strom, Alexander,Tong, Cher Ling,Wagner, Carston R.
-
p. 1497 - 1505
(2020/02/25)
-
- Preparation method of tadalafil and intermediate of tadalafil
-
The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.
- -
-
Paragraph 0026-0034
(2019/11/20)
-
- Synthesis of Spiro-Pyrrolidinyloxindoles by Oxidative Rearrangement of N-Acyltetrahydro-β-carbolines Using an Oxone/Aqueous Acetone Mixture
-
Spiro-pyrrolidinyl-2-oxindoles were prepared by the oxidative rearrangement of Na-acetyl-1,2,3,4-tetrahydro-β-carbolines (THBC) using dimethyldioxirane generated in situ. The Na-acetyl THBC substrates were obtained by Pictet-Spengler and acyl-Pictet-Spengler reactions of L-tryptophan methyl ester, followed by Na-acetylation. The stereoselectivity of the oxidative rearrangement was evaluated and 2D nuclear magnetic resonance (NMR) was used to determine the stereochemistry of the oxindole products relative to L-tryptophan. Density functional theory calculations were consistent with a face selective, substrate controlled, epoxidation of the indolic double bond. The calculations indicated that the resulting epoxide would readily rearrange at room temperature via a concerted ring opening/ring contraction process to give the 3-substituted-2-oxindole.
- Mar?al, Luisa L.,Garden, Simon J.
-
-
- Preparation method of amino-acid ester
-
The invention relates to a preparation method of amino-acid ester, and belongs to the field of synthesis of organic compounds. The preparation method of the amino-acid ester comprises the following steps: taking sulfur trioxide as a catalyst and a water-binding agent, catalyzing amino acid and alcohol to react so as to prepare sulfate of the amino-acid ester, then concentrating a reaction system to remove a reaction solvent and then adding water for dissolving, and neutralizing ammonia water to prepare the amino-acid ester. According to the technical scheme, the provided preparation method ofthe amino-acid ester has the advantages of mild reaction process, high yield, good purity, simplicity in operation and low cost. Concentrated condensate water of central mother liquor of the preparation method of the amino-acid ester can be directly subjected to biochemical treatment, solid by-products are high-purity ammonium sulfate, and can serve as chemical fertilizers, a reaction process is green and pollution-free, and thus, environmental protection is facilitated.
- -
-
Paragraph 0011
(2019/03/15)
-
- Synthesis of 2-D-L-tryptophan by sequential Ir-catalyzed reactions
-
Herein, we report a practical synthesis of 2-D-l-tryptophan via sequential Ir-catalyzed C–H borylation, and Ir-catalyzed C-2-deborylative deuteration steps. In this synthetic sequence, deprotection of the Boc and methyl ester groups proved challenging, due to replacement of deuterium with hydrogen. However, mild deprotection conditions were developed to avoid this D/H scrambling. Further, 2-D-L-Tryptophan is stable in many buffers used for biological studies.
- Vallakati, Ravikrishna,Plotnikov, Abel T.,Altman, Ryan A.
-
p. 2261 - 2264
(2019/03/04)
-
- NOVEL PYRROLO-LACTONE AND PYRROLE COMPOUNDS INDUCING CELLULAR GLUTATHIONE RECOVERY EFFECT AGAINST REACTIVE OXYGEN SPECIES, AND METHOD FOR PREPARING THE SAME
-
The present invention provides: a novel pyrrolo-lactone compound, which can be used as an improved pain therapeutic agent containing various substituents by using glucose and ribose as reducing sugars and conducting a reaction with various kinds of natural and unnatural amino acids; and novel pyrrolo compounds produced during a process of manufacturing the same. The novel pyrrolo-lactone and pyrrole compounds are substances which can be used as improved pain therapeutic agent by having increased restoration ability of glutathione in living cells against reactive oxygen species.COPYRIGHT KIPO 2019
- -
-
Paragraph 0102-0106; 0160; 0164
(2019/05/10)
-
- Preparation and medical application of tetrahydrocarboline-tetrahydroisoquinoline compounds
-
The invention discloses structural analogs of anti-tumor marine natural product ecteinascidins, specifically discloses compounds represented by a general formula I shown in the description, pharmaceutically-acceptable salts of the compounds, and a preparation method of the compounds, and relates to a pharmaceutical composition containing the compounds represented by the general formula I shown inthe description, a preparation method of the pharmaceutical composition, and an application of the compounds and the pharmaceutical composition in anti-tumor aspects.
- -
-
Paragraph 0178-0180; 0181
(2019/05/16)
-
- Synthesis and in vitro cytotoxicity evaluation of β-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition
-
To explore a new set of cytotoxic agents, β-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung cancer) cell line having IC50 value 1.01 μM and 1.17 μM respectively. Further, it was speculated that treatment with compound 10v may induce apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest.
- Jadala, Chetna,Sathish,Reddy, T. Srinivasa,Reddy, Velma Ganga,Tokala,Bhargava, Suresh K.,Shankaraiah, Nagula,Nagesh, Narayana,Kamal
-
p. 3285 - 3298
(2019/06/20)
-
- Synthesis and application of axially chiral biscarbolines with functional N-O and sulfone for 1,2-transfer hydrogenations of ketimines
-
A series of axially chiral biscarboline-based sulfones were synthesized from L-tryptophane and applied for enantioselective 1,2-transfer hydrogenations of ketimines using trichlorosilane. The catalyst 4e, which had a tertiary butyl group, exhibited a good conversion and high enantioselectivities up to 96%ee in the series of reactions.
- Xing, Yongfei,Wu, Shijie,Dong, Mengxian,Wang, Jie,Liu, Li,Zhu, Huajie
-
supporting information
(2019/08/08)
-
- Axially chiral N,N′-dioxides ethers for catalysis in enantioselective allylation of aldehydes
-
A series of axially chiral ethers synthesized from biscarboline N,N′-dioxides, (S)-1a to (S)-1n, was investigated in enantioselectivity addition reactions of allyltrichlorosilane with a series of substituted aldehydes, including bulky substituted aldehydes. High enantioselectivities (up to 96%ee) were achieved using the catalyst (S)-1k at 1 mol % loading.
- Wu, Shijie,Xing, Yongfei,Wang, Jie,Guo, Xingchen,Zhu, Huajie,Li, Wan
-
supporting information
p. 947 - 957
(2019/08/30)
-
- Catalytic Mechanism Study on the 1,2- and 1,4-Transfer Hydrogenation of Ketimines and β-Enamino Esters Catalyzed by Axially Chiral Biscarboline-Based Alcohols
-
Axial N-O alcohols, which have two large carboline moieties connected to the axis were synthesized and used in catalytic enantioselective 1,2- and 1,4-transfer hydrogenations of total 26 ketimines and β-enamino esters. Excellent levels of enantioselectivity ranging from 91% to 99% were achieved by using catalyst (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide. Interestingly, a mixture of (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide and (aR)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide was also able to provide high enantioselectivities up to 95% that is the same as that using pure (aS)-(S)-3,3′-bis((S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl)-9,9′-dimethyl-9H,9′H-[1,1′-bipyrido[3,4-b]indole] 2-oxide. A plausible catalytic mechanism was suggested and total four kinds of transition states (TS) including almost 60 TS structures were investigated using density functional theory (DFT) with different basis sets such as 6-311G(2d,p). The predicted activation energy data are consistent with the experimental results. (Figure presented.).
- Dong, Mengxian,Wang, Jie,Wu, Shijie,Zhao, Yang,Ma, Yangyang,Xing, Yongfei,Cao, Fei,Li, Longfei,Li, Zhenqiu,Zhu, Huajie
-
supporting information
p. 4602 - 4610
(2019/08/30)
-
- ZnO-NP assisted synthesis of fluorescent β-carboline C-1 tethered benzimidazole/benzothiazole/benzoxazole derivatives and assessment of their photophysical properties
-
A facile transformation of 1-formyl β-carboline into fluorescent β-carboline C-1 tethered benzazole derivatives is described under the catalysis of ZnO nanoparticles. The reaction proceeded with the reaction of 1-formyl β-carboline and substituted o-diaminobenzene/2-aminobenzenethiol/2-aminophenol, which results in formation of a Schiff base, followed by an intramolecular cylization reaction to generate β-carboline linked benzimidazole, benzothiazole and benzoxazole derivatives. This appraoch displayed a wide substrate scope and high regioselectivity to yield the desired products in moderate to good yields. The photophysical properties of the synthesized derivatives were also evaluated and they exhibited excellent fluorescence properties. Among these β-carboline substituted azoles, the benzothiazole derivative displayed the maximum quantum yield (ΦF up to 28%).
- Kumar, Vipin,Singh, Dharmender,Paul, Avijit Kumar,Shrivastava, Rahul,Singh, Virender
-
supporting information
p. 18304 - 18315
(2019/12/02)
-
- Design, synthesis, and molecular docking studies of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives as xanthine oxidase inhibitors
-
A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC50?=?3.0?μm) and the D-phenylalanine derivative 1i (IC50?=?2.9?μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50?=?8.1?μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.
- Zhang, Ting-Jian,Li, Song-Ye,Yuan, Wei-Yan,Zhang, Yi,Meng, Fan-Hao
-
p. 893 - 901
(2018/03/21)
-
- Asymmetric synthesis of 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives
-
The invention discloses an asymmetric synthesis method for synthesizing 1-aryl-1H-pyridine[3,4-4]indole-3-carboxylic acid methyl ester derivatives containing two chiral centers from (R)methyl-2-amino-3-(1H-indol-3-yl)propanoate and aldehyde as main starting materials under catalysis of a catalyst, namely, chiral Lewis acid formed by a chiral tridentate ligand compound L and Ti(O-iPr)4. Compared with the prior art, the method has the advantages that the reaction yield is increased and the reaction non-correspondence selectivity is remarkably improved.
- -
-
Paragraph 0020
(2018/04/01)
-
- Exciton-Coupled Circular Dichroism Characterization of Monotopically Binding Guests in Host?Guest Complexes with a Bis(zinc porphyrin) Tweezer
-
A stiff-stilbene-linked bisporphyrin tweezer with inherent helicity was used for exciton-coupled circular dichroism (ECCD) characterization of a series of monotopically binding amine guest molecules. CD signals were observed for a variety of monoamines at relatively low tweezer/amine (host/guest) ratios between 1 : 10 to 1 : 70. For the amines producing the most intense CD signals, a binding stoichiometry of 1 : 2 was found. A likely explanation is the presence of guest-guest interactions in the complexes. This is supported by the correlation observed between CD signal intensity and magnitude of possible noncovalent binding between the guests, which can be divided into three groups showing no, moderate and strong response, respectively. Further support for this rationalization comes from molecular modelling.
- Olsson, Sandra,Sch?fer, Clara,Blom, Magnus,Gogoll, Adolf
-
p. 1169 - 1178
(2019/01/04)
-
- An auxin-tyrosine derivative based biocompatible supergelator: A template for fabrication of nanoparticles for sustained release of model drugs
-
Bioinspired self-assembling peptides serve as powerful building blocks in the manufacturing of nanomaterials with tailored features. Inspired by the supergelating ability of naphthyl-Phe-OH (hydrogelator I), we synthesized naphthyl-Tyr-OH (hydrogelator II) and naphthyl-Trp-OH (hydrogelator III) with the objective of exploring the propensities of the phenolic OH of Tyr and the NH of the indole for controlling the gelation process. However, our experimental investigation reveals that hydrogelator II, containing Tyr as the aromatic core, shows an excellent gelation ability. But the Trp analogue fails to do so under similar conditions. To validate our results we performed MD simulation in an aqueous environment which significantly justifies that hydrogelator II exhibits a better hydrogelation ability than hydrogelators I and III. The characterisation of hydrogelator II was then performed in detail using various analytical and microscopic techniques and its biocompatibility was tested using an MTT assay. To examine the potentiality of hydrogelator II in drug delivery we developed hydrogel nanoparticles (HNPs) using the concept of self-assembly entirely governed by an ecofriendly approach i.e. weak interactions (like H-bonding, π-π and hydrophobic interactions). Our hydrogel nanoparticles display good release kinetics of the model drugs 5-fluorouracil and curcumin from the hydrogel matrix depending on their chemical structure, molecular weight and hydrophobicity. Thus our research shows that the choice of the core residue has a profound impact on the self-assembly process and thus on the gelation properties. Moreover, nanoparticles generated from our novel biocompatible hydrogelator II hold promise for future drug delivery applications.
- Tiwari, Priyanka,Basu, Anindya,Sahu, Sonu,Gound, Sadhna,Christman, Ryann M.,Tiwari, Amit K.,Trivedi, Piyush,DuttKonar, Anita
-
p. 4915 - 4922
(2018/03/30)
-
- Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
-
Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
- Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
-
p. 3738 - 3745
(2018/04/14)
-
- Design and Synthesis of DNA-Interactive β-Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis-Inducing Agents
-
A new series of (E)-3-[(1-aryl-9H-pyrido[3,4-b]indol-3-yl)methylene]indolin-2-one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT-15, HCT-116, A549, NCI-H460, and MCF-7, including HFL. Among the tested compounds, (E)-1-benzyl-5-bromo-3-{[1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl]methylene}indolin-2-one (10 s) showed potent cytotoxicity against HCT-15 cancer cells with an IC50 value of 1.43±0.26 μm and a GI50 value of 0.89±0.06 μm. Notably, induction of apoptosis by 10 s on the HCT-15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V-FITC/PI, DCFDA, and JC-1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT-15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT-15 cancer cells led to decreased expression of anti-apoptotic Bcl-2 and increased protein expression of both pro-apoptotic Bax and caspase-3, -8, and -9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT-15 cancer cells by 10 s in a dose-dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular-docking studies showed that compound 10 s has typical intercalation with DNA.
- Tokala, Ramya,Thatikonda, Sowjanya,Vanteddu, Usha Sree,Sana, Sravani,Godugu, Chandraiah,Shankaraiah, Nagula
-
p. 1909 - 1922
(2018/09/14)
-
- Indole-quinolizine-6-methylol-glucuronate, preparation, activity and application thereof
-
The invention provides (6S)-3-acetyl base-6-methylol-4,6,7,12-tetrahydrofuran-4-oxyindole[2,3-alpha]quinolizine-alph-D-furan glucuronate, provides a preparation method thereof, discloses the anti-tumor activity thereof in a mice S180 transplanted sarcoma model, discloses the anti-tumor metastasis activity thereof in a mice Lewis lung cancer metastasis model, discloses an anti-inflammation role thereof in a mice ear swelling model, and further discloses an anti-thrombus role thereof in a rat common carotid artery-external jugular vein circulation bypath thread method anti-thrombus model. The invention discloses application of (6S)-3-acetyl base-4-oxo-4,6,7,12-tetraindole-[2,3-alpha]quinolizine-6-formyl-glucuronate in preparation of anti-tumor drugs, anti-lung cancer metastasis drugs, anti-inflammation drugs and anti-thrombus drugs.
- -
-
Paragraph 0018; 0020; 0021
(2018/04/02)
-
- Synthesis, antileishmanial activity and mechanism of action studies of novel β-carboline-1,3,5-triazine hybrids
-
A series of novel hybrids β-carboline-1,3,5-triazine were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and amastigote forms of Leishmania amazonensis. Among the compounds tested, the hybrids 9d, 9e, 16a and 16b showed potent activity against the promastigote forms with IC50 values less than 8 μM. Compounds 9e and 16b were also active against amastigote forms, displaying IC50 values of 1.0 ± 0.1 μM and 1.2 ± 0.5 μM, respectively. Besides that, the hybrid 16b bearing the 4-methoxyphenyl group at C-1 of β-carboline and isopropylamino group at 1,3,5-triazine, showed low toxicity, being 23.5 and 121.4 times more toxic for promastigotes and axenic amastigotes, respectively, than for macrophage J774-A1 cell lines. Investigation of action mechanism in promastigotes showed that compound 16b caused alterations in cell division cycle and an increase of lipid-storage bodies, leading the cells to death through various factors. The accumulation of lipid bodies may be associated with apoptotic cell death.
- Baréa, Paula,Barbosa, Valéria Aquilino,Bidóia, Danielle Lazarin,de Paula, Jéssica Carreira,Stefanello, Talitha Fernandes,da Costa, Willian Ferreira,Nakamura, Celso Vataru,Sarragiotto, Maria Helena
-
p. 579 - 590
(2018/03/21)
-
- Synthesis of podophyllotoxin linked β-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors
-
A series of new podophyllotoxin linked β-carboline congeners have been synthesized by coupling various substituted β-carboline acids with 4β-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07 ± 0.07 μM and 1.14 ± 0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.
- Sathish, Manda,Kavitha, Botla,Nayak, V. Lakshma,Tangella, Yellaiah,Ajitha, Ayyappan,Nekkanti, Shalini,Alarifi, Abdullah,Shankaraiah, Nagula,Nagesh, Narayana,Kamal, Ahmed
-
p. 557 - 571
(2018/01/01)
-
- Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents
-
Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3′-amino-[1,1′-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 μM) and Gram-negative Escherichia coli (MIC = 7.8 μM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli.
- Kuppusamy, Rajesh,Yasir, Muhammad,Berry, Thomas,Cranfield, Charles G.,Nizalapur, Shashidhar,Yee, Eugene,Kimyon, Onder,Taunk, Aditi,Ho, Kitty K.K.,Cornell, Bruce,Manefield, Mike,Willcox, Mark,Black, David StC,Kumar, Naresh
-
p. 1702 - 1722
(2017/11/17)
-
- Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors
-
A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13–45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.
- Sathish, Manda,Chetan Dushantrao, Sabanis,Nekkanti, Shalini,Tokala, Ramya,Thatikonda, Soujanya,Tangella, Yellaiah,Srinivas, Gunda,Cherukommu, Shirisha,Hari Krishna, Namballa,Shankaraiah, Nagula,Nagesh, Narayana,Kamal, Ahmed
-
p. 4916 - 4929
(2018/09/11)
-
- Synthesis and in vitro cytotoxicity evaluation of β-carboline-linked 2,4-thiazolidinedione hybrids: potential DNA intercalation and apoptosis-inducing studies
-
A series of new β-carboline-thiazolidinedione hybrids was synthesized and assessed for in vitro cytotoxicity potential against selected human cancer cell lines, namely, PC-3, A549, MG-63, HCT-15, MDA-MB-231, A431, and PANC-1 along with a normal human cell line (L-132). Among this new series, compound 19e was found to exhibit promising cytotoxic effects against triple negative breast cancer cell line (MDA-MB-231) with IC50 value of 0.97 ± 0.13 μM. Hence, further mechanistic studies of the apoptosis-inducing effect of 19e were conducted on the MDA-MB-23 cell line. Moreover, characteristic apoptotic features such as membrane blebbing, chromatin condensation, and apoptotic body formation were observed with the effect of 19e on MDA-MB-231 cells using AO/EB and DAPI staining. The Annexin V-Alexa Flour 488/PI assay confirmed significant early apoptosis induction. Notably, DCFDA assay indicated that 19e induced ROS generation. Moreover, mitochondrial membrane potential collapse was observed through JC-1 staining by 19e. Furthermore, cell cycle analysis revealed that 19e arrested cells in the sub G1 phase. In addition, clonogenic and wound healing assays indicated inhibition of colony formation and cell migration by 19e in a dose-dependent manner. Next, molecular modelling and DNA binding affinity studies such as relative viscosity, circular dichroism and UV-visible spectroscopy denoted classic intercalation of 19e with CT-DNA with binding constant of 1 × 105 M?1.
- Tokala, Ramya,Thatikonda, Sowjanya,Sana, Sravani,Regur, Phanindranath,Godugu, Chandraiah,Shankaraiah, Nagula
-
p. 16226 - 16236
(2018/10/04)
-
- Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors
-
A series of new β-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 μM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV–Visible, fluorescence, circular dichroism and molecular docking studies revealed that the β-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.
- Kovvuri, Jeshma,Nagaraju, Burri,Nayak, V. Lakshma,Akunuri, Ravikumar,Rao, M.P. Narasimha,Ajitha, Ayyappan,Nagesh, Narayan,Kamal, Ahmed
-
p. 1563 - 1577
(2017/11/15)
-
- Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease
-
To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 μM, respectively), Aβ1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aβ1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.
- Zhao, Yifan,Ye, Feng,Xu, Jian,Liao, Qinghong,Chen, Lei,Zhang, Weijia,Sun, Haopeng,Liu, Wenyuan,Feng, Feng,Qu, Wei
-
p. 3812 - 3824
(2018/06/30)
-
- Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold
-
A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10?nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1?±?0.1?μm than positive control (15.5?±?0.4?μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
- Yang, Dezhi,Tong, Dongdong,Zhang, Qian,Wang, Yongtao,Sun, Jing,Zhang, Fenghe,Zhao, Guisen
-
p. 791 - 803
(2017/09/30)
-
- Non-correspondence selective synthesis of 1-aryl-1H-pyridine[3,4-b]indole derivative
-
The invention discloses an asymmetric synthesis method for synthesizing 1-aryl-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester derivatives containing two chiral centers by taking (R)-tryptophan methyl ester and aldehyde as main starting raw materials, taking chiral Lewis acid Salen-Mn as a catalyst and taking (R)-alpha-methyl-4-nitrophenylacetic acid as a chiral additive. Compared with the prior art, the reaction yield is improved and the non-correspondence selectivity of the reaction is remarkably improved.
- -
-
Paragraph 0025
(2018/03/28)
-
