Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation.


:A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50=14nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24μM against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation.


Bioorg Med Chem


Ma X,Lv X,Qiu N,Yang B,He Q,Hu Y




Has Abstract


2015-12-15 00:00:00














  • Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines.

    abstract::In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concen...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Temburnikar KW,Ross CR,Wilson GM,Balzarini J,Cawrse BM,Seley-Radtke KL

    更新日期:2015-08-01 00:00:00

  • Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced Aβ aggregation and antioxidant.

    abstract::A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer's disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1-42 aggregation, rapid ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Wang B,Wang Z,Chen H,Lu CJ,Li X

    更新日期:2016-10-01 00:00:00

  • In vitro cytotoxicity of 5-aminosubstituted 20(S)-camptothecins. Part 1.

    abstract::A number of 5-aminosubstituted 20(S)-camptothecin analogues were prepared via semi-synthesis starting from 20(S)-camptothecin and 9-methoxy 20(S)-camptothecin. In vitro anti-cancer activity of these analogues was determined using 60 human tumor cell line assay. Although water solubility of most of these compounds was ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Subrahmanyam D,Sarma VM,Venkateswarlu A,Sastry TV,Kulakarni AP,Rao DS,Reddy KV

    更新日期:1999-09-01 00:00:00

  • Novel synthetic 2-amino-10-(3,5-dimethoxy)benzyl-9(10H)-acridinone derivatives as potent DNA-binding antiproliferative agents.

    abstract::A series of novel 9(10H)-acridinone derivatives with terminal amino substituents at C2 position on the acridinone ring were synthesized and studied for their antiproliferative activity and underlying mechanisms. These compounds demonstrated promising cytotoxicity to leukemia cells CCRF-CEM, displaying IC(50) values in...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gao C,Liu F,Luan X,Tan C,Liu H,Xie Y,Jin Y,Jiang Y

    更新日期:2010-11-01 00:00:00

  • Synthesis and Th1-immunostimulatory activity of α-galactosylceramide analogues bearing a halogen-containing or selenium-containing acyl chain.

    abstract::A novel series of CD1d ligand α-galactosylceramides (α-GalCers) were synthesized by incorporation of the heavy atoms Br and Se in the acyl chain backbone of α-galactosyl-N-cerotoylphytosphingosine. The synthetic analogues are potent CD1d ligands and stimulate mouse invariant natural killer T (iNKT) cells to selectivel...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Hossain MI,Hanashima S,Nomura T,Lethu S,Tsuchikawa H,Murata M,Kusaka H,Kita S,Maenaka K

    更新日期:2016-08-15 00:00:00

  • 4,4'-Dihydroxy-trans-stilbene, a resveratrol analogue, exhibited enhanced antioxidant activity and cytotoxicity.

    abstract::Resveratrol (3,5,4'-trans-trihydroxystibene) is a natural phytoalexin present in grapes and red wine, which possesses a variety of biological activities including antioxidant activity. In order to find more active antioxidant with resveratrol as the lead compound we synthesized 4,4'-dihydroxy-trans-stilbene (4,4'-DHS)...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Fan GJ,Liu XD,Qian YP,Shang YJ,Li XZ,Dai F,Fang JG,Jin XL,Zhou B

    更新日期:2009-03-15 00:00:00

  • Norbornyllactone-substituted xanthines as adenosine A(1) receptor antagonists.

    abstract::During the search for second-generation adenosine A(1) receptor antagonist alternatives to the clinical candidate 8-(3-oxa-tricyclo[,4)]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (BG9719), we developed a series of novel xanthines substituted with norbornyl-lactones that possessed high binding affinit...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Kiesman WF,Zhao J,Conlon PR,Petter RC,Jin X,Smits G,Lutterodt F,Sullivan GW,Linden J

    更新日期:2006-06-01 00:00:00

  • Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase.

    abstract::Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds sh...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Sun Y,Xu W,Fan N,Sun X,Ning X,Ma L,Liu J,Wang X

    更新日期:2017-02-01 00:00:00

  • Benzodiazepine receptor ligands. 8: synthesis and pharmacological evaluation of new pyrazolo[5,1-c] [1,2,4]benzotriazine 5-oxide 3- and 8-disubstituted: high affinity ligands endowed with inverse-agonist pharmacological efficacy.

    abstract::The synthesis and the binding study of new 3-arylesters and 3-heteroarylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 8-substituted are reported. The nature of these substituents (in terms of lipophilic and electronic features) seems to influence the binding affinity. High-affinity ligands were studied in mice in vivo f...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Guerrini G,Costanzo A,Ciciani G,Bruni F,Selleri S,Costagli C,Besnard F,Costa B,Martini C,De Siena G,Malmberg-Aiello P

    更新日期:2006-02-01 00:00:00

  • Electronic effects of para-substitution on acetophenones in the reaction of rat liver 3alpha-hydroxysteroid dehydrogenase.

    abstract::Stereoselective reductive metabolism of various p-substituted acetophenone derivatives was studied using isolated rat liver 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). Kinetic experiments were performed and analyzed by measuring the products by HPLC using a chiral column. The results demonstrated that the presen...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Uwai K,Konno N,Yasuta Y,Takeshita M

    更新日期:2008-02-01 00:00:00

  • Fancy bioisosteres: synthesis, SAR, and pharmacological investigations of novel nonaromatic dopamine D3 receptor ligands.

    abstract::Structural variations of the lead compound FAUC 88 led to dopaminergic enynes with an extended pi-system when Pd-catalyzed cross coupling reactions were employed for the key reaction steps. The dienyne 9b displayed substantial affinity for the dopamine receptor subtype D3 and remarkable selectivity over D4. Compared t...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lenz C,Boeckler F,Hübner H,Gmeiner P

    更新日期:2005-07-15 00:00:00

  • On the topological evidences for modelling lipophilicity.

    abstract::Topological evidences for modelling lipophilicity of a large series of diversed compounds have been provided on the basis of distance-based topological indices. A pool of topological indices along with indicator parameters related to the type of the compounds present in the set of 140 compounds were used for this purp...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Agrawal VK,Singh J,Khadikar PV

    更新日期:2002-12-01 00:00:00

  • Triterpene sapogenin-polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains.

    abstract::Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charge...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Na H,Li X,Zou C,Wang C,Wang C,Liu K

    更新日期:2016-07-01 00:00:00

  • Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors.

    abstract::Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, uro...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Gulcan HO,Unlu S,Esiringu I,Ercetin T,Sahin Y,Oz D,Sahin MF

    更新日期:2014-10-01 00:00:00

  • Novel inhibitors of RANKL-induced osteoclastogenesis: Design, synthesis, and biological evaluation of 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones.

    abstract::A series of novel 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives were synthesized and evaluated for their inhibitory effects on osteoclast activities by using TRAP-staining assay. Among the tested compounds, 3d and 3h exhibited more potent osteoclast-inhibitory activities than the le...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Lee CC,Liu FL,Chen CL,Chen TC,Liu FC,Ahmed Ali AA,Chang DM,Huang HS

    更新日期:2015-08-01 00:00:00

  • Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro.

    abstract::Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure o...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Paine HA,Nathubhai A,Woon EC,Sunderland PT,Wood PJ,Mahon MF,Lloyd MD,Thompson AS,Haikarainen T,Narwal M,Lehtiö L,Threadgill MD

    更新日期:2015-09-01 00:00:00

  • Synthesis, molecular modeling and biological evaluation of β-ketoacyl-acyl carrier protein synthase III (FabH) as novel antibacterial agents.

    abstract::A series of novel cinnamic acid secnidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of FabH. These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylo...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Zhang HJ,Zhu DD,Li ZL,Sun J,Zhu HL

    更新日期:2011-08-01 00:00:00

  • Synthesis and antioxidant activity evaluation of new 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes obtained by Buchwald-Hartwig C-N cross-coupling.

    abstract::New 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes were prepared by palladium-catalyzed Buchwald-Hartwig cross-coupling of 7-bromo or 7-amino-2,3-dimethylbenzo[b]thiophenes, previously prepared by us, with substituted (4-methoxy or 3,4-dimethoxy) anilines and 3-aminopyridine or with substituted (3-methoxy ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Queiroz MJ,Ferreira IC,Calhelha RC,Estevinho LM

    更新日期:2007-02-15 00:00:00

  • Synthesis and characterization of a small analogue of the anticancer natural product leinamycin.

    abstract::Leinamycin (1) is a Streptomyces-derived natural product that displays nanomolar IC(50) values against human cancer cell lines. In the work described here, we report the synthesis and characterization of a small leinamycin analogue 19 that closely resembles the 'upper-right quadrant' of the natural product, consisting...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Keerthi K,Rajapakse A,Sun D,Gates KS

    更新日期:2013-01-01 00:00:00

  • Novel structure-activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators.

    abstract::Synthesized series of cage dimeric 1,4-dihydropyridines have been systematically evaluated as MDR modulators in in vitro assays to investigate structure-dependent selectivity properties of inhibiting most cancer-relevant efflux pump proteins. Structure-activity relationships of each P-glycoprotein (P-gp) and multidrug...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Coburger C,Wollmann J,Krug M,Baumert C,Seifert M,Molnár J,Lage H,Hilgeroth A

    更新日期:2010-07-15 00:00:00

  • meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity.

    abstract::Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculo...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Reyes-Melo K,García A,Romo-Mancillas A,Garza-González E,Rivas-Galindo VM,Miranda LD,Vargas-Villarreal J,Favela-Hernández JMJ,Camacho-Corona MDR

    更新日期:2017-10-15 00:00:00

  • Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents.

    abstract::Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amid...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ling Y,Wang Z,Zhu H,Wang X,Zhang W,Wang X,Chen L,Huang Z,Zhang Y

    更新日期:2014-01-01 00:00:00

  • Inhibition studies of new ureido-substituted sulfonamides incorporating a GABA moiety against human carbonic anhydrase isoforms I-XIV.

    abstract::Reaction of γ-Boc-GABA, prepared by protecting the γ-amino moiety of the amino butyric acid with the tert-butyloxycarbonyl (Boc) protecting group, with 4-methyl/ethyl benzenesulfonamide, followed by removal of the Boc protecting group in 3 M HCl afforded the corresponding hydrochlorides, which were further derivatized...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Ceruso M,Antel S,Vullo D,Scozzafava A,Supuran CT

    更新日期:2014-12-15 00:00:00

  • Inhibitory effects of flavonoids isolated from Fragaria ananassa Duch on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3.

    abstract::We isolated the 4 kinds of flavonoids from strawberry 'Nohime' and examined the effect of these flavonoids on the degranulation in RBL-2H3 cells. The flavonoids were found to suppress the degranulation from Ag-stimulated RBL-2H3 cells to different extents. To disclose the inhibitory mechanism of degranulation by flavo...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Itoh T,Ninomiya M,Yasuda M,Koshikawa K,Deyashiki Y,Nozawa Y,Akao Y,Koketsu M

    更新日期:2009-08-01 00:00:00

  • Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein.

    abstract::Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shen X,Wong J,Prakash TP,Rigo F,Li Y,Napierala M,Corey DR

    更新日期:2020-06-01 00:00:00

  • Nanomolar affinity, iminosugar-based chemical probes for specific labeling of lysosomal glucocerebrosidase.

    abstract::Three different photoprobes were synthesized to label beta-glucosidases; one probe was based on glucose, two probes on the iminosugar deoxynojirimycin. The affinity of the probes for three different beta-glucosidases was determined. Furthermore, their labeling efficiencies, binding specificities through competition wi...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: van Scherpenzeel M,van den Berg RJ,Donker-Koopman WE,Liskamp RM,Aerts JM,Overkleeft HS,Pieters RJ

    更新日期:2010-01-01 00:00:00

  • Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors.

    abstract::The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl g...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Shimamoto Y,Hattori Y,Kobayashi K,Teruya K,Sanjoh A,Nakagawa A,Yamashita E,Akaji K

    更新日期:2015-02-15 00:00:00

  • Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin.

    abstract::Germanicane-type triterpenes allobetulin (3) and 28-oxoallobetulin (4) can be obtained by the Wagner-Meerwein rearrangement of the more available lupane-type triterpenes betulin (1) and betulinic acid (2), respectively. The medical uses of betulinic acid (2) and its derivatives are limited because of their poor hydros...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Thibeault D,Gauthier C,Legault J,Bouchard J,Dufour P,Pichette A

    更新日期:2007-09-15 00:00:00

  • Impact of stereochemistry on the biological activity of novel oleandomycin derivatives.

    abstract::A set of 8-methylene-, 8-methyl-, and 8-methyl-9-dihydro-oleandomycin derivatives having different combinations of stereochemistries at positions C-8 and/or C-9 have been prepared in a chemoselective and stereoselective manner and tested in vitro for antibacterial activity and inhibition of IL-6 production. Configurat...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Bauer J,Vine M,Corić I,Bosnar M,Pašalić I,Turkalj G,Lazarevski G,Culić O,Kragol G

    更新日期:2012-04-01 00:00:00

  • High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones.

    abstract::Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and p...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章


    authors: Carotti A,Altomare C,Savini L,Chiasserini L,Pellerano C,Mascia MP,Maciocco E,Busonero F,Mameli M,Biggio G,Sanna E

    更新日期:2003-11-17 00:00:00