- Design, synthesis and apoptosis inducing activity of nonsteroidal flavone-methanesulfonate derivatives on MCF-7 cell line as potential sulfatase inhibitor
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In recent years, focusing on new potent anticancer agents with selective activity is one of the greatest challenges in cancer therapy. Breast cancer is the most common cancer and the main cause of cancer deaths in women. The sulfatase enzyme plays an important role in converting the sulfated steroids into non-sulfate steroid hormones, which increases the growth and development of many hormone-dependent cancers, such as breast cancer. In this regard, structure-based optimization was conducted to design novel flavone-sulfonates pharmacophore as a new steroid sulfatase inhibitor. In the present work, the conventional methods for the synthesis of 4-oxo-2-phenyl-4H-chromen-7-yl methanesulfonate derivatives were reported. Their cytotoxicity was evaluated with MTT assay against a breast cancer cell line (MCF-7). The apoptosis inducing activity of the most cytotoxic compound 3c with an IC50 value of 0.615 μM was evaluated in comparison to docetaxel in the presence of estradiol which is a crucial growth factor to survive the cancerous cells. The results of double staining Annexin V-FITC/PI analysis suggested that the cytotoxic activity of this compound 3c in MCF-7 cells occurs via apoptosis. Molecular docking studies were conducted to clarify the inhibition mode of the most promising compound (3c) over the sulfatase (1P49) binding site. The analysis revealed the role of hydrogen bond interaction with Gly181 and hydrophobic interactions through the 1P49 active site in the ligand-receptor complex as significant descriptors to rationalize the potential inhibition activity. [Figure not available: see fulltext.]
- Javadi, Mahdiyeh H. S.,Iraji, Aida,Safavi, Maliheh,Montazeri, Hamed,Tarighi, Parastoo,Eftekhari, Samane,Navidpour, Latifeh,Mirfazli, Seyedeh Sara
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p. 1677 - 1687
(2021/07/26)
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- Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki-Miyaura cross-coupling reactions
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3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrateviatwo complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki-Miyaura cross-coupling reactions.
- Dinh, Long P.,Harris, Nekoda W.,Jacoby, Seth A.,Semsey, Rebecca Y.,Swann, William A.,Tran, Ryan Q.,Williamson, Savannah N.,Yet, Larry
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p. 28347 - 28351
(2021/09/15)
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- 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers
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Aiming to deepen the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.
- Bartolucci, Gianluca,Braconi, Laura,Colabufo, Nicola Antonio,Contino, Marialessandra,Dei, Silvia,Giampietro, Roberta,Manetti, Dina,Perrone, Maria Grazia,Riganti, Chiara,Romanelli, Maria Novella,Teodori, Elisabetta,Chiaramonte, Niccolò
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p. 974 - 992
(2020/04/24)
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- Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness
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In a recent investigation carried out on a panel of trimethoxybenzanilides, we showed that the formation of an intramolecular hydrogen bond is a key element for tuning P-gp inhibitory activity. In this study, we designed new structurally simplified trimet
- Stefanachi, Angela,Mangiatordi, Giuseppe Felice,Tardia, Piero,Alberga, Domenico,Leonetti, Francesco,Niso, Mauro,Colabufo, Nicola Antonio,Adamo, Carlo,Nicolotti, Orazio,Cellamare, Saverio
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p. 820 - 831
(2016/11/11)
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- Beyond directed ortho metalation: Ru-catalyzed CAr-O activation/cross-coupling reaction by amide chelation
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Disclosed is a new, catalytic, and general methodology for the chemical synthesis of biaryl, heterobiaryl, and polyaryl molecules by the cross-coupling of o-methoxybenzamides with aryl boroneopentylates. The reaction is based on the activation of the unreactive C-OMe bond by the proximate amide directing group using catalytic RuH2(CO)(PPh3)3 conditions. A one-step, base-free coupling process is thereby established that has the potential to supersede the useful two-step directed ortho metalation/cross- coupling reaction involving cryogenic temperature and strong base conditions. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, minimum waste, and convenient scale-up make these reactions suitable for industrial applications.
- Zhao, Yigang,Snieckus, Victor
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supporting information
p. 11224 - 11227
(2014/09/29)
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- Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4- pyridyl)acetyl]-2,3-dimethoxyphenoxy}- N -propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis
-
Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clin
- Felding, Jakob,S?rensen, Morten D.,Poulsen, Tina D.,Larsen, Jens,Andersson, Christina,Refer, Pia,Engell, Karen,Ladefoged, Lotte G.,Thormann, Thorsten,Vinggaard, Anne Marie,Hegardt, Pontus,S?hoel, Anders,Nielsen, Simon Feldb?k
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p. 5893 - 5903
(2014/08/18)
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- Trimethoxybenzanilide-based P-glycoprotein modulators: An interesting case of lipophilicity tuning by intramolecular hydrogen bonding
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One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently sh
- Tardia, Piero,Stefanachi, Angela,Niso, Mauro,Stolfa, Diana Antonella,Mangiatordi, Giuseppe Felice,Alberga, Domenico,Nicolotti, Orazio,Lattanzi, Gianluca,Carotti, Angelo,Leonetti, Francesco,Perrone, Roberto,Berardi, Francesco,Azzariti, Amalia,Colabufo, Nicola Antonio,Cellamare, Saverio
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p. 6403 - 6418
(2014/10/16)
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- N,N+hu 1 +l SUBSTITUTED PIPERAZINES HAVING COMBINED ANTIAGGREGANT, ANTICOAGULANT AND VASODILATORY ACTIVITY, AND METHOD FOR PRODUCING SAME
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The invention relates to derivatives of N,N′-substituted piperazines of the general formula (I): where R1 and R2 denote linear or branched (C1-C4)alkyl, linear or branched (C1-C4)alkoxy, CH
- -
-
Paragraph 0075; 0077
(2013/10/22)
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- Synthesis and biological evaluation of phenyl substituted polyoxygenated xanthone derivatives as anti-hepatoma agents
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A series of novel derivatives of phenyl substituted tetramethoxy xanthone were synthesized and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor hepatic cells. Among these derivatives, compound 6 was more potent than positive control 5-fluorouracil (5-Fu) on QGY-7703 and SMMC-7721 cells with IC50 values of 6.27 μM, 7.50 μM and 15.56 μM, 14.55 μM, respectively. Furthermore, compounds 6, 14, 16, and 29 exhibited much better selectivity toward the normal hepatic cell line QSG-7701 than 5-Fu. Additionally, compound 6 significantly induced cell apoptosis in QGY-7703 cells. Our findings suggested that these phenylxanthone derivatives may hold promise as chemotherapeutic agents for the treatment of human HCC.
- Dai, Ming,Yuan, Xing,Kang, Jian,Zhu, Zhi-Jun,Yue, Rong-Cai,Yuan, Hu,Chen, Bing-Yang,Zhang, Wei-Dong,Liu, Run-Hui,Sun, Qing-Yan
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p. 159 - 166
(2013/10/01)
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- Process development of the PDE4 inhibitor K-34
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A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.
- Yanagisawa, Arata,Taga, Masashi,Atsumi, Toshiyuki,Nishimura, Koichiro,Ando, Kyoji,Taguchi, Tsuyoshi,Tsumuki, Hiroshi,Chujo, Iwao,Mohri, Shin-Ichiro
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experimental part
p. 376 - 381
(2012/02/01)
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- Anti-tumoral activities of dioncoquinones B and C and related naphthoquinones gained from total synthesis or isolation from plants
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Dioncoquinones belong to a family of natural naphthoquinone products of interest due to their promising anti-tumoral and anti-infective activities. In particular, dioncoquinones A (5) and B (6) have been shown to be highly active against Leishmania major and multiple myeloma cells without any significant toxicity toward normal blood cells. Their effective concentrations against multiple myeloma cell lines were similar to those of melphalan, a well known DNA-alkylating agent used in a standard therapy against B cell lymphoma and multiple myeloma. We report on the first total synthesis of the highly oxygenated anti-tumoral agent dioncoquinone B (6) and the isolation of its new, even higher-oxygenated analogs, dioncoquinones C (7), D (8), and E (9), from cell cultures of Triphyophyllum peltatum. In addition, several derivatives of these compounds were synthesized, including dioncoquinone C (7), and a small library of naphthoquinones was created. Furthermore, the first structure-activity relationship (SAR) study on this class of compounds was conducted, showing that each of the three hydroxy groups, at C-3, C-5, and C-6, is required for improved anti-tumoral activities and decreased cytotoxicities.
- Bringmann, Gerhard,Zhang, Guoliang,Hager, Anastasia,Moos, Michael,Irmer, Andreas,Bargou, Ralf,Chatterjee, Manik
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experimental part
p. 5778 - 5789
(2012/02/01)
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- (4-ALKYLPIPERAZINYL)(PHENYL) METHANONES
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The invention provides a therapeutic method for treating at least one symptom of Alzheimer’s disease in a mammal, such as a human, wherein the toxicity of a pathogen of β amyloid peptide mammalian cells is implicated and inhibition of the subsequently-ind
- -
-
Page/Page column 19
(2008/06/13)
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- Exploratory chemistry toward the identification of a new class of multidrug resistance reverters inspired by pervilleine and verapamil models
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On the basis of the present knowledge of the substrate recognition site of ABC transporter proteins and inspired by the structures of verapamil and pervilleine A, a new class of Pgp-mediated multidrug resistance (MDR) reverters has been designed and synthesized. The new compounds are flexible molecules carrying one or two basic nitrogen atoms flanked, at properly modulated distance, by two aromatic moieties. Most of the molecules studied possess MDR inhibitory activity on anthracycline-resistant erythroleukemia K 562 cells, showing a potency that is higher than that of the reference compound verapamil and, in a few cases (7, 12, 13, 17, 20, 22, 28), is in the high nanomolar range. These compounds may be useful leads to develop new MDR reverting agents. In fact, the chemical structure of the class is fairly simple and can be implemented in a variety of ways that will allow the synthesis of new compounds that might be useful leads for the development of drugs to control Pgp-dependent MDR.
- Teodori, Elisabetta,Dei, Silvia,Garnier-Suillerot, Arlette,Gualtieri, Fulvio,Manetti, Dina,Martelli, Cecilia,Romanelli, Maria Novella,Scapecchi, Serena,Sudwan, Paiwan,Salerno, Milena
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p. 7426 - 7436
(2007/10/03)
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- Relationship between protective effect of xanthone on endothelial cells and endogenous nitric oxide synthase inhibitors
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1,3,5,6-tetrahydroxyxanthone was synthesized. The relationship between protective effect of xanthone on endothelial cells and endogenous nitric oxide synthase inhibitors was investigated. Endothelial cells were treated with ox-LDL (100 μg/mL) for 48 h. Ad
- Jiang, De-Jian,Hu, Gao-Yun,Jiang, Jun-Lin,Xiang, Hong-Lin,Deng, Han-Wu,Li, Yuan-Jian
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p. 5171 - 5177
(2007/10/03)
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- Synthesis and structure-activity relationship of diarylamide derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells
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A series of diarylamide derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2w was superior to the lead compound, Tranilast, in terms of the potency of the activity and cell selectivity.
- Gita, Haruhisa,Sobe, Yoshiaki,Akaku, Haruo,Ekine, Rena,Oto, Yuso,Isawa, Satoru,Hayashi, Hideya
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p. 549 - 551
(2007/10/03)
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- Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives
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Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2- aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofu
- Monte, Aaron P.,Waldman, Steve R.,Marona-Lewicka, Danuta,Wainscott, David B.,Nelson, David L.,Sanders-Bush, Elaine,Nichols, David E.
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p. 2997 - 3008
(2007/10/03)
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- An asymmetric synthesis of (+)-apogossypol hexamethyl ether
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The first asymmetric synthesis of the gossypol backbone via a stereocontrolled oxazoline mediated 2,2' Ullmann coupling has been achieved.
- Meyers,Willemsen, Jeffrey J.
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p. 791 - 792
(2007/10/03)
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- Synthesis of pentasubstituted benzamides via orthometallation: Base and substituent effects
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The synthesis of diversely substituted ori/io-methyl JV,./V-diethylbenzamides using the orthometallation concept is described. A dramatic effect of the substituents and the additive TMEDA is observed during metallation ortho to the N1N-diethylcarboxamido group. Molecular modeling confirms the conformational effect of substituents. A role for the TMEDA additive is proposed. Elscvier,.
- Khaldi, Mustapha
-
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- γ-Pyrone compounds. II: Synthesis and antiplatelet effects of tetraoxygenated xanthones
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Norathyriol and its analogues, 1,3,5,6-, 3,4,5,6-, 3,4,6,7- and 2,3,6,7- tetrahydroxyxanthone, were synthesized from benzophenone precursors by Friedel-Crafts acylation and subsequent base-catalyzed cyclization to eliminate methanol. Both 3,4,6,7- and 2,3,6,7-tetrahydroxyxanthone tetraacetate showed potent anti-platelet aggregation effects on arachidonic acid-induced platelet aggregation. 3,4,6,7-Tetrahydroxyxanthone tetraacetate and 1,3,5,6-tetrahydroxyxanthone showed potent and significant anti-platelet aggregation effects on collagen-induced platelet aggregation.
- Lin,Liou,Ko,Teng
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p. 1109 - 1112
(2007/10/02)
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- A Complex Induced Proximity Effect in the Anionic Fries Rearrangement of o-Iodophenyl Benzoates: Synthesis of Dihydro-O-methylsterigmatocystin and Other Xanthones
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The success of an anionic Fries rearrangement, used to synthesise dihydro-O-methylsterigmatocystin and other xanthones, is dependent on the presence of a remote methoxyl substituent.
- Horne, Stephen,Rodrigo, Russell
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p. 4520 - 4522
(2007/10/02)
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- Synthesis and dopaminergic binding of 2-aryldopamine analogues: Phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes
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A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2/s
- Ladd,Weinstock,Wise,Gessner,Sawyer,Flaim
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p. 1904 - 1912
(2007/10/02)
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- Synthesis of indenoisoquinolines
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1-Methyl and 1-benzyl-1,2,3,10b-tetrahydro-5,6,8,9-tetramethoxyindenoisoquinoline have been synthesized from the corresponding 8-phenyl-3,4-dihydro-1(2H)isoquinolinones by treatment with POCl3 under Vilsmeier conditions followed the borohydride
- Patel, Hemant A.,MacLean, David B.
-
-