- Anticancer profile and anti-inflammatory effect of new N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives
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A new series of N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives 11a-o were designed and synthesized based on our previous works. The new series was tested for its anticancer and anti-inflammatory effects. The anticancer profile of
- Abdel-Maksoud, Mohammed S.,Mohamed Hassan, Rasha,Abdel-Sattar El-Azzouny, Aida,Nabil Aboul-Enein, Mohamed,Oh, Chang-Hyun
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- Discovery of New Imidazo[2,1- b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising in Vitro and in Vivo Anti-melanoma Activity
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BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.
- Abdel-Maksoud, Mohammed S.,El-Gamal, Mohammed I.,Lee, Bong S.,Gamal El-Din, Mahmoud M.,Jeon, Hong R.,Kwon, Dow,Ammar, Usama M.,Mersal, Karim I.,Ali, Eslam M. H.,Lee, Kyung-Tae,Yoo, Kyung Ho,Han, Dong Keun,Lee, Jae Kyun,Kim, Garam,Choi, Hong Seok,Kwon, Young Jik,Lee, Kwan Hyi,Oh, Chang Hyun
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p. 6877 - 6901
(2021/06/25)
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- Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors
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The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAFV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13 μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 μM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.
- Ali, Eslam M.H.,El-Telbany, Rania Farag A.,Abdel-Maksoud, Mohammed S.,Ammar, Usama M.,Mersal, Karim I.,Zaraei, Seyed-Omar,El-Gamal, Mohammed I.,Choi, Se-In,Lee, Kyung-Tae,Kim, Hee-Kwon,Lee, Kwan Hyi,Oh, Chang-Hyun
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- Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF
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Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 μM and 0.080 μM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.
- Abdel-Maksoud, Mohammed S.,Ali, Eslam M. H.,Ammar, Usama M.,Mersal, Karim I.,Oh, Chang-Hyun,Yoo, Kyung Ho
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- Tertiary enamide-promoted diastereoselective domino: N-acyliminium ion trapping and nazarov cyclization
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N-Acyliminium ions generated from enamidyl vinyl ketones provided cyclopentenoid-fused diazepines diastereoselectively using BF3·Et2O in one pot through a domino N-acyliminium ion trapping/Nazarov reaction, simultaneously generating three new stereogenic centers. The particular structural design of the cross-conjugated dienone dictates the torquoselectivity observed in this polarized Nazarov reaction. Various N-bridgehead polycyclic scaffolds of putative pharmacological interest were obtained. Cyclic voltammetry was used to support the preferred reaction sequence within this domino reaction.
- Zheng, Yongxiang,Andna, Lucile,Bistri, Olivia,Miesch, Laurence
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supporting information
p. 6771 - 6775
(2020/09/15)
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- Structural optimization of imidazothiazole derivatives affords a new promising series as B-Raf V600E inhibitors; synthesis, in vitro assay and in silico screening
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BRAF mutation is commonly known in a number of human cancer types. It is counted as a potential component in treating cancer. In this study, based on structural optimization of previously reported inhibitors (3-fluro substituted derivatives of imidazo[2,1-b]thiazole-based scaffold), we designed and synthesized sixteen new imidazo[2,1-b]thiazole derivatives with m-nitrophenyl group at position 6. The electron withdrawing properties was reserved while the polarity was modified compared to previously synthesized compounds (-F). Furthermore, the new substituted group (–NO2) provided an additional H-bond acceptor(s) which may bind with the target enzyme through additional interaction(s). In vitro cytotoxicity evaluation was performed against human cancer cell line (A375). In addition, in vitro enzyme assay was performed against mutated B-Raf (B-Raf V600E). Compounds 13a, 13g and 13f showed highest activity on mutated B-Raf with IC50 0.021, 0.035 and 0.020 μM. All target compounds were tested for in vitro cytotoxicity against NCI 60 cell lines. Compounds 13a and 13g were selected for 5 doses test mode. Moreover, in silico molecular simulation was explored in order to explore the possible interactions between the designed compounds and the B-Raf V600E active site.
- Abdel-Maksoud, Mohammed S.,Ali, Eslam M. H.,Ammar, Usama M.,Ho Yoo, Kyung,Mersal, Karim I.,Oh, Chang-Hyun
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- Modification of imidazothiazole derivatives gives promising activity in B-Raf kinase enzyme inhibition; synthesis, in vitro studies and molecular docking
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B-Raf mutation was identified as a key target in cancer treatment. Based on structural features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH2-based imidazothiazole derivatives was carried out affording new highly potent derivatives of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and 10o showed higher inhibitory activities (IC50 = 1.20, 4.31 and 6.21 nM, respectively). In vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested derivatives showed cytotoxic activities against melanoma cell line. Compound 10k exhibited most potent activity (IC50 = 2.68 μM). Molecular docking study revealed that the new designed derivatives preserved the same binding mode of dabrafenib with V600E B-Raf active site. It was investigated that the new modification in the synthesized derivatives (substituted with NH2) had a significant inhibitory activity towards V600E B-Raf. This core scaffold is considered a key compound for further structural and molecular optimization.
- Ammar, Usama M.,Abdel-Maksoud, Mohammed S.,Mersal, Karim I.,Ali, Eslam M.H.,Yoo, Kyung Ho,Choi, Hong Seok,Lee, Jae Kyun,Cha, Sun Young,Oh, Chang-Hyun
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supporting information
(2020/08/14)
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- Anticancer profile of newly synthesized BRAF inhibitors possess 5-(pyrimidin-4-yl)imidazo[2,1-b]thiazole scaffold
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In this work, a new series of imidazo[2,1-b]thiazole was designed and synthesized. The new compounds are having 3-fluorophenyl at position 6 of imidazo[2,1-b]thiazole and pyrimidine ring at position 5. The pyrimidine ring containing either amide or sulphonamide moiety attached to a linker (ethyl or propyl) at position 2 of the pyrimidine ring. The final compounds were selected by NCI for in vitro cytotoxicity screening. Most derivatives showed cytotoxic activity against colon cancer and melanoma cell lines. In addition, IC50s of the target compounds were determined over A375 and SK-MEL-28 cell lines using sorafenib as positive control. Compounds12b, 12c, 12e, 12f, 15a, 15d, 15f, 14g and 15h exhibited superior activity when compared to sorafenib. The most potent compounds were tested against wild type BRAF, v600e BRAF, and CRAF. Compound 15h exhibited a potential inhibitory effect againstV600EBRAF (IC50 = 9.3 nM).
- Abdel-Maksoud, Mohammed S.,Ammar, Usama M.,Oh, Chang-Hyun
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p. 2041 - 2051
(2019/04/05)
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- Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors
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In the present work, a novel series of B-RAF kinase inhibitors having imidazo[2,1-b]oxazole scaffold was designed and synthesized based on the structures of the well-known B-RAF inhibitors. The twenty two final compounds were tested over A375 and SKMEL28 cell lines to determine the primary cytotoxic activity of these compounds, and their activities were compared with that of sorafenib as a standard. Compounds 11c, 11e, 11o, 11q, 11r, and 11u exhibited higher cellular activity compared to sorafenib with IC50 values of 7.25, 8.03, 9.81, 8.47, 4.70, and 9.04 μM, respectively and 10.38 μM for sorafenib. In addition, the target compounds were screened for their anticancer activity by the NCI-60 cell line assay. Compounds 11v and 11u were the most active compounds with percent inhibition reached 95.99% for 11v and 87.03% for 11u over K562 cell line at 10 μM concentration. Compound 11v was selected for 5-dose test mode. Furthermore, the kinase inhibitory activities of 11a, 11c, 11e, 11i, 11o, 11q, 11r, 11u, and 11v were determined against wild-type B-RAF, V600E-B-RAF, and RAF1. Compound 11o was the most potent against V600E-B-RAF with IC50 34 nM followed by 11q and 11u with IC50 92 and 93 nM, respectively.
- Abdel-Maksoud, Mohammed S.,Ammar, Usama M.,El-Gamal, Mohammed I.,Gamal El-Din, Mahmoud M.,Mersal, Karim I.,Ali, Eslam M.H.,Yoo, Kyung Ho,Lee, Kyung-Tae,Oh, Chang-Hyun
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- Trapping of N-Acyliminium Ions with Enamides: An Approach to Medium-Sized Diaza-Heterocycles
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Enamides equipped with N-acyliminium ion precursors were obtained through reduction of ynamides tethered to N-imides. Intramolecular TMSOTf-mediated trapping of N-acyliminium ions provided a variety of polyfunctionalized medium-sized diaza-heterocycles of putative pharmacological interest.
- Andna, Lucile,Miesch, Laurence
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supporting information
p. 3430 - 3433
(2018/06/11)
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- Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies
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Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogues bearing a benzyl tail group and nine
- Chawla, Reena,Van Puyenbroeck, Victor,Pflug, Nicholas C.,Sama, Alekhya,Ali, Rameez,Schols, Dominique,Vermeire, Kurt,Bell, Thomas W.
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p. 2633 - 2647
(2016/04/10)
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- Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents
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A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of differen
- Gamal El-Din, Mahmoud M.,El-Gamal, Mohammed I.,Abdel-Maksoud, Mohammed S.,Yoo, Kyung Ho,Baek, Daejin,Choi, Jungseung,Lee, Huiseong,Oh, Chang-Hyun
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p. 111 - 122
(2016/12/14)
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- Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1- b ]thiazole derivatives
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Design and synthesis of a new series of 5,6-diarylimidazo[2,1-b]thiazole derivatives possessing terminal aryl sulfonamide moiety are described. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 8a, 8b, 8n, 8q, 8t, and 8u showed the highest mean % inhibition values over the 57 cell line panel at 10 1/4M, and they were further tested in 5-dose testing mode to determine their IC50 values. Among the six compounds, compound 8u possessing terminal para-hydroxybenzenesulfonamido moiety and ethylene linker showed the highest potency. It demonstrated superior potency than Sorafenib against eight different cell lines, and was equipotent to Sorafenib against COLO 205 colon cancer cell line. Its IC50 values over NCI-H460 non-small cell lung cancer cell line and MCF7 breast cancer cell line were 0.845 1/4M and 0.476 1/4M, respectively. Compounds 8a, 8b, 8q, 8t, and 8u showed high selectivity indices towards cancer cells over L132 normal lung cell line. Compound 8u showed potential inhibitory effects over the components of ERK pathway. Its IC50 value over V600E-B-RAF and C-RAF kinases were 39.9 nM and 19.0 nM, respectively.
- Abdel-Maksoud, Mohammed S.,Kim, Mi-Ryeong,El-Gamal, Mohammed I.,Gamal El-Din, Mahmoud M.,Tae, Jinsung,Choi, Hong Seok,Lee, Kyung-Tae,Yoo, Kyung Ho,Oh, Chang-Hyun
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p. 453 - 463
(2015/04/14)
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- 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion
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A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure-activity relationships of these inhibitors, which show potential as antibacterial agents.
- Sayer, James R.,Walldn, Karin,Pesnot, Thomas,Campbell, Frederick,Gane, Paul J.,Simone, Michela,Koss, Hans,Buelens, Floris,Boyle, Timothy P.,Selwood, David L.,Waksman, Gabriel,Tabor, Alethea B.
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supporting information
p. 6459 - 6470
(2015/01/09)
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- Evaluation of novel trans-sulfonamide platinum complexes against tumor cell lines
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Platinum-based drugs, mainly cisplatin, are employed for the treatment of solid malignancies. However, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. Here, the antitumor activity of different trans-sulfonamide platinum complexes in a panel of human cell lines is presented. The cytotoxicity profiles and cell cycle analyses of these platinum sulfonamide complexes were different from those of cisplatin. These studies showed that complex 2b with cyclohexyldiamine and dansyl moieties had the best antitumoral activities.
- Pérez, Carlos,Díaz-García, C. Vanesa,Agudo-López, Alba,Del Solar, Virginia,Cabrera, Silvia,Agulló-Ortu?o, M. Teresa,Navarro-Ranninger, Carmen,Alemán, José,López-Martín, José A.
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p. 360 - 368
(2014/03/21)
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- Expanding the synthesis of new trans-sulfonamide platinum complexes: Cytotoxicity, SAR, fluorescent cell assays and stability studies
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In this manuscript, we describe the synthesis of new trans-N-sulfonamide platinum complexes and their antiproliferative activity (GI50, μM) in human solid tumors cells. The structure activity relationships (SAR), with different new synthesized
- Del Solar, Virginia,Qui?ones-Lombra?a, Adolfo,Cabrera, Silvia,Padrón, José M.,Ríos-Luci, Carla,Alvarez-Valdés, Amparo,Navarro-Ranninger, Carmen,Alemán, José
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p. 128 - 140
(2013/10/01)
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- SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (TDP1)- TOPOISOMERASE I (TOP1) INHIBITORS
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The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.
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Paragraph 0117
(2014/02/15)
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- SUBSTITUTED 8 - AMINO - IMIDAZO [1, 2-A] PYRAZ1NES AS ANTIBACTERIAL AGENTS
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The present invention relates to substituted imidazo[1,2-a]pyrazines of Formula (I) and their use as antibacterial agents.
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Page/Page column 103-104
(2013/02/27)
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- Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors
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Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC 50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors.
- Nguyen, Trung Xuan,Morrell, Andrew,Conda-Sheridan, Martin,Marchand, Christophe,Agama, Keli,Bermingam, Alun,Stephen, Andrew G.,Chergui, Adel,Naumova, Alena,Fisher, Robert,O'Keefe, Barry R.,Pommier, Yves,Cushman, Mark
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scheme or table
p. 4457 - 4478
(2012/08/07)
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- Unsymmetrical cyclotriazadisulfonamide (CADA) compounds as human CD4 receptor down-modulating agents
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Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. The specific biomolecular target of CADA compounds is unknown, but previous studies led to an unsymmetrical binding model. To test this model, methods were developed for effective synthesis of diverse, unsymmetrical CADA compounds. A total of 13 new, unsymmetrical target compounds were synthesized, as well as one symmetrical analogue. The new compounds display a wide range of potency for CD4 down-modulation in CHO-CD4-YFP cells. VGD020 (IC50 = 46 nM) is the most potent CADA compound discovered to date, and VGD029 (IC50 = 730 nM) is the most potent fluorescent analogue. Structure-activity relationships are analyzed from the standpoint of additive or nonadditive energy effects of different substituents. They appear to be consistent with the zipper-type mechanism in which entropy costs are reduced for additional stabilizing interactions between the small molecule and its protein target.
- Demillo, Violeta G.,Goulinet-Mateo, Florian,Kim, Jessica,Schols, Dominique,Vermeire, Kurt,Bell, Thomas W.
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experimental part
p. 5712 - 5721
(2011/10/08)
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- Synthesis of 2-substituted 1-tosyl-3-(1-tosyliminoalkyl)imidazolidines and-hexahydropyrimidines
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Reactions of N-tosylimidoyl chlorides with the Schiff bases of the general formula TsNH(CH2)nN=CHR (n = 2 or 3; R = Pri, 4-MeOC6H4, 4-Me2NC6H4, and 3-O2NCs
- Pokhvisneva,Luk'Yanov
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p. 903 - 906
(2007/10/03)
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- Process for the preparation of trans-(R,R)-actinol
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A process for the manufacture of trans-(R,R)-actinol by diasteroselective transfer hydrogenation of levodione comprises hydrogenating (R)-levodione in the presence of a hydrogen donor, which simultaneously can be used as the solvent, and an amino-amide-ruthenium complex, especially of the formula RuH(L{—H})(Y), wherein Y signifies a neutral ligand and L signifies an optionally optically active monosulphonylated diamine ligand, as defined in more detail in the description. Moreover, the invention is concerned with some of the amino-amide-ruthenium complexes and with the corresponding precursors to these complexes, which have halogen in place of H. The product of the process in accordance with the invention, trans-(R,R)-actinol, is known as an important building block for the synthesis of carotenoids, e.g. zeaxanthin. By the process trans-(R,R)-actinol is made available in particularly high enantiomeric and diasteromeric purity.
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- 84. Selective Monoderivatization of Propane-1,3-diamine with Acid Chlorides: 'Hexahydropyrimidine Method' vs. Statistic Methods
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The selective N-monoderivatization of propane-1,3-dmmine (5) with carbonyl and sulfonyl chlorides via 2-phenylhexahydropyrimidine (6) was compared with the direct statistic monoderivatization. It was found that, under optimized conditions, both methods ar
- Jentgens, Christian,Bienz, Stefan,Hesse, Manfred
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p. 1133 - 1143
(2007/10/03)
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- Synthesis of N1,4-Di(p-coumaroyl)spermine, a possible biogenetic precursor of aphelandrine
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Coupling of two differently substituted 1,3-diaminopropane units 5 and 6 (Schemes 1 and 2) lead to the key intermediate 8, a tetra-N-protected spermine derivative. By selective deprotection and alkylation with (E)-4-(mesy1oxy) cinnamoyl chloride, followed
- Veznik, Frantisek,Guggisberg, Armin,Hesse, Manfred
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p. 654 - 661
(2007/10/02)
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