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Jian Ding - One of the best experts on this subject based on the ideXlab platform.
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repositioning hiv 1 integrase inhibitors for cancer therapeutics 1 6 Naphthyridine 7 carboxamide as a promising scaffold with drug like properties
Journal of Medicinal Chemistry, 2012Co-Authors: Lifan Zeng, Yong Wang, Roza Kazemi, Tino W Sanchez, Liu Meng Yang, Bikash Debnath, Srinivas Odde, Hua Xie, Yongtang Zheng, Jian DingAbstract:Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]Naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of Naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-Naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]Naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]Naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]Naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.
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repositioning hiv 1 integrase inhibitors for cancer therapeutics 1 6 Naphthyridine 7 carboxamide as a promising scaffold with drug like properties
Journal of Medicinal Chemistry, 2012Co-Authors: Lifan Zeng, Yong Wang, Roza Kazemi, Tino W Sanchez, Liu Meng Yang, Bikash Debnath, Srinivas Odde, Hua Xie, Yongtang Zheng, Jian DingAbstract:Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]Naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of Naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-Naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]Naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]Naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]napht...
Lifan Zeng - One of the best experts on this subject based on the ideXlab platform.
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repositioning hiv 1 integrase inhibitors for cancer therapeutics 1 6 Naphthyridine 7 carboxamide as a promising scaffold with drug like properties
Journal of Medicinal Chemistry, 2012Co-Authors: Lifan Zeng, Yong Wang, Roza Kazemi, Tino W Sanchez, Liu Meng Yang, Bikash Debnath, Srinivas Odde, Hua Xie, Yongtang Zheng, Jian DingAbstract:Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]Naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of Naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-Naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]Naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]Naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]Naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.
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repositioning hiv 1 integrase inhibitors for cancer therapeutics 1 6 Naphthyridine 7 carboxamide as a promising scaffold with drug like properties
Journal of Medicinal Chemistry, 2012Co-Authors: Lifan Zeng, Yong Wang, Roza Kazemi, Tino W Sanchez, Liu Meng Yang, Bikash Debnath, Srinivas Odde, Hua Xie, Yongtang Zheng, Jian DingAbstract:Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]Naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of Naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-Naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]Naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]Naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]napht...
E. Barocelli - One of the best experts on this subject based on the ideXlab platform.
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1 8 Naphthyridines ix potent anti inflammatory and or analgesic activity of a new group of substituted 5 amino 1 2 4 triazolo 4 3 a 1 8 Naphthyridine 6 carboxamides of some their mannich base derivatives and of one novel substituted 5 amino 10 oxo 10h pyrimido 1 2 a 1 8 Naphthyridine 6 carboxamide derivative
European Journal of Medicinal Chemistry, 2014Co-Authors: M. Di Braccio, G. Grossi, S. Alfei, V. Ballabeni, M. Tognolini, L. Flammini, C. Giorgio, S. Bertoni, E. BarocelliAbstract:Abstract A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3- a ][1,8]Naphthyridine derivatives bearing a CONHR group at the 6-position ( 1c – g ), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)- N,N -diethyl [1,2,4]triazolo[4,3- a ][1,8]Naphthyridine-6-carboxamides ( 2b – d ). Besides, a new class of analogues of compounds 1 and 2 , bearing a Mannich base moiety at the 9-position ( 12a – d ), as well as the novel N,N -diethyl-5-(isobutylamino)-8-methyl-10-oxo-10 H -pyrimido[1,2- a ][1,8]Naphthyridine-6-carboxamide ( 15 ) were prepared and tested. Compounds 1c – g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b – d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice. On the contrary, the Mannich bases 12a – d resulted inactive. The most effective (80% inhibition of oedema) and potent (threshold dose 1.6 mg kg −1 with 31% inhibition of oedema) anti-inflammatory compound 1d did not show gastrolesive effects following 100 mg kg −1 oral administration in rats.
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1,8-Naphthyridines IX. Potent anti-inflammatory and/or analgesic activity of a new group of substituted 5 amino[1,2,4]triazolo[4,3-a] [1,8]Naphthyridine-6 carboxamides, of some their Mannich base derivatives and of one novel substituted 5-amino-10-oxo
2014Co-Authors: M. Di Braccio, G. Grossi, S. Alfei, V. Ballabeni, M. Tognolini, L. Flammini, C. Giorgio, S. Bertoni, E. BarocelliAbstract:A new group of 5-(alkylamino)-9-isopropyl[1,2,4]triazolo[4,3-a][1,8]Naphthyridine derivatives bearing a CONHR group at the 6-position (1c–g), designed to obtain new effective analgesic and/or anti-inflammatory agents, were synthesized and tested along with three new 9-alkyl-5-(4-alkyl-1-piperazinyl)-N,N-diethyl [1,2,4]triazolo[4,3-a][1,8]Naphthyridine-6-carboxamides (2b–d). Besides, a new class of analogues of compounds 1 and 2, bearing a Mannich base moiety at the 9-position (12a–d), as well as the novel N,N-diethyl-5-(isobutylamino)-8-methyl-10-oxo-10H-pyrimido[1,2-a][1,8]Naphthyridine-6-carboxamide (15) were prepared and tested. Compounds 1c–g exhibited very interesting anti-inflammatory properties in rats, whereas compounds 2b–d and 15 proved to be endowed with prevalent analgesic activity frequently associated with sedative effects in mice. On the contrary, the Mannich bases 12a–d resulted inactive. The most effective (80% inhibition of oedema) and potent (threshold dose 1.6 mg kg−1 with 31% inhibition of oedema) anti-inflammatory compound 1d did not show gastrolesive effects following 100 mg kg−1 oral administration in rats
Alejandro Romero - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological assessment of diversely substituted pyrazolo 3 4 b quinoline and benzo b pyrazolo 4 3 g 1 8 Naphthyridine derivatives
European Journal of Medicinal Chemistry, 2011Co-Authors: Daniel Silva, Mourad Chioua, Abdelouahid Samadi, Carmo M Carreiras, M L Jimeno, Eduarda Mendes, Cristobal De Los Rios, Alejandro RomeroAbstract:The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]Naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedlander-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC(50) (EeAChE) = 0.069 ± 0.006 μM; IC(50) (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K(i) = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.
Isao Saito - One of the best experts on this subject based on the ideXlab platform.
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the binding of guanine guanine mismatched dna to Naphthyridine dimer immobilized sensor surfaces kinetic aspects
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Akio Kobori, Kazuhiko Nakatani, Hiroyuki Kumasawa, Yuki Goto, Isao SaitoAbstract:Naphthyridine dimer composed of two Naphthyridine chromophores and a linker connecting them strongly, and selectively, binds to the guanine-guanine mismatch in duplex DNA. The kinetics for the binding of the G-G mismatch to the Naphthyridine dimer was investigated by surface plasmon resonance assay. The sensor surface was prepared by immobilizing Naphthyridine dimer through a long poly(ethylene oxide) linker with the ligand density of 9.1 x 10(-12) fmolnm(-2). The kinetic analyses revealed that the binding of the G-G mismatch was sequence dependent on the flanking base pairs, and the G-G mismatches flanking at least one G-C base pair bound to the surface via a two-step process with a 1:1 DNA-ligand stoichiometry. The first association rate constant for the binding of the G-G mismatch in the 5'-CGG-3'/3'-GGC-5' sequence to the Naphthyridine dimer-immobilized sensor surface was 3.2 x 10(3)M(-1)s(-1) and the first dissociation rate constant was 1.4 x 10(-2)s(-1). The association and dissociation rate constants for the second step were insensitive to the flanking sequences, and were almost of the same order of magnitude as the first dissociation rate constant. This indicates that the second step had only a small energetic contribution to the binding. The association constant calculated from kinetic parameters was 2.7 x 10(5)M(-1), which is significantly smaller than the apparent association constants obtained from experiments in solution. Electrospray ionization time-of-flight (ESI-TOF) mass spectrometry on the complex produced from the G-G mismatch and Naphthyridine dimer showed the formation of the 1:1 complex and a 1:2 DNA-ligand complex in solution. The latter complex became the dominant complex when a six-fold excess of Naphthyridine dimer was added to DNA.
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affinity labeling of a single guanine bulge
Journal of the American Chemical Society, 2003Co-Authors: Kazuhiko Nakatani, Souta Horie, Isao SaitoAbstract:We have developed a conceptually new method for the selective labeling of duplex DNA containing a guanine bulge with a masked form of fluorescent 2-amino-1,8-Naphthyridine. A Naphthyridine derivative 2 tethering DNA-alkylating epoxide was synthesized from (S)-epichlorohydrin and Naphthyridine derivative 1, which selectively binds to the guanine bulge duplex. HPLC analysis of the labeling reaction of bulge duplex d(GTT GTGTTG GA)/d(CAA CA A ACC T) (TGT/A_A) with 2 showed a formation of 2−TGT adduct for the guanine bulge. The reaction proceeded for the guanine bulge and a reduced efficiency for the cytosine bulge, but not at all for adenine and thymine bulges. The site of covalent bond formation in 2−TGT was unambiguously identified at the guanine two bases away from the bulge by the use of MALDI-TOF MS analysis of the oligomer fragments produced by strand scission. The labeling reaction was also observed for the guanine bulge flanking two G−C base pairs (CGC/G_G), producing a 2:1 adduct (2·2-CGC). Upon hyd...
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recognition of guanine guanine mismatches by the dimeric form of 2 amino 1 8 Naphthyridine
Journal of the American Chemical Society, 2001Co-Authors: Kazuhiko Nakatani, Hiroyuki Kumasawa, Shinsuke Sando, Jun Kikuchi, Isao SaitoAbstract:Dimeric 2-amino-1,8-Naphthyridine selectively binds to a G−G mismatch with high affinity (Kd = 53 nM). We have investigated a binding mechanism of Naphthyridine dimer 2 to a G−G mismatch by spectroscopic studies, thermodynamic analysis, and structure−activity studies for the thermal stabilization of the mismatch. 1H NMR spectra of a complex of 2 with 9-mer duplex d(CATCGGATG)2 containing a G−G mismatch showed that all hydrogens in two Naphthyridine rings of 2 were observed upfield compared to those of 2 in a free state. The 2D-NOESY experiments showed that each Naphthyridine of 2 binds to a guanine in the G−G mismatch within the π-stack. In CD spectra, a large conformational change of the G−G mismatch-containing duplex was observed upon complex formation with 2. Isothermal calorimetry titration of 2 binding to the G−G mismatch showed that the stoichiometry for the binding is about 1:1 and that the binding is enthalpy-controlled. It is clarified by structure−activity studies that show (i) the linker connec...
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improved selectivity for the binding of Naphthyridine dimer to guanine guanine mismatch
Bioorganic & Medicinal Chemistry, 2001Co-Authors: Kazuhiko Nakatani, Shinusuke Sando, Isao SaitoAbstract:Naphthyridine dimer composed of two 2-amino-1,8-Naphthyridines and a connecting linker strongly binds to guanine-guanine (G-G) mismatch in duplex DNA. In order to improve G-G selectivity for the binding, we have examined structure modification of the linker. A new Naphthyridine dimer possessing 3,6-diazaoctanedioic acid linker binds to G-G mismatch with an association constant of 1.18 x 10(7) M(-1), which is somewhat weaker than that of the original Naphthyridine dimer having a shorter connecting linker. However, the binding of the modified Naphthyridine dimer to G-A mismatch was almost negligible as compared to that of the original. This results in a net increase of the selectivity for the binding to G-G mismatch by 4-folds.
