- Structural optimization towards promising β-methyl-4-acrylamido quinoline derivatives as PI3K/mTOR dual inhibitors for anti-cancer therapy: The in vitro and in vivo biological evaluation
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Built upon the 4-acrylamido quinoline derivative 4, a previously discovered PI3K/mTOR dual inhibitor, structural modification was undertaken in this study with the attempt to improve its oral exposure via introducing steric hindrance to the 4-acrylamido functionality. Consequently, 14d, as the representative among the synthesized compounds, exhibited IC50 values of 0.80, 0.67, 1.30, 1.30 and 5.0 nM against PI3Kα, PI3Kβ, PI3Kγ, PI3Kδ and mTOR, respectively. Besides, 14d displayed comparable anti-proliferative activity against both PC3 and U87MG cell lines to that of the positive reference GSK2126458 with respective GI50 value of 0.36 and 0.14 μM. Kinase selectivity assay showed that 14d was selective to PI3K family. In U87MG cells, 14d can strongly down-regulate PI3K/Akt/mTOR pathway via blocking both PI3K and mTOR signaling at the concentration as low as 25 nM. Importantly, following a PO dose of 5 mg/kg in male SD rats, 14d displayed favorable oral exposure (AUC0-t = 1336.16 h × ng/mL, AUC0-∞ = 1447.63 h × ng/mL) and high maximum plasma concentration (Cmax = 903.00 ng/mL). In a U87MG glioblastoma xenograft model, tumor growth inhibition of 93.5% and tumor regression were observed at PO dose of 30 and 60 mg/kg, respectively. Meanwhile, no overt loss of body weight was observed in the 14d-treated groups. Taken together, 14d, by virtue of its attractive performance, merits further development as a potential anti-tumor candidate.
- He, Ruoyu,Xu, Bingyong,Ping, Li,Lv, Xiaoqing
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Read Online
- TGFβ INHIBITOR AND PRODRUGS
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A compound of formula (I) with improved TGFβ signaling pathway inhibitory activity, improved therapeutic efficacy and improved toxicity profile, as well as two prodrugs thereof are disclosed. Compositions comprising said TGFβ signaling pathway inhibitor a
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Page/Page column 46
(2020/06/10)
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- Synthesis and antileishmanial evaluation of thiazole orange analogs
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Cyanine compounds have previously shown excellent in vitro and promising in vivo antileishmanial efficacy, but the potential toxicity of these agents is a concern. A series of 22 analogs of thiazole orange ((Z)-1-methyl-4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium salt), a commercial cyanine dye with antileishmanial activity, were synthesized in an effort to increase the selectivity of such compounds while maintaining efficacy. Cyanines possessing substitutions on the quinolinium ring system displayed potency against Leishmania donovani axenic amastigotes that differed little from the parent compound (IC50 12–42 nM), while ring disjunction analogs were both less potent and less toxic. Changes in DNA melting temperature were modest when synthetic oligonucleotides were incubated with selected analogs (ΔTm ≤ 5 °C), with ring disjunction analogs showing the least effect on this parameter. Despite the high antileishmanial potency of the target compounds, their toxicity and relatively flat SAR suggests that further information regarding the target(s) of these molecules is needed to aid their development as antileishmanials.
- Abdelhameed, Ahmed,Liao, Xiaoping,McElroy, Craig A.,Joice, April C.,Rakotondraibe, Liva,Li, Junan,Slebodnick, Carla,Guo, Pu,Wilson, W. David,Werbovetz, Karl A.
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supporting information
(2019/11/28)
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- Optimization of a dihydropyrrolopyrazole series of transforming growth factor-β type I receptor kinase domain inhibitors: Discovery of an orally bioavailable transforming growth factor-β receptor type I inhibitor as antitumor agent
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In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
- Li, Hong-Yu,McMillen, William T.,Heap, Charles R.,McCann, Denis J.,Yan, Lei,Campbell, Robert M.,Mundla, Sreenivasa R.,King, Chi-Hsin R.,Dierks, Elizabeth A.,Anderson, Bryan D.,Britt, Karen S.,Huss, Karen L.,Voss, Matthew D.,Wang, Yan,Clawson, David K.,Yingling, Jonathan M.,Sawyer, J. Scott
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p. 2302 - 2306
(2008/12/20)
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- QUINOLINYL-PYRROLOPYRAZOLES
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A compound according to formula II and the pharmaceutically acceptable salts thereof and the method of treating cancer in a patient in need thereof by administration of said compound.
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- Efficient microwave-assisted synthesis of quinolines and dihydroquinolines under solvent-free conditions
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A convenient and efficient procedure for the synthesis of quinolines and dihydroquinolines has been developed by a simple one-pot reaction of anilines with alkyl vinyl ketones on the surface of silica gel impregnated with indium(III) chloride under microwave irradiation without any solvent.
- Ranu, Brindaban C.,Hajra, Alakananda,Dey, Suvendu S.,Jana, Umasish
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p. 813 - 819
(2007/10/03)
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- Microwave-assisted simple synthesis of quinolines from anilines and alkyl vinyl ketones on the surface of silica gel in the presence of indium(III) chloride
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A simple and efficient procedure has been developed for the synthesis of 4-alkylquinolines by a one-pot reaction of anilines with alkyl vinyl ketones on the surface of silica gel impregnated with indium(III) chloride under microwave irradiation without any solvent.
- Ranu, Brindaban C.,Hajra, Alakananda,Jana, Umasish
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p. 531 - 533
(2007/10/03)
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