2107-78-0Relevant articles and documents
Development and preclinical studies of broad-spectrum anti-HIV agent (3′R,4′R)-3-cyanomethyl-4-methyl-3′,4′-di-O-(S) -camphanoyl-(+)-cis-khellactone (3-cyanomethyl-4-methyl-DCK)
Xie, Lan,Guo, Huan-Fang,Lu, Hong,Zhuang, Xiao-Mei,Zhang, An-Ming,Wu, Gang,Ruan, Jin-Xiu,Zhou, Ting,Yu, Donglei,Qian, Keduo,Lee, Kuo-Hsiung,Jiang, Shibo
, p. 7689 - 7696 (2008)
In prior investigation, we discovered that (3′R,4′R)-3- cyanomethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (4, 3-cyanomethyl-4-methyl-DCK) showed promising anti-HIV activity. In these current studies, we developed and optimized successfully a practical 10-step synthesis for scale-up preparation to increase the overall yield of 4 from 7.8% to 32%. Furthermore, compound 4 exhibited broad-spectrum anti-HIV activity against wild-type and drug-resistant viral infection of CD4+ T cell lines as well as peripheral blood mononuclear cells by both laboratory-adapted and primary HIV-1 isolates with distinct subtypes and tropisms. Compound 4 was further subjected to in vitro and in vivo pharmacokinetic studies. These studies indicated that 4 has moderate cell permeability, moderate oral bioavailability, and low systemic clearance. These results suggest that 4 should be developed as a promising anti-HIV agent for development as a clinical trial candidate.
2-Aminobenzoxazole-appended coumarins as potent and selective inhibitors of tumour-associated carbonic anhydrases
Fuentes-Aguilar, Alma,Merino-Montiel, Penélope,Montiel-Smith, Sara,Meza-Reyes, Socorro,Vega-Báez, José Luis,Puerta, Adrián,Fernandes, Miguel X.,Padrón, José M.,Petreni, Andrea,Nocentini, Alessio,Supuran, Claudiu T.,López, óscar,Fernández-Bola?os, José G.
, p. 168 - 177 (2021/12/21)
We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (K i within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (K i > 10 μM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in?vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.
Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anti-cancer agents
Yu, Haonan,Hou, Zhuang,Tian, Ye,Mou, Yanhua,Guo, Chun
, p. 434 - 449 (2018/04/14)
To develop novel agents with anticancer activities, thirty-four new dihydroartemisinin-coumarin hybrids were designed and synthesized in this study. Those compounds were identified that had great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29). The structure-activity relationships of the derivatives were also discussed, and the results of docking analysis had shown that carbonic anhydrases IX (CA IX) was very likely to be one of the drug targets of the hybrids. Meanwhile, to clarify the mechanism of the anticancer activity of the hybrids molecule, we did further exploration in the bioactivity of the hybrids. The results had shown that these derivatives obviously inhibited proliferation of HT-29 cell lines, arrested G0/G1 phase of HT-29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells. Interestingly, the hybrids also induced the other cell death pathway-ferroptosis.