3093-97-8Relevant articles and documents
Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: A novel and potent cell cycle arrest and apoptosis inducer through the p53-MDM2 pathway
Shen, Qing-Kun,Deng, Hao,Wang, Shi-Ben,Tian, Yu-Shun,Quan, Zhen-Shan
, p. 15 - 31 (2019/04/10)
A series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised. Their antitumour activity was evaluated in vitro against three human cancer cell lines (HCT116, BEL7402, and MCF7). Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil (5-Fu). Among them, compound C7 (IC50 = 0.16 μM) exhibited the most potent anti-proliferative activity against HCT116 cells; it was about 43- and 155-fold more efficacious than that of oridonin (IC50 = 6.84 μM) and 5-Fu (IC50 = 24.80 μM) in HCT116 cancer cells. Interestingly, the IC50 value of compound C7 in L02 normal cells was 23.6-fold higher than that in HCT116 cells; it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu. Furthermore, compound C7 possibly induced cell cycle arrest and apoptosis by regulating the p53-MDM2 signalling pathway. Notably, C7 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%. Therefore, compound C7 could be a potential lead compound for the development of a novel antitumour agent.
Synthesis and structure of fluoroindole nucleosides
Bozilovic, Jelena,Bats, Jan W.,Engels, Joachim W.
, p. 283 - 292 (2008/02/11)
Chemically modified bases are frequently used to stabilize nucleic acids, to study the driving forces for nucleic acid structure formation, and to tune DNA and RNA hybridization conditions. Nucleoside analogues are chemical means to investigate hydrogen bonds, base stacking, and solvation as the three predominant forces that are responsible for the stability of nucleic acids. To obtain deeper insight into the contributions of these interactions to RNA stability, we decided to synthesize some novel nucleic acid analogues where the nucleobases are replaced by fluoroindoles. Fluorinated indoles can be compared with fluorinated benzimidazoles to determine the role of nitrogen in five-membered ring systems. The synthesis of fluoroindole ribonucleosides as well as the X-ray crystal structures of all synthesized fluoroindole ribonucleosides are reported here. These compounds could also be building blocks for a variety of biologically active RNA analogues.
Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines
Blair,Kurrasch-Orbaugh,Marona-Lewicka,Gumbay,Watts,Barker,Nichols
, p. 4701 - 4710 (2007/10/03)
A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT(1A) agonist activity and in vitro radioligand competition assays for their affinity at 5-HT(2A), 5-HT(2C), and 5-HT(1A) receptor sites. Functional activity at the 5-HT(2A) receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT(1A) receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT(1A) agonist activity, with potency greater than that of the 5-HT(1A) agonist 8-OH-DPAT. The ED50 of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT(1A) agonist LY293284 was 0.17μmol/kg, and the K(i) at [3H]8-OH-DPAT-labeled 5-HT(1A) receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT(2A/2C) receptor affinity or intrinsic activity. Affinity at the 5-HT(1A) receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT(1A) receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT(2A) receptor activation, the present results suggest a possible role for involvement of the 5-HT(1A) receptor with tryptamines.
