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141.
Zheng Zhai Ridong Li Xinyu Bai Xianling Ning Zhiqiang Lin Xuyang Zhao Yan Jin Yuxin Yin 《Bioorganic & medicinal chemistry》2019,27(18):4124-4142
Bruton’s tyrosine kinase (BTK) has emerged as an attractive target related to B-lymphocytes dysfunctions, especially hematologic malignancies and autoimmune diseases. In our study, a series of diphenylaminopyrimidine derivatives bearing dithiocarbamate moieties were designed and synthesized as novel BTK inhibitors for treatment of B-cell lymphoma. Among all these compounds, 30ab (IC50 = 1.15 ± 0.19 nM) displays similar or more potent inhibitory activity against BTK than spebrutinib (IC50 = 2.12 ± 0.32 nM) and FDA approved drug ibrutinib (IC50 = 3.89 ± 0.57 nM), which is attributed to close binding of 30ab with BTK predicted by molecular docking. In particular, 30ab exhibits enhanced anti-proliferative activity against B-lymphoma cell lines at the IC50 concentration of 0.357 ± 0.02 μM (Ramos) and 0.706 ± 0.05 μM (Raji), respectively, almost 10-fold better than ibrutinib and spebrutinib. In addition, 30ab displays stronger selectivity on B-cell lymphoma over other cancer cell lines than spebrutinib. Furthermore, 30ab efficiently blocks BTK downstream pathways and results in apoptosis of cancer cells. In vivo xenograft model evaluation demonstrates the significant efficacy and broad safety margin of 30ab in treatment of B-cell lymphoma. We propose that compound 30ab is a candidate for further study and development based on our current findings. 相似文献
142.
Lingling Yang Yang Chen Junlin He Emmanuel Mfotie Njoya Jianjun Chen Siyan Liu Congqiang Xie Wenze Huang Fei Wang Zhouyu Wang Yuzhi Li Shan Qian 《Bioorganic & medicinal chemistry》2019,27(6):1087-1098
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74?μM in an enzymatic assay and 1.37?μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93?μM in the enzymatic assay and 7.54?μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment. 相似文献
143.
Tsutomu Fukuda Yusuke Nanjo Masahiro Fujimoto Kenyu Yoshida Yuko Natsui Fumito Ishibashi Fumiyasu Okazaki Hideto To Masatomo Iwao 《Bioorganic & medicinal chemistry》2019,27(2):265-277
A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan. 相似文献
144.
《Bioorganic & medicinal chemistry letters》2019,29(18):2632-2634
The colchicine site inhibitors (CSIs) displayed both antimitotic and vascular disrupting activities, therefore are promising potential antitumor agents. In this study, a series 1-phenyl-4,5-dihydro-2H-benzo[e]indazoles were found as new CSIs of which the bioactive configuration was locked. Among them, compounds C1 and C2 displayed the best activity, with tubulin polymerization IC50 of 3.4 and 1.5 μM, and growth IC50 of low nanomolar concentrations against human colon cancer cell lines. In addition, compound C1 showed excellent broad-spectrum antitumor activity in the NCI-60 Human Tumor Cell Lines Screen, encouraging further study of this antitumor compound. 相似文献
145.
François Tillequin 《Phytochemistry Reviews》2007,6(1):65-79
The chemical diversity of alkaloids in the Rutaceae is correlated with biosynthetic pathways involving various aromatic amino
acid precursors, tyrosine, tryptophan, histidine, and anthranilic acid. The interest of rutaceous polyheteroaromatic alkaloids
as models for the development of anticancer agents relies on their frequent ability to interact with DNA or with systems involved
in the control of its topology, repair, and replication. Fagaronine and nitidine, from Zanthoxylum, demonstrate antileukemic activity, associated with topoisomerases inhibition. Evodiamine from Euodia rutaecarpa, displays antimetastatic properties. The pyranoacridone acronycine, from Sarcomelicope, exhibits antitumor activity against a broad spectrum of solid tumors. Development of synthetic analogues based on this latter
natural product template followed the isolation of the unstable acronycine epoxide, which led to a hypothesis of bioactivation
of acronycine by transformation of the 1,2-double bond into the corresponding oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine
derivatives exhibited antitumor properties, with a broadened spectrum of activity and an increased potency. The demonstration
that acronycine interacted with DNA led to develop benzo[a], [b], and [c]acronycine analogs. Benzo[a] and [b] derivatives displayed significant antitumor activities. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters were active in human orthotopic models of cancers xenografted in nude mice. The activity of
these compounds was correlated with their ability to give covalent adducts with DNA, involving reaction between the N-2 amino
group of guanines and the ester group at the benzylic position of the drug. Cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine, currently developed under the code S23906-1, successfully underwent phase I and is currently under phase II clinical
trials. 相似文献
146.
A major triterpenoid saponin from Gypsophila oldhamiana 总被引:1,自引:0,他引:1
A new saponin, gypoldoside A (1), was isolated from the roots of Gypsophila oldhamiana. On the basis of in-depth NMR-spectroscopic and mass-spectrometric analysis, in combination with chemical evidence, its structure was established as 3-O-{beta-D-galactopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->3)]-beta-D-glucuronopyranosyl}quillaic acid 28-[alpha-L-arabinopyranosyl-(1-->2)-alpha-L-arabinopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-fucopyranosyl] ester. Compound 1 was found to be highly active against three different human cancer cell lines, with IC50 values in the low micromolar range. 相似文献
147.
小分子肽-肿瘤抑素19肽纯化及抗肿瘤活性研究 总被引:3,自引:0,他引:3
目的:利用已构建好的肿瘤抑素抗肿瘤活性肽-19肽高效表达基因重组菌纯化19肽,并进行抗肿瘤活性检测。方法:经几丁质亲和层析柱纯化出19肽,SDS-PAGE聚丙烯酰胺电泳后用Bradford法测其浓度,进行体内活性检测。结果:19肽可促进H22小鼠肝癌细胞死亡,血管数量减少,抑瘤率达48.46%。结论:得到了具有抗肿瘤活性的肿瘤抑素相关肽—19肽,为肿瘤抑素的作用机制研究和肿瘤的临床治疗奠定了基础。 相似文献
148.
Synthesis and Biological Evaluation of Novel Oxazolo[5,4‐d]pyrimidines as Potent VEGFR‐2 Inhibitors 下载免费PDF全文
Ya‐Hui Deng Dan Xu Ye‐Xiang Su Yi‐Juan Cheng Yan‐Li Yang Xiu‐Yun Wang Juan Zhang Qi‐Dong You Li‐Ping Sun 《化学与生物多样性》2015,12(4):528-537
Tumor angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) and other protein kinases. Inhibition of these kinases presents an attractive approach for developing anticancer therapeutics. In this work, a series of 2,5,7‐trisubstituted oxazolo[5,4‐d]pyrimidines were synthesized, and their inhibitory activities were investigated against VEGFR‐2 and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 9n exhibited the most potent inhibitory activity with IC50 values of 0.33 and 0.29 μM for VEGFR‐2 kinase and HUVEC, respectively. A further kinase selectivity assay revealed that these compounds exhibit good VEGFR and moderate EGFR inhibitory activities. Docking analysis suggested a common mode of interaction at the ATP‐binding site of VEGFR‐2. 相似文献
149.
150.
Hideaki Yamaguchi Yumi Kidachi Katsuyoshi Kamiie Toshiro Noshita Hironori Umetsu 《Bioinformation》2012,8(22):1066-1074
Homology modeling and structural analysis of human P-glycoprotein (hP-gp) were performed with a software package the
Molecular Operating Environment (MOE). A mouse P-gp (mP-gp; PDB code: 3G5U) was selected as a template for the 3D structure
modeling of hP-gp. The modeled hP-gp showed significant 3D similarities at the drug biding site (DBS) to the mP-gp structure. The
contact energy profiles of the hP-gp model were in good agreement with those of the mP-gp structure. Ramachandran plots
revealed that only 3.5% of the amino acid residues were in the disfavored region for hP-gp. Further, docking simulations between
6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) and the P-gp models revealed the similarity of the ligand-receptor bound location
between the hP-gp and mP-gp models. These results indicate that the hP-gp model was successfully modeled and analyzed. To the
best of our knowledge, this is the first report of a hP-gp model with a naturally occurring isothiocyanate, and our data verify that
the model can be utilized for application to target hP-gp for the development of antitumor drugs.