- Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins
-
Nineteen biotinylated squamocin/bullatacin derivatives have been synthesized for targeted delivery to biotin receptor overexpressed tumor cells. Most biotinylated squamocin and bullatacin derivatives show similar in vitro cytotoxicity against the biotin receptor non-overexpressed L1210 cells as squamocin and bullatacin, respectively, while against biotin receptor overexpressed 4T1 and P815 tumor cells, several derivatives show significantly higher potency and better selectivity. Among all the synthesized compounds, 15,28-di-O-(6-biotinylamidohexanoyl)squamocin (16) is the most potent, which is 10 and 26 times more active than squamocin against 4T1 and P815 cells, respectively. Compound 16 also appears to be six and fifteen times more selective than squamocin towards 4T1 and P815 cells, respectively, against L1210 cells. The structure activity relationship analysis has revealed that the preferred site for biotinylation is different for squamocin and bullatacin, and it also depends on whether a linking spacer is present.
- Shi, Jing-Fang,Wu, Ping,Jiang, Zi-Hua,Wei, Xiao-Yi
-
-
Read Online
- Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming
-
Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.
- Sheng, Yuwen,Chen, Yuwen,Zeng, Zhongqiu,Wu, Wenbi,Wang, Jing,Ma, Yuling,Lin, Yuan,Zhang, Jichao,Huang, Yulan,Li, Wenhua,Zhu, Qiyu,Wei, Xiao,Li, Suiyan,Wisanwattana, Wisanee,Li, Fu,Liu, Wanli,Suksamrarn, Apichart,Zhang, Guolin,Jiao, Wei,Wang, Fei
-
p. 460 - 484
(2022/01/03)
-
- Synthesis and in?vitro anticancer activities of biotinylated derivatives of glaucocalyxin A and oridonin
-
Fourteen glaucocalyxin A biotinylated derivatives, one glaucocalyxin C biotinylated derivative, and two oridonin biotinylated derivatives were designed and synthesized. Their structures were confirmed from 1H NMR, 13C NMR and HRMS data. The derivatives were evaluated for cytotoxic activities against lung (A549), cervical cancer cell line HeLa derivative (KB), multidrug-resistant KB subline (KB-VIN), triple-negative breast (MDA-MB-231), and estrogen receptor-positive breast (MCF-7) cancer cell lines. (Figure presented.).
- Huang, Xiao-Lei,Chen, Jing-Lei,Li, Xian-Lun,Zhao, Lei,Cui, Ya-Dong,Liu, Jiang-Yun,Morris-Natschke, Susan L.,Masuo, Goto,Cheng, Yung-Yi,Lee, Kuo-Hsiung,Chen, Dao-Feng,Zhang, Jian
-
p. 703 - 711
(2020/06/03)
-
- Design and synthesis of biotinylated cardiac glycosides for probing Nur77 protein inducting pathway
-
The orphan nuclear receptor Nur77 (also known as TR3 or nerve growth factor-induced clone B NGFI-B) functions as a nuclear transcription factor in the regulation of target gene expression and plays a critical role in the regulation of differentiation, proliferation, apoptosis, and survival of many different cell types. Recent studies demonstrate that Nur77 also involves many important physiological and pathological processes including cancer, inflammation and immunity, cardiovascular diseases, and bone diseases. Our previous studies showed that cardiac glycosides could induce the expression of Nur77 protein and its translocation from the nucleus to the cytoplasm and subsequent targeting to mitochondria, leading to apoptosis of cancer cells. In order to probe the Nur77 protein inducting pathway, we designed and synthesized a series of novel biotinylated cardiac glycosides from β-Antiarin and α-Antiarin, two typical cardiac glycosides from the plant of Antiaris toxicaria. The induction of Nur77 protein expression of these biotinylated cardiac glycosides and their inhibitory effects on NIH-H460 cancer cell proliferation were evaluated. Results displayed that some biotinylated cardiac glycosides could significantly induce the expression of Nur77 protein comparable with their parent compounds β-Antiarin and α-Antiarin. Also, their streptavidin binding activities were evaluated. Among them, biotinylated cardiac glycosides P4b and P5a exhibited significant effect on the induction of Nur77 expression along with high binding capacity with streptavidin, suggesting that they can be used as probes for probing Nur77 protein inducting pathway.
- Tian, Dan-mei,Qiao, Jia,Bao, Yu-zhou,Liu, Jie,Zhang, Xiao-kun,Sun, Xue-long,Zhang, You-wei,Yao, Xin-sheng,Tang, Jin-shan
-
p. 707 - 712
(2019/01/22)
-
- BIOCONJUGATES WITH A CONTROLLED DEGREE OF CONJUGATION, THEIR PROCESS OF PREPARATION, AND THE REAGENTS FOR THEIR PREPARATION
-
The present invention relates to a process for preparation of heterogeneous monodisperse mixtures of protein conjugates with a defined degree of conjugation (1-8) obtained by using a tri-functional reagent allowing affinity concentration followed by subse
- -
-
Page/Page column 35
(2019/01/22)
-
- Corroboration of Zn(ii)-Mg(ii)-tertiary structure interplays essential for the optimal catalysis of a phosphorothiolate thiolesterase ribozyme
-
The TW17 ribozyme, a catalytic RNA selected from a pool of artificial RNA, is specific for the Zn2+-dependent hydrolysis of a phosphorothiolate thiolester bond. Here, we describe the organic synthesis of both guanosine α-thio-monophosphate and the substrates required for selecting and characterizing the TW17 ribozyme, and for deciphering the catalytic mechanism of the ribozyme. By successively substituting the substrate originally conjugated to the RNA pool with structurally modified substrates, we demonstrated that the TW17 ribozyme specifically catalyzes phosphorothiolate thiolester hydrolysis. Metal titration studies of TW17 ribozyme catalysis in the presence of Zn2+ alone, Zn2+ and Mg2+, and Zn2+ and [Co(NH3)6]3+ supported our findings that Zn2+ is absolutely required for ribozyme catalysis, and indicated that optimal ribozyme catalysis involves the presence of outer-sphere and one inner-sphere Mg2+. A survey of the TW17 ribozyme activity at various pHs revealed that the activity of the ribozyme critically depends on the alkaline conditions. Moreover, a GNRA tetraloop-containing ribozyme constructed with active catalysis in trans provided catalysis and multiple substrate turnover efficiencies significantly higher than ribozymes lacking a GNRA tetraloop. This research supports the essential roles of Zn2+, Mg2+, and a GNRA tetraloop in modulating the TW17 ribozyme structure for optimal ribozyme catalysis, leading also to the formulation of a proposed reaction mechanism for TW17 ribozyme catalysis.
- Wang, Tzu-Pin,Su, Yu-Chih,Chen, Yi,Severance, Scott,Hwang, Chi-Ching,Liou, Yi-Ming,Lu, Chia-Hui,Lin, Kun-Liang,Zhu, Rui Jing,Wang, Eng-Chi
-
p. 32775 - 32793
(2018/10/15)
-
- The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity
-
Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.
- Hu, Jing,Wu, Tian-Ming,Li, Hong-Ze,Zuo, Ze-Ping,Zhao, Ying-Lan,Yang, Li
-
p. 3591 - 3594
(2017/07/07)
-
- Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: Potent agents restrain tumor cell growth and invasion
-
A new series of novel 1-phenanthryl-tetrahydroisoquinoline derivatives were designed, synthesized and biologically evaluated for their PAK4 inhibitory activities and anti-proliferative effects against three cancer cell lines A549, MCF-7 and HT-1080. Among them, compound 12a exhibited the most potent inhibitory activity against PAK4 with an IC50 value of 0.42 μM. Moreover, this compound inhibited the invasion of A549 tumor cells by regulating the PAK4-LIMK1-cofilin signaling pathway in vitro, and exhibited anti-tumor activity in vivo in the A549 tumor xenograft model. To further evaluate the binding mode of 12a with PAK4, the biotinylated 12a derivative has been synthesized and it was used for immunoprecipitation assay. Intriguingly, our observations suggest that 12a interacts with both the N- and C-termini of PAK4.
- Hao, Chenzhou,Li, Xiaodong,Song, Shuai,Guo, Bingyu,Guo, Jing,Zhang, Jian,Zhang, Qiaoling,Huang, Wanxu,Wang, Jian,Lin, Bin,Cheng, Maosheng,Li, Feng,Zhao, Dongmei
-
p. 7676 - 7690
(2016/08/24)
-
- METHOD FOR PREPARING N-SUCCINIMIDYL N-BIOTINYL-6-AMINOCAPROATE
-
The invention relates to a method for preparing N-succinimidyl N-biotinyl-6-aminocaproate, characterised in that said method includes a step of activating N-biotinyl-6-aminocaproic acid in the form of a mixed anhydride, followed by coupling said mixed anhydride with N-hydroxysuccinimide.
- -
-
Page/Page column 3
(2012/09/22)
-
- METHODS FOR CONJUGATING NUCLEIC ACIDS WITH SMALL MOLECULES
-
A method for conjugating a nucleic acid with a molecule is provided. The method includes steps of (a) reacting the nucleic acid having a 5′-monophosphate with an activating agent in a first buffer to form a solution; (b) mixing an alcohol with the solution formed in the step (a) to obtain an intermediate; and (c) dissolving the intermediate in a second buffer containing an ethylenediaminetetraacetic acid (EDTA) and adding a nucleophile thereinto to react the intermediate with the nucleophile.
- -
-
-
- Versatile phosphoramidation reactions for nucleic acid conjugations with peptides, proteins, chromophores, and biotin derivatives
-
Chemical conjugations of nucleic acids with macromolecules or small molecules are common approaches to study nucleic acids in chemistry and biology and to exploit nucleic acids for medical applications. The conjugation of nucleic acids such as oligonucleotides with peptides is especially useful to circumvent cell delivery and specificity problems of oligonucleotides as therapeutic agents. However, current approaches are limited and inefficient in their ability to afford peptide - oligonucleotide conjugates (POCs). Here, we report an effective and reproducible approach to prepare POCs and other nucleic acid conjugates based on a newly developed nucleic acid phosphoramidation method. The development of a new nucleic acid phosphoramidation reaction was achieved by our successful synthesis of a novel amine-containing biotin derivative used to systematically optimize the reactions. The improved phosphoramidation reactions dramatically increased yields of nucleic acid - biotin conjugates up to 80% after 3 h reaction. Any nucleic acids with a terminal phosphate group are suitable reactants in phosphoramidation reactions to conjugate with amine-containing molecules such as biotin and fluorescein derivatives, proteins, and, most importantly, peptides to enable the synthesis of POCs for therapeutic applications. Polymerase chain reactions (PCRs) to study incorporation of biotin or fluorescein-tagged DNA primers into the reaction products demonstrated that appropriate controls of nucleic acid phosphoramidation reactions incur minimum adverse effects on inherited base-pairing characteristics of nucleotides in nucleic acids. The phosphoramidation approach preserves the integrity of hybridization specificity in nucleic acids when preparing POCs. By retaining integrity of the nucleic acids, their effectiveness as therapeutic reagents for gene silencing, gene therapy, and RNA interference is ensured. The potential for POC use was demonstrated by two-step phosphoramidation reactions to successfully synthesize nucleic acid - tetraglycine conjugates. In addition, phosphoramidation reactions provided a facile approach to prepare nucleic acid - BSA conjugates with good yields. In summary, the new approach to phosphoramidation reactions offers a universal method to prepare POCs and other nucleic acid conjugates with high yields in aqueous solutions. The methods can be easily adapted to typical chemistry or biology laboratory setups which will expedite the applications of POCs for basic research and medicine.
- Wang, Tzu-Pin,Chiou, Yi-Jang,Chen, Yi,Wang, Eng-Chi,Hwang, Long-Chih,Chen, Bing-Hung,Chen, Yen-Hsu,Ko, Chun-Han
-
experimental part
p. 1642 - 1655
(2011/11/06)
-
- Small molecule microarray-facilitated screening of affinity-based probes (AfBPs) for γ-secretase
-
A small molecule microarray (SMM) platform is developed herein, which enables high-throughput discovery of affinity-based probes (AfBPs) against γ-secretase.
- Shi, Haibin,Liu, Kai,Xu, Ashley,Yao, Shao Q.
-
supporting information; experimental part
p. 5030 - 5032
(2010/01/06)
-
- Artificial metalloenzymes: (Strept)avidin as host for enantioselective hydrogenation by achiral biotinylated rhodium-diphosphine complexes
-
We report on the generation of artificial metalloenzymes based on the noncovalent incorporation of biotinylated rhodium-diphosphine complexes in (strept)avidin as host proteins. A chemogenetic optimization procedure allows one to optimize the enantioselectivity for the reduction of acetamidoacrylic acid (up to 96% ee (R) in streptavidin S112G and up to 80% ee (S) in WT avidin). The association constant between a prototypical cationic biotinylated rhodium-diphosphine catalyst precursor and the host proteins was determined at neutral pH: log Ka = 7.7 for avidin (pl = 10.4) and log Ka = 7.1 for streptavidin (pl = 6.4). It is shown that the optimal operating conditions for the enantioselective reduction are 5 bar at 30 °C with a 1% catalyst loading.
- Skander, Myriem,Humbert, Nicolas,Collot, Jerome,Gradinaru, Julieta,Klein, Gerard,Loosli, Andreas,Sauser, Jerome,Zocchi, Andrea,Gilardoni, Francois,Ward, Thomas R.
-
p. 14411 - 14418
(2007/10/03)
-
- Synthesis of biotinylated thymocartins
-
Four biotinylated derivatives of Arg-Lys-Asp-Val immunostimulating tetrapeptide labelled either at the α-amino group of arginyl or the ε-amino moiety of lysyl residue have been synthesized for biological studies using classical methods.
- Schoen, Istvan,Nyeki, Olga,Demeter, Adam
-
p. 309 - 322
(2007/10/03)
-