Synthesis of Some Novel 6‐Benzyl(or Substituted Benzyl)‐2‐β‐d‐Glucopyranosyl‐1,2,4‐Triazolo[4,3‐b][1,2,4]Triazines as Potential Antimicrobial Chemotherapeutics

Glucosidation of the new 8‐amino‐6‐benzyl(or substituted benzyl)‐2,8‐dihydro‐1,2,4‐triazolo[4,3‐b][1,2,4]triazin‐7(3H)‐ones (3a–d) with 2,3,4,6‐tetra‐O‐acetyl‐α‐d‐glucopyranosyl bromide 4 gave the corresponding N‐glucosides 5a–d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7–12. Antimicrobial activity of compounds 5a–c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.     

Cyclin B1 is an efficacy-predicting biomarker for Chk1 inhibitors

Chk1 is the major mediator of cell-cycle checkpoints in response to various forms of genotoxic stress. Although it was previously speculated that checkpoint abrogation due to Chk1 inhibition may potentiate the efficacy of DNA-damaging agents through induction of mitotic catastrophe, there has not been direct evidence proving this process. Here, through both molecular marker and morphological analysis, we directly demonstrate that specific downregulation of Chk1 expression by Chk1 siRNA potentiates the cytotoxicities of topoisomerase inhibitors through the induction of premature chromosomal condensation and mitotic catastrophe. More importantly, we discovered that the cellular cyclin B1 level is the major determinant of the potentiation. We show that downregulation of cyclin B1 leads to impairment of the induction of mitotic catastrophe and correspondingly a reduction of the potentiation ability of either Chk1 siRNA or a small molecule Chk1 inhibitor. More significantly, we have extended the study by examining a panel of 10 cancer cell-lines with different tissue origins for their endogenous levels of cyclin B1 and the ability of a Chk1 inhibitor to sensitize the cells to DNA-damaging agents. The cellular levels of cyclin B1 positively correlate with the degrees of potentiation achieved. Of additional interest, we observed that the various colon cancer cell lines in general appear to express higher levels of cyclin B1 and also display higher sensitivity to Chk1 inhibitors, implying that Chk1 inhibitor may be more efficacious in treating colon cancers. In summary, we propose that cyclin B1 is a biomarker predictive of the efficacy of Chk1 inhibitors across different types of cancers. Unlike previously established efficacy-predictive biomarkers that are usually the direct targets of the therapeutic agents, cyclin B1 represents a non-drug-target biomarker that is based on the mechanism of action of the target inhibitor. This finding may be potentially very useful for the stratification of patients for Chk1 inhibitor clinical trials and hence, maximize its chance of success.     

WrbA bridges bacterial flavodoxins and eukaryotic NAD(P)H:quinone oxidoreductases

The crystal structure of the flavodoxin-like protein WrbA with oxidized FMN bound reveals a close relationship to mammalian NAD(P)H:quinone oxidoreductase, Nqo1. Structural comparison of WrbA, flavodoxin, and Nqo1 indicates how the twisted open-sheet fold of flavodoxins is elaborated to form multimers that extend catalytic function from one-electron transfer between protein partners using FMN to two-electron reduction of xenobiotics using FAD. The structure suggests a novel physiological role for WrbA and Nqo1.     

Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain

Adriamycin (ADR) is a chemotherapeutic agent useful in treating various cancers. ADR is a quinone-containing anthracycline chemotherapeutic and is known to produce reactive oxygen species (ROS) in heart. Application of this drug can have serious side effects in various tissues, including brain, apart from the known cardiotoxic side effects, which limit the successful use of this drug in treatment of cancer. Neurons treated with ADR demonstrate significant protein oxidation and lipid peroxidation. Patients under treatment with this drug often complain of forgetfulness, lack of concentration, dizziness (collectively called somnolence or sometimes called chemobrain). In this study, we tested the hypothesis that ADR induces oxidative stress in brain. Accordingly, we examined the in vivo levels of brain protein oxidation and lipid peroxidation induced by i.p. injection of ADR. We also measured levels of the multidrug resistance-associated protein (MRP1) in brain isolated from ADR- or saline-injected mice. MRP1 mediates ATP-dependent export of cytotoxic organic anions, glutathione S-conjugates and sulphates. The current results demonstrated a significant increase in levels of protein oxidation and lipid peroxidation and increased expression of MRP1 in brain isolated from mice, 72 h post i.p injection of ADR. These results are discussed with reference to potential use of this redox cycling chemotheraputic agent in the treatement of cancer and its chemobrain side effect in brain.     

金属有机骨架在肿瘤治疗中的应用进展

金属有机骨架(metal-organic frameworks,MOFs)是一类由金属结点和有机配体配位组装而成的晶体材料.金属有机骨架具有孔隙度大、孔径和尺寸可调、生物相容性好、成分可调、表面可修饰等优越性能,在肿瘤治疗领域具有重要的应用潜力.本文首先介绍了金属有机骨架用于小分子药物、生物大分子药物等药物递送体系的构建方法.随后,我们总结了近年来MOFs药物递送体系在肿瘤的化学治疗、光动力学治疗、放射性治疗、免疫治疗、光热治疗等方面的应用进展.最后,本文总结了MOFs在肿瘤治疗方面的进展和特点,并展望了MOFs在肿瘤治疗领域的研究挑战和应用前景.     

Inhibition of cancer cell growth by cyclin dependent kinase 4 inhibitors synthesized based on the structure of fascaplysin

Tryptamine derivatives, a new structural class of cyclin dependent kinase 4 inhibitors, have been identified during extensive biological screening of synthetic molecules. The molecules were synthesized based on the structure of fascaplysin, which is not only a specific inhibitor of the Cdk4-cyclin D1 enzyme but also a relatively toxic molecule, probably because it binds and intercalates DNA. Interestingly, the new structural analogues of fascaplysin do not interact or intercalate with double-stranded DNA, although they inhibit Cdk4-cyclin D1 specifically. We found that compound CA199 was the most potent molecule, showing at least 25-fold specificity towards Cdk4-cyclin D1 (IC50 for Cdk4-cyclin D1 = 20 microM, Cdk2 > 500 microM). CA199 inhibits the growth of different cancer cell lines at concentrations ranging from 10-40 microM. It blocks growth of asynchronous cells at G0/G1 in a retinoblastoma protein (pRb) dependent manner. Moreover, CA199 blocks growth only at early G1 in synchronised cells released from a mimosine-induced G1/S block. These observations are reminiscent of a true Cdk4 inhibitor.     

Protecting normal cells from the cytotoxicity of chemotherapy

Comment on: van Leeuwen IMM, et al. Cell Cycle 2012; 11:1851-61     

Low expression of MRP1/GS-X pump ATPase in lymphocytes of Walker 256 tumour-bearing rats is associated with cyclopentenone prostaglandin accumulation and cancer immunodeficiency

Immunosuppression is a life-threatening complication of late cancer stages. In this regard, overproduction in the host plasma of the anti-inflammatory cyclopentenone prostaglandins (CP-PGs), which are strongly antiproliferative at high concentrations, may impair immune function. In fact, lymphoid tissues of tumour-bearing rats accumulated large amounts of CP-PGs while the tumour tissue itself did not. Expression of the CP-PG-induced 72-kDa heat shock protein (hsp70) was elevated in lymphocytes from tumour-bearing animals related to controls. As the capacity for CP-PG uptake by lymphocytes is the same as tumour cells, we investigated whether the latter could overexpress the multidrug resistance-associated protein (MRP1/GS-X pump) which extrudes CP-PGs towards the extracellular space as glutathione S-conjugates. Walker 256 tumour cells extruded 15-fold more S-conjugates than lymphocytes from the same rats (p < 0.001). This did not appear to be related to deficiency in lymphocyte glutathione (GSH) metabolism, since the major GSH metabolic routes are consistent with CP-PG conjugation in lymphocytes. This was not the case, however, for the MRP1/GS-X pump activity in lymphocyte membranes (in pmol/min/mg protein: 3.1 +/- 1.7 from normal rats, 0.2 +/- 0.2 from tumour-bearing animals vs 64.3 +/- 7.0 in tumour cells) which was confirmed by Western blot analysis for MRP1 protein. Transfection of lymphocytes with MRP1 gene completely abolished CP-PG (0-40 microM) toxicity. Taken together, these findings suggest that CP-PG accumulation in lymphocytes may be, at least partially, responsible for cancer immunodeficiency. Clinical approaches for overexpressing MRP1/GS-X pump in lymphocytes could then play a role as a tool for the management of cancer therapeutics.     

Mapping the Human Kinome in Response to DNA Damage

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