Chemical Glycobiology on Anthracyclines

蒽环类药物的化学糖生物学

• 批准号: 7900642
• 负责人: Peng George Wang
• 金额: $ 5.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900642
• 关键词: Anthracyclines; Antineoplastic Agents; Binding; Biological; Carbohydrates; Cardiac; Cardiotoxicity; Cells; Cervical; Chemicals; Combined Modality Therapy; Complex; Computer Simulation; DNA Topoisomerases; Daunorubicin; Development; Disaccharides; Doxorubicin; Drug Kinetics; Drug effect disorder; Drug resistance; Enzymes; Epirubicin; Exhibits; Generations; Glycobiology; Goals; Head and Neck Cancer; Idarubicin; In Vitro; Inhibitory Concentration 50; Investigation; K-562; K562 Cells; Lead; Legal patent; Libraries; Malignant Neoplasms; Modeling; Modification; Molecular; Molecular Models; Mono-S; Monosaccharides; Multi-Drug Resistance; Mus; Ohio; P-Glycoprotein; P-Glycoproteins; Parents; Pharmaceutical Preparations; Poisoning; Preclinical Drug Evaluation; Preparation; Research; Research Personnel; Resistance; Screening procedure; Series; Solid Neoplasm; Structure; Testing; Time; Topoisomerase; Toxic effect; Trisaccharides; Universities; Validation; X-Ray Crystallography; Xenograft procedure; amino group; analog; anticancer activity; base; cancer cell; cancer therapy; carbohydrate structure; daunosamine; design; drug candidate; drug discovery; in vivo; leukemia; leukemia/lymphoma; lung small cell carcinoma; malignant breast neoplasm; molecular modeling; mouse model; novel strategies; pharmacophore; pre-clinical; preference; programs; research study; success; sugar; virtual

DESCRIPTION (provided by applicant): Anthracyclines are considered to be some of the most effective anticancer drugs ever developed, either used as single agents or in combination therapy. Several natural and semi-synthetic anthracycline compounds are clinically used as the front-line anticancer drugs. Daunorubicin (DNR) and idarubicin are primarily used in leukemia and lymphoma, whereas doxorubicin (DOX) and epirubicin have broader anticancer activities against leukemia, lymphomas, and a variety of solid tumors including breast cancers, small cell lung cancers, cervical, as well as head and neck cancers. Despite the widespread use in cancer therapy, drug resistance and cardiotoxicity are the two major limitations for anthracycline drugs. Over the past 30 years, search for new anthracyclines to overcome these limitations has never ceased. We have been systematically altering the structure of the carbohydrate portion of anthracyclines. Recently, we made our major breakthrough: we discovered that by simply converting the 3'-amino group (-NH2) on daunosamine in daunorubicin into an azido (-N3) group with one organic transformation, the resulted 3'-azido daunorubicin (ADNR) confers both activity against drug-resistant cancers and much lower toxicity in mice. The Ohio State University has submitted a patent application for such a seemingly simple, but very effective modification of a clinically important drug. To further enhance the activity of ADNR, we connected a second 2,6-dideoxysugar to the first 3'-azido daunosamine in ADNR, the resulting disaccharide anthracyclines have an enhanced efficacy towards anthracycline-resistant cancer cells and different selectivity against topoisomerase 2 (Top2) and Top1 targets. All of these observations prompt us to make a central hypothesis for this proposed research program: The structures of the second or third sugar on the established pharmacophore of 3'-azidodaunorubicin (ADNR) or its analogs can enhance anthracycline activity and overcome drug resistance with much lower cardiac toxicity by presenting an essential binding motif to the DNA-topoisomerase-drug ternary complex. Based on this hypothesis, a structure-based approach is proposed to investigate interaction and selectivity of designed anthracyclines in DNA-drug complex (as in the first step of drug action) and in Top-DNA-drug complex (as in the next step of drug action). The program will focus on three closely related and synergistic aims. Aim I. Establishment of a platform for molecular modeling and screening of anthracycline drugs. The platform consists of two levels of modeling. A simpler binary DNA-drug complex model will be used for initial structural screening for a possible di- & trisaccharide anthracyclines and their O- or N-substituted analogs. Both NMR and X-ray crystallography will be used to validate the DNA-drug complex model. At the next more challenging level, molecular modeling and virtual drug screening will be performed on both Top2-DNA-drug and Top1-DNA-drug complex models. Insightful understanding from these models will be tested with new synthetic anthracyclines and with a series of biological and mechanistic approaches in Aim III. Aim II. Synthesis of di- or trisaccharide anthracyclines. A selective subset of an uncommon sugar library will be synthesized using our established convergent approaches. Then both chemical and enzymatic approaches will be further developed to transfer these uncommon sugars to aglycones for the preparation of di- & trisaccharide anthracyclines. Aim III. Biological and mechanistic investigation of the new synthetic anthracyclines. The molecular mechanisms of Top2 & Top1 poisoning will be clarified experimentally. Activities of the drug to drug-resistant leukemia and breast cancers will be investigated both in vitro & in vivo. Cardiac toxicity and pharmacokinetics will be studied on xenograft mice models. In summary, for the very first time, this program will combine molecular modeling and experimental validation to develop a new approach for designing carbohydrate-modified anthracyclines. The success of such a platform will accelerate new drug discovery in the field of anticancer drug involving DNA-enzyme-drug complex. This research program should produce new generations of preclinical anthracycline drug candidates.

描述（由申请人提供）：蒽环类药物被认为是有史以来开发的一些最有效的抗癌药物，要么用作单一药物或联合疗法。几种天然和半合成蒽环类化合物在临床上用作前线抗癌药。 Daunorubicin (DNR) and idarubicin are primarily used in leukemia and lymphoma, whereas doxorubicin (DOX) and epirubicin have broader anticancer activities against leukemia, lymphomas, and a variety of solid tumors including breast cancers, small cell lung cancers, cervical, as well as head and neck cancers.尽管在癌症治疗中广泛使用，但耐药性和心脏毒性是蒽环类药物的两个主要局限性。在过去的30年中，寻找克服这些限制的新的蒽环类动物从未停止过。 我们一直在系统地改变蒽环类药物的碳水化合物部分的结构。 Recently, we made our major breakthrough: we discovered that by simply converting the 3'-amino group (-NH2) on daunosamine in daunorubicin into an azido (-N3) group with one organic transformation, the resulted 3'-azido daunorubicin (ADNR) confers both activity against drug-resistant cancers and much lower toxicity in mice.俄亥俄州立大学已提交了专利申请，以对临床上重要的药物进行如此简单但非常有效的修改。为了进一步增强ADNR的活性，我们将第二个2,6-脱氧氧化物连接到ADNR中的第一个3'-氮杂daunosamine，所得的二糖蒽环类细胞具有增强的抗蒽环类癌细胞的功效，对topoisomerase 2（Topoisomerase 2（top2）和Top2）和Top1靶标具有不同的选择性。所有这些观察结果都促使我们为此提出的研究计划做出了中心假设： 第二或第三糖在已建立的3'-氮杂霉素（ADNR）或其类似物的既定药效团上的结构可以增强蒽环类药物的活性，并通过对DNA-型tna-topoosomerase-drug drug trug ternary ternary ternary complent具有较低心脏毒性的耐药性来克服耐药性。 基于这一假设，提出了一种基于结构的方法来研究DNA-prug复合物（在药物作用的第一步）和上型DNA-drug复合物（如下一步的药物作用的下一步）中设计的蒽环类药物的相互作用和选择性。该计划将重点关注三个密切相关和协同的目标。 AIM I.建立一个分子建模和筛查蒽环类药物的平台。该平台由两个级别的建模组成。更简单的二进制DNA-grug复合模型将用于可能的二糖和trisaccharide Antlacyclines及其O-或N-取代的类似物的初始结构筛选。 NMR和X射线晶体学均将用于验证DNA-prug复合物模型。在下一个更具挑战性的水平上，将在Top2-DNA-rug和Top1-DNA-DRUG复合物模型上进行分子建模和虚拟药物筛查。这些模型的有见地的理解将通过新的合成蒽环类动物以及AIM III中的一系列生物学和机械方法进行测试。 目标II。二糖或三糖蒽环类药物的合成。 不常见的糖文库的选择性子集将使用我们已建立的收敛方法合成。然后，将进一步开发化学方法和酶促方法，以将这些不常见的糖转移到粘合聚糖中，以制备二糖和三糖蒽环类药物。 目标三。新合成蒽环类药物的生物学和机械研究。 TOP2和TOP1中毒的分子机制将通过实验阐明。该药物对耐药性白血病和乳腺癌的活性将在体外和体内进行研究。心脏毒性和药代动力学将在异种移植小鼠模型上进行研究。 总而言之，该程序将首次结合分子建模和实验验证，以开发一种新方法来设计碳水化合物修饰的蒽环类药物。这种平台的成功将加速涉及DNA-酶 - 药物复合物的抗癌药物领域的新药物发现。该研究计划应生产新一代的临床前蒽环类药物候选者。

项目成果

The roles of 3' and 4' hydroxy groups in alpha-galactosylceramide stimulation of invariant natural killer T cells.

• DOI: 10.1002/cmdc.200900350
• 发表时间: 2009-11
• 期刊: CHEMMEDCHEM
• 影响因子: 3.4
• 作者: Xia, Chengfeng;Zhang, Wenpeng;Zhang, Yalong;Chen, Wenlan;Nadas, Janos;Severin, Ryan;Woodward, Robert;Wang, Bin;Wang, Xin;Kronenberg, Mitchell;Wang, Peng G.
• 通讯作者: Wang, Peng G.

Synthesis and biological activities of a 3'-azido analogue of Doxorubicin against drug-resistant cancer cells.

• DOI: 10.3390/ijms13033671
• 发表时间: 2012
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Yu S;Zhang G;Zhang W;Luo H;Qiu L;Liu Q;Sun D;Wang PG;Wang F
• 通讯作者: Wang F

Histone deacetylase inhibitors through click chemistry.

• DOI: 10.1021/jm8005355
• 发表时间: 2008-12-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Shen J;Woodward R;Kedenburg JP;Liu X;Chen M;Fang L;Sun D;Wang PG
• 通讯作者: Wang PG

In vitro reconstitution of Escherichia coli O86 O antigen repeating unit.

• DOI: 10.1007/978-1-60761-454-8_7
• 发表时间: 2010
• 期刊: Methods in molecular biology
• 作者: Weiqing Han;Lei Li-;N. Pettit;W. Yi;R. Woodward;Xianwei Liu;W. Guan;V. Bhatt;J. Song;P. Wang-P.-W