Chemical Glycobiology on Anthracyclines

蒽环类药物的化学糖生物学

• 批准号: 7442243
• 负责人: Peng George Wang
• 金额: $ 25.85万
• 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/7442243
• 关键词: Anthracycline Antibiotics; Anthracyclines; Antineoplastic Agents; Binding; Biological; Carbohydrates; Cardiac; Cardiotoxicity; Cells; Cervical; Chemicals; Combined Modality Therapy; Complex; Computers; DNA Topoisomerases; Daunorubicin; Development; Disaccharides; Doxorubicin; Drug Kinetics; Drug effect disorder; Drug resistance; Enzymes; Epirubicin; Exhibits; Experimental Models; 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; 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 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最有效的抗癌药物之一，无论是作为单药使用还是联合治疗。一些天然和半合成的蒽环类化合物被临床用作一线抗癌药物。柔红霉素（DNR）和伊达比星主要用于白血病和淋巴瘤，而多柔比星（DOX）和表柔比星对白血病、淋巴瘤和各种实体瘤（包括乳腺癌、小细胞肺癌、宫颈癌以及头颈癌）具有更广泛的抗癌活性。尽管蒽环类药物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限制。在过去的30年里，寻找新的蒽环类药物来克服这些限制从未停止。 我们一直在系统地改变蒽环类抗生素的碳水化合物部分的结构。最近，我们取得了重大突破：我们发现，通过简单地将柔红霉素中柔红霉素胺上的3 '-氨基（-NH 2）转化为叠氮基（-N3），所产生的3'-叠氮柔红霉素（ADNR）既具有抗耐药癌症的活性，又具有低得多的小鼠毒性。俄亥俄州州立大学已经为这样一种看似简单，但非常有效的对临床重要药物的修饰提交了专利申请。为了进一步增强ADNR的活性，我们将第二个2，6-双脱氧糖连接到ADNR中的第一个3 '-叠氮基道诺糖胺，所得的二糖蒽环类药物对蒽环类耐药癌细胞具有增强的功效，并且对拓扑异构酶2（Top2）和Top1靶标具有不同的选择性。所有这些观察促使我们为这个拟议的研究计划提出一个中心假设： 叠氮柔红霉素（ADNR）或其类似物的药效团上的第二或第三个糖的结构可以通过向DNA-拓扑异构酶-药物三元复合物呈现必需的结合基序来增强蒽环类药物活性并克服药物抗性，同时具有低得多的心脏毒性。 基于这一假设，提出了一种基于结构的方法来研究设计的蒽环类药物在DNA-药物复合物（如药物作用的第一步）和Top-DNA-药物复合物（如药物作用的下一步）中的相互作用和选择性。该计划将侧重于三个密切相关和协同增效的目标。 艾姆岛蒽环类药物分子模拟与筛选平台的建立。该平台包括两个层次的建模。一个更简单的二元DNA-药物复合物模型将用于初步结构筛选可能的二-和三糖蒽环类药物及其O-或N-取代的类似物。NMR和X射线晶体学将用于验证DNA-药物复合物模型。在下一个更具挑战性的水平上，将在Top2-DNA-药物和Top1-DNA-药物复合物模型上进行分子建模和虚拟药物筛选。从这些模型的深刻理解将测试与新的合成蒽环类药物和一系列的生物和机制的方法在目标III。 Aim II.二糖或三糖蒽环类抗生素的合成。 将使用我们建立的收敛方法合成不常见糖库的选择性子集。然后将进一步发展化学和酶法将这些不常见的糖转化为糖苷配基以制备二糖和三糖蒽环类药物。 Aim III.新合成蒽环类抗生素的生物学及作用机理研究。 Top2和Top1中毒的分子机制将通过实验阐明。该药物对耐药白血病和乳腺癌的活性将在体外和体内进行研究。将在异种移植小鼠模型上研究心脏毒性和药代动力学。 总之，这一计划将首次将联合收割机分子模拟和实验验证相结合，以开发一种新的方法来设计碳水化合物修饰的蒽环类药物。该平台的成功将加速DNA-酶-药物复合物抗癌药物领域的新药发现。这项研究计划应产生新一代的临床前蒽环类药物候选人。