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Synthesis of Antiinfective Agents

抗感染剂的合成

基本信息

批准号：
8081870
负责人：
SAMUEL J DANISHEFSKY
金额：
$ 59.89万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-03-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081870
关键词：
Acids Amaze Ampicillin Anabolism Anti-Bacterial Agents Anti-Infective Agents Antibodies Antigens Apoptosis Architecture Area Binding Biochemistry Biological Biological Factors Biology Calibration Cancer cell line Carbohydrates Carboxypeptidase Categories Cell Wall Cellular biology Chemicals Chemistry Clinical Collaborations Complex Coupled Cytotoxic agent Depsipeptides Development Diagnosis Diagnostic Educational process of instructing Epothilones Estrogen Receptors Evaluation Exercise Failure Family Fruit Glutamate Carboxypeptidase II Glycopeptides Goals Grant HIV HIV Envelope Protein gp120 HIV vaccine Habitats Health Housing Human Resources Immune response Immune system Immunology Institutes Laboratories Malignant Neoplasms Malignant neoplasm of prostate Medicine Membrane Methodology Minor Mission Modality Modification Molecular Molecular Biology Molecular Weight Nature Neoplasm Metastasis Oligonucleotides Oligosaccharides Organ Organic Chemistry Organic Synthesis Paclitaxel Pathway interactions Pharmaceutical Preparations Planning Techniques Primary Neoplasm Process Prostate-Specific Antigen Proteins Reading Research Resources Risk Route Science Screening procedure Selection Criteria Series Site Source Staging Steroids Structure System Tamoxifen Technology Terpenes Testing Time Translations Ursidae Family Vaccines Vancomycin analog antiangiogenesis therapy atorvastatin base biomaterial compatibility cancer cell cancer pharmacology cancer therapy career chemical synthesis clinical application cortistatin design drug discovery experience frontier functional group high throughput screening hyperforin improved in vitro activity inhibitor/antagonist insight meetings member migrastatin novel outcome forecast pharmacophore piperazic acid preclinical evaluation programs small molecule tumor zocor

项目摘要

DESCRIPTION (provided by applicant): This proposal weaves together three themes with a view toward producing modalities of value in regards to cancer. The first is that synthetic organic chemistry has made major advances, such as to render it a usable resource in the discovery of new modalities in medicine. The second theme is that a class of structurally diverse, biologically active molecules, in most cases with respect to cancer targets, known as SMNPs (small molecule natural products), have a remarkable record in producing new drugs. This may take the form of SMNPs themselves, chemical derivatives of SMNPs, or synthetic intermediates derived through the process of molecular editing. The third notion is that synthesis has reached the stage where biologicals, including oligosaccharides and glycopeptides of high complexity and value, can be assembled in the laboratory. The proposal is divided into 11 programs. Eight use SMNPs as springboard for new discoveries in therapy. Three others are focused on synthetic biologicals which are directed to immune system targets - one against HIV and two against prostate cancer, either via improved prospects for diagnosis or as a means of creating a prostate cancer-directed vaccine. The SMNP-based programs center around: (1) Migrastatin, which finds potentially critical application against tumor metastasis. We have found, through a sequence of synthesis, diverted total synthesis, and molecular editing, a series of simplified migrastatins that virtually block colonization of primary tumors to other target organs; (2) Maoecrystal, a complex terpenoid-like structure which is about 50 times more potent against certain cancer cell lines than cis-platin; (3) Cortistatin, a potent anti-angiogenesis agent of complex molecular architecture; (4) Platensimycin, a gram-positive antibacterial, whose target is cell wall biosynthesis; (5) Aplykurodinone, a stereochemically challenging terpene-like structure, and a member of a family of cytotoxic agents; (6) Hyperforin, a complex polyprenyloid which induces apoptosis in cancer cells; (7) Actinophyllic Acid, an alkaloidal submicromolar inhibitor of carboxypeptidases; and (8) Piperazimycin, a complex depsipeptide, containing two difficultly installable piperazic acids, which is active against a panel of cancer cell lines at 100 nM. In addition, three programs will be directed to the synthesis of biological level molecules. Program 9 contemplates an anti-HIV vaccine based on the carbohydrate sector of the gp120 antigen. Program 10 involves assembling a PSA-based construct using the very complex carbohydrate domain to differentiate between highly aggressive and less aggressive prostate cancers, thereby providing additional calibration of conventional PSA readings. Program 11 entails the synthesis and evaluation of a complex vaccine against prostate cancer, based on the membrane-localized PSMA. In summary, we foresee a program which integrates chemistry, cell biology, immunology, and development for chemical evaluation with a view to advancing synthesis and medicine. PUBLIC HEALTH RELEVANCE: The proposal brings to bear the resources of target directed organic synthesis to create complex molecular entities with opportunities for translation to medicine, particularly in the context of cancer and HIV.

描述（由申请人提供）：该提案将三个主题编织在一起，以期产生与癌症有关的价值模式。首先，合成有机化学取得了重大进展，例如使其成为发现医学新模式的可用资源。第二个主题是一类结构多样、具有生物活性的分子，在大多数情况下与癌症目标有关，被称为SMNPs（小分子天然产物），在生产新药方面有着非凡的记录。这可能采取SMNPs本身的形式，SMNPs的化学衍生物，或通过分子编辑过程衍生的合成中间体。第三个概念是，合成已经达到了生物制剂的阶段，包括高复杂性和高价值的低聚糖和糖肽，可以在实验室中组装。该提案分为11个项目。其中8个使用SMNPs作为治疗新发现的跳板。另外三个重点是针对免疫系统靶点的合成生物制剂——一个针对艾滋病毒，两个针对前列腺癌，要么通过改善诊断前景，要么作为制造前列腺癌定向疫苗的手段。基于smnp的项目主要围绕以下几个方面展开：(1)迁移他汀（Migrastatin），发现其在肿瘤转移方面具有潜在的关键应用。我们已经发现，通过一系列合成、转移全合成和分子编辑，一系列简化的迁移他汀类药物实际上可以阻止原发肿瘤向其他靶器官的定植；(2) maocrystal，一种复杂的萜类结构，对某些癌细胞的杀伤能力是顺式铂的50倍；(3)皮质抑素，复杂分子结构的有效抗血管生成剂；(4)铂霉素，一种革兰氏阳性抗菌药物，其作用靶点是细胞壁生物合成；(5) applykurodinone，一种具有立体化学挑战性的萜类结构，是细胞毒性药物家族的成员；(6) hyperperforin，一种诱导癌细胞凋亡的复杂聚丙烯样蛋白；(7)放线素茶酸，一种生物碱类亚微摩尔羧基肽酶抑制剂；(8)哌嗪霉素（Piperazimycin），一种复杂的沉积肽，含有两种难以安装的哌嗪酸，在100 nM下对一组癌细胞有活性。此外，三个项目将直接用于生物水平分子的合成。计划9考虑一种基于gp120抗原碳水化合物部分的抗hiv疫苗。程序10包括使用非常复杂的碳水化合物结构域组装基于PSA的结构来区分高侵袭性和低侵袭性前列腺癌，从而提供常规PSA读数的额外校准。项目11需要合成和评估一种基于膜定位PSMA的前列腺癌复合疫苗。总之，我们预见到一个整合化学、细胞生物学、免疫学和化学评价发展的项目，以期推进合成和医学。公共卫生相关性：该提案利用目标导向有机合成的资源，创造复杂的分子实体，并有机会转化为医学，特别是在癌症和艾滋病毒的背景下。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering of therapeutic polypeptides through chemical synthesis: early lessons from human parathyroid hormone and analogues.

DOI：
10.1021/ja306637u
发表时间：
2012-09-12
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Dong S;Shang S;Li J;Tan Z;Dean T;Maeda A;Gardella TJ;Danishefsky SJ
通讯作者：
Danishefsky SJ

A Simple Method for the Conversion of Carboxylic Acids into Thioacids with Lawesson's Reagent.

DOI：
10.1016/j.tetlet.2009.09.080
发表时间：
2009-12-02
期刊：
Tetrahedron letters
影响因子：
1.8
作者：
Rao Y;Li X;Nagorny P;Hayashida J;Danishefsky SJ
通讯作者：
Danishefsky SJ

Thio-mediated two-component coupling reaction of carboxylic acids and isonitriles under mild conditions.

DOI：
10.1016/j.tetlet.2009.01.046
发表时间：
2009-04-08
期刊：
TETRAHEDRON LETTERS
影响因子：
1.8
作者：
Wu, Xiangyang;Li, Xuechen;Danishefsky, Samuel J.
通讯作者：
Danishefsky, Samuel J.

Total synthesis of the α-subunit of human glycoprotein hormones: toward fully synthetic homogeneous human follicle-stimulating hormone.

DOI：
10.1021/ja2111459
发表时间：
2012-02-22
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Aussedat, Baptiste;Fasching, Bernhard;Johnston, Eric;Sane, Neeraj;Nagorny, Pavel;Danishefsky, Samuel J.
通讯作者：
Danishefsky, Samuel J.

Total synthesis of (+)-suaveolindole: establishment of its absolute configuration.

( )-suaveolindole 的全合成：建立其绝对构型。