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Synthesis of Antiinfective Agents

抗感染剂的合成

基本信息

批准号：
7523809
负责人：
SAMUEL J DANISHEFSKY
金额：
$ 59万
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/7523809
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 Vaccines Cancer cell line Carbohydrates Carboxypeptidase Categories Cell Wall Cellular biology Chemicals Chemistry Class Clinical Collaborations Compatible Complex Condition Coupled Cytotoxic agent Depsipeptides Development Diagnosis Diagnostic Educational process of instructing Epothilones Estrogen Receptors Evaluation Exercise Facility Construction Funding Category Failure Family Fruit Glutamate Carboxypeptidase II Glycopeptides Goals Grant HIV HIV Envelope Protein gp120 HIV vaccine Habitats Housing Human Resources Immune response Immune system Immunology In Vitro Institutes Laboratories Localized Malignant Neoplasms Malignant neoplasm of prostate Medicine Membrane Methodology Minor Mission Modality Modification Molecular Molecular Biology Molecular Weight Nature Neoplasm Metastasis Numbers Oligonucleotides Oligosaccharides Organ Organic Chemistry Organic Synthesis Paclitaxel Pathway interactions Personal Satisfaction Pharmaceutical Preparations Planning Techniques Primary Neoplasm Process Prostate-Specific Antigen Proteins Public Health Range Rate 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 day design desire drug discovery experience frontier functional group high throughput screening hyperforin improved inhibitor/antagonist insight member migrastatin novel outcome forecast pharmacophore piperazic acid pre-clinical programs size 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形态。首先是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有用资源。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，与癌症靶标有关，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、SMNPs的化学衍生物或通过分子编辑过程衍生的合成中间体的形式。第三个概念是，合成已经达到了可以在实验室中组装生物制品的阶段，包括高复杂性和高价值的寡糖和糖肽。该提案分为11个项目。其中8人使用SMNPs作为治疗新发现的跳板。另外三种专注于针对免疫系统靶点的合成生物制品-一种是针对艾滋病毒的，两种是针对前列腺癌的，要么是通过改善诊断前景，要么是作为创造前列腺癌导向疫苗的一种手段。基于SMNP的计划围绕：(1)Migrastatin，它发现了潜在的关键应用，抗肿瘤转移。通过一系列的合成、转移全合成和分子编辑，我们已经发现了一系列简化的米曲他汀类化合物，它们实际上阻止了原发肿瘤向其他靶器官的定植；(2)毛晶素，一种复杂的萜类结构，对某些癌细胞的杀伤能力大约是顺铂的50倍；(3)皮质抑素，一种强大的复杂分子结构的抗血管生成药物；(4)普拉替西霉素，一种革兰氏阳性抗菌素，其靶标是细胞壁生物合成；(5)阿普利库罗地酮，一种立体化学挑战的萜类结构，是一类细胞毒剂；(6)金丝桃素，一种复杂的多戊烯类化合物，可诱导癌细胞凋亡；(7)放线酸，一种生物碱型的羧肽酶亚微摩尔抑制剂；及(8)哌齐霉素，一种复杂的去脂肽，含有两种难以安装的哌齐酸，它在100 nm处对一组癌细胞具有活性。此外，将有三个项目针对生物水平分子的合成。计划9设想了一种基于gp120抗原碳水化合物部分的抗艾滋病毒疫苗。程序10涉及使用非常复杂的碳水化合物结构域组装基于PSA的结构，以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需要基于膜定位的PSMA合成和评估一种复杂的前列腺癌疫苗。综上所述，我们预见了一个综合了化学、细胞生物学、免疫学和发展的化学评价计划，以期促进合成和医学的发展。公共卫生相关性：该提案利用靶向有机合成的资源，以创建复杂的分子实体，并有机会转化为医学，特别是在癌症和艾滋病毒的背景下。