Synthesis of Antiinfective Agents

抗感染剂的合成

• 批准号: 7864113
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 90.49万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/7864113
• 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; 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; 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; public health relevance; small molecule; tumor; zocor

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，旨在产生关于癌症的价值模式。首先，合成有机化学已经取得了重大进展，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的生物活性分子，在大多数情况下与癌症靶点有关，称为SMNP（小分子天然产物），在生产新药方面有着卓越的记录。这可以采取SMNP本身、SMNP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，合成已经达到了生物制品的阶段，包括高复杂性和价值的寡糖和糖肽，可以在实验室中组装。该方案分为11个方案。八个使用SMNPs作为治疗新发现的跳板。另外三个专注于针对免疫系统靶点的合成生物制剂-一个针对HIV，两个针对前列腺癌，无论是通过改善诊断前景还是作为创建前列腺癌靶向疫苗的手段。基于SMNP的项目围绕：（1）Migrastatin，其发现潜在的抗肿瘤转移的关键应用。通过一系列合成、转向全合成和分子编辑，我们发现了一系列简化的偏头痛抑制素，其实际上阻断原发性肿瘤向其他靶器官的定殖;（2）Maoecystal，一种复杂的萜类化合物样结构，其对某些癌细胞系的效力比顺铂强约50倍;（3）皮质抑素，一种具有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剂，其靶点是细胞壁生物合成;（5）黑曲霉素酮，一种立体化学上具有挑战性的三联体样结构，是细胞毒性剂家族的成员;（6）Hyperorin，一种诱导癌细胞凋亡的复合多聚戊烯类化合物;（7）Actinophyllic Acid，一种羧肽酶的亚微摩尔抑制剂;和（8）阿齐霉素，一种复杂的缩酚酸肽，含有两个难以安装的哌嗪酸，其在100 nM时对一组癌细胞系有活性。此外，三个项目将针对生物水平分子的合成。计划9设想了基于gp 120抗原的碳水化合物部分的抗HIV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的构建体，以区分高度侵袭性和侵袭性较低的前列腺癌，从而提供常规PSA读数的额外校准。计划11需要基于膜定位的PSMA合成和评估针对前列腺癌的复杂疫苗。总之，我们预见到一个整合化学，细胞生物学，免疫学和化学评价开发的计划，以推进合成和医学。 公共卫生关系：该提案利用靶向有机合成的资源来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。