New Radiation-Activated Antitumor Agents That Target Hypoxia

针对缺氧的新型辐射激活抗肿瘤药物

基本信息

批准号：
7981141
负责人：
Xiaohua Peng
金额：
$ 35.85万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7981141
关键词：
Address Aerobic Antineoplastic Agents Biochemical Biochemistry Biological Biological Assay Cancer Biology Cells Cellular biology Chemicals Clinical Coenzymes Coupling DNA DNA Alkylation DNA Damage DNA Interstrand Crosslinking DNA biosynthesis Data Development Discipline Dose Electrons Enzymes FDA approved Funding Generations Genetic Transcription Goals Gray unit of radiation dose Human Hypoxia In Vitro Ionizing radiation Knowledge Malignant Neoplasms Methodology Mission Motivation Necrosis New Agents Normal tissue morphology Oligonucleotides Organic Chemistry Oxidoreductase Oxygen Pharmaceutical Chemistry Pharmaceutical Preparations Phase Prodrugs Property Public Health Radiation Reaction Reducing Agents Research Series Solid Solid Neoplasm Specificity Synthesis Chemistry Techniques Technology Testing Therapeutic Tissues Toxicology Tumor Tissue United States National Institutes of Health Water Work analog antitumor agent base cancer cell cancer therapy crosslink cytotoxicity design drug candidate drug development drug discovery functional group in vivo irradiation killings neoplastic cell public health relevance success tool tumor

项目摘要

DESCRIPTION (provided by applicant): Cancer therapies kill cancer cells, but are only marginally less toxic to healthy cells. We need more selective agents to specifically kill cancer cells. Since cancer cells divide so rapidly, they are very often hypoxic (oxygen-starved). This hypoxia can be used to specifically target cancer cells for destruction. The long-term goal of this research is to develop new hypoxia-targeting anticancer drugs that are less toxic, more selective, and more potent. The objective of this particular application is to design and synthesize a series of new radiation-activated antitumor agents that contain dual potent effectors and more efficient triggers, and to perform biological studies with both synthetic and cellular DNA. These agents should be non-toxic in normal tissue, and can be selectively activated to release multiple toxic species (effectors) upon irradiation under the hypoxic conditions found in tumor tissue. The effectors are designed to form deleterious DNA damage, such as DNA interstrand cross-links (ICLs) or DNA alkylations that can block DNA replication or transcription and kill tumor cells. The proposed research has been formulated on the basis of our recent discovery that the arylmethyl radicals form the DNA interstrand crosslinks under hypoxic condition. The rationale for the proposed research is that, once the efficient triggers and the potent effectors are developed, the new agents will be more selective and more potent anticancer drug candidates for the treatment of aggressive cancers. Synthetic methodologies will be developed to prepare the proposed compounds. They will be incorporated into short oligonucleotides via solid- phase DNA synthesis. Their DNA-damage profiles and mechanism with respect to cross-link formation and DNA alkylation will be studied. The hypoxia-specificity will be evaluated by examining cross-linking efficiency under hypoxic or aerobic conditions. The most promising agents will be pushed forward for in vitro and in vivo study with tumor cells. In addition, new, potent DNA- damaging functional groups will be prepared, as well as other analogs. The knowledge gained from this study will be useful for addressing fundamental questions concerning DNA damage and anticancer drug development and will benefit a broad range of disciplines, including organic chemistry, biochemistry, medicinal chemistry, toxicology, and cell biology. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the development of new hypoxia- targeting antitumor agents has the potential to identify a new class of anticancer drugs for the treatment of aggressive cancers. The knowledge acquired will be useful for addressing fundamental questions concerning DNA damage and anticancer drug development. Thus, the proposed research is relevant to the part of NIH's mission that is in pursuit of fundamental knowledge that will help to reduce the burdens of human illness.

描述（由申请人提供）：癌症杀死癌细胞，但对健康细胞的毒性较小。我们需要更多的选择性剂来特别杀死癌细胞。由于癌细胞分裂如此迅速，因此通常是缺氧（耗尽氧气）。该缺氧可用于专门针对癌细胞进行破坏。这项研究的长期目标是开发新的针对低氧靶向抗癌药物，这些药物毒性较小，更有选择性且更有效。该特定应用的目的是设计和合成一系列含有双重有效效应子和更有效触发因素的新辐射激活的抗肿瘤剂，并使用合成和细胞DNA进行生物学研究。这些药物在正常组织中应无毒，并且可以在肿瘤组织中发现的低氧条件下辐照后选择性地激活以释放多种有毒物种（效应子）。效应子设计为形成有害的DNA损伤，例如DNA间交联（ICL）或可以阻止DNA复制或转录并杀死肿瘤细胞的DNA烷基化。拟议的研究是根据我们最近发现的，即在低氧条件下芳基甲基自由基形成了DNA链间交联。拟议的研究的理由是，一旦有效的触发因素和有效的效应子，新的药物将变得更加选择性，更有效的抗癌药物候选物来治疗侵略性癌症。将开发合成方法来制备所提出的化合物。它们将通过固相DNA合成掺入短寡核苷酸中。将研究它们相对于交联形成和DNA烷基化的DNA破坏谱和机制。缺氧特异性将通过在缺氧或有氧条件下检查交联效率来评估。最有前途的药物将被推向体外和体内研究肿瘤细胞的研究。此外，还将准备新的，有效的DNA损害官能团以及其他类似物。从这项研究中获得的知识将有助于解决有关DNA损伤和抗癌药物开发的基本问题，并将受益于广泛的学科，包括有机化学，生物化学，药物化学，毒理学和细胞生物学。公共卫生相关性：拟议的研究与公共卫生有关，因为针对抗肿瘤剂的新缺氧的发展有可能识别一种新的抗癌药物来治疗侵略性癌症。获得的知识将有助于解决有关DNA损伤和抗癌药物开发的基本问题。因此，拟议的研究与NIH使命的一部分有关，该任务是追求基本知识，这将有助于减轻人类疾病的负担。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

ROS-inducible DNA cross-linking agent as a new anticancer prodrug building block.

DOI：
10.1002/chem.201200075
发表时间：
2012-03-26
期刊：
CHEMISTRY-A EUROPEAN JOURNAL
影响因子：
4.3
作者：
Cao, Sheng;Wang, Yibin;Peng, Xiaohua
通讯作者：
Peng, Xiaohua

Design, Synthesis, and Characterization of Binaphthalene Precursors as Photoactivated DNA Interstrand Cross-Linkers.

作为光激活 DNA 链间交联剂的联萘前体的设计、合成和表征。

DOI：
10.1021/acs.joc.8b00642
发表时间：
2018
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Lin,Zechao;Fan,Heli;Zhang,Qi;Peng,Xiaohua
通讯作者：
Peng,Xiaohua

Photoswitchable formation of a DNA interstrand cross-link by a coumarin-modified nucleotide.

DOI：
10.1002/anie.201310609
发表时间：
2014-07-01
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Haque, Mohammad Mojibul;Sun, Huabing;Liu, Shuo;Wang, Yinsheng;Peng, Xiaohua
通讯作者：
Peng, Xiaohua

A Template-Mediated Click-Click Reaction: PNA-DNA, PNA-PNA (or Peptide) Ligation, and Single Nucleotide Discrimination.

DOI：
10.1002/ejoc.201000615
发表时间：
2010-08-01
期刊：
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
影响因子：
2.8
作者：
Peng, Xiaohua;Li, Hong;Seidman, Michael
通讯作者：
Seidman, Michael

Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.

DOI：
10.1016/j.ejmech.2017.03.041
发表时间：
2017-06-16
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Wang Y;Fan H;Balakrishnan K;Lin Z;Cao S;Chen W;Fan Y;Guthrie QA;Sun H;Teske KA;Gandhi V;Arnold LA;Peng X
通讯作者：
Peng X