希少なアビス・セスクイターペノイドの総合成,生物学的評価,および標的の特定
Dexter C Davis1, Dominic G Hoch2, Li Wu3
1Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery , Purdue University , West Lafayette , Indiana 47907 , United States.
Journal of the American Chemical Society
|November 22, 2018
まとめ
研究者は,絶滅危惧種の中国杉からアビエス・セスクイターペノイドを合成し,弱いタンパク質チロシン・フォスファテーズ1Bの抑制を検証し,SHP2を標的とする新しい類似体を特定した. 彼らはDNAポリメラーゼエプシロンサブユニット3 (POLE3) を癌治療の新たな標的として発見した.
科学分野:
- 自然製品合成
- 薬剤化学
- 化学生物学
背景:
- ベシャンズエノネスCとDは,絶滅危惧種の中国杉 (Abies beshanzuensis) から分離されたアビス・セスキーターペノイドである.
- これらの化合物は,タンパク質チロシンフォスファタゼ1B (PTP1B) に対して弱い抑制活性を示します.
研究 の 目的:
- アビエスピロシドA,ベシャンズエノンC,そしてベシャンズエノンDの最初の完全合成を達成するために.
- これらの合成化合物とその類似体の生物学的活動を調査する.
- アビエス・セスキートペノイドの新しい細胞標的を特定する.
主な方法:
- クイラルプールの出発材料として (+) -カルボンを利用した総合成.
- パラジアム触媒による炭化水素乳酸化とドレーディング・シュミット反応による主要な構造モチーフの構築.
- 化学タンパク質標的の識別のためのアジドタグの探査分子の開発.
主要な成果:
- Abies sesquiterpenoids 1-3の完全な合成が成功しました.
- ベシャンズエノンCの弱小なPTP1B抑制作用の検証
- 強力で選択的なSHP2抑制活性を持つ合成アナログの特定
- 新しい細胞標的としてDNAポリメラーゼエプシロンサブユニット3 (POLE3) の発見.
- POLE3の無活性化がDNAダメージを与える物質に対する化学的敏感性を高めることを示した.
結論:
- トータル合成は,貴重なアビス・セスキートペノイドとその類型へのアクセスを提供します.
- POLE3を小さな分子で標的にすることは,がん治療の新たな戦略であり,特に化学反応への感受性です.
- これらの発見は,POLE3阻害に基づく新しいがん治療法の開発への道を開きます.
関連する概念動画
01:57What is Conservation Biology?
24.3K
Conservation biology is a scientific field that focuses on the preservation of biodiversity in order to protect ecosystems while meeting the needs of the human population. Humans require properly functioning ecosystems to maintain our supply of natural resources, including food, medicines, and building materials.
24.3K
01:15Dehydration Synthesis
149.7K
Overview
Dehydration synthesis (also called a condensation reaction) is the chemical process in which two molecules covalently link together to form a new molecule, along with the release of a water molecule. Many physiologically important compounds form by dehydration synthesis reactions, such as complex carbohydrates, proteins, DNA, and RNA.
Synthesis of carbohydrates
Sugar molecules are covalently linked together by dehydration synthesis. During the reaction, the hydroxyl (-OH) group from...
Dehydration synthesis (also called a condensation reaction) is the chemical process in which two molecules covalently link together to form a new molecule, along with the release of a water molecule. Many physiologically important compounds form by dehydration synthesis reactions, such as complex carbohydrates, proteins, DNA, and RNA.
Synthesis of carbohydrates
Sugar molecules are covalently linked together by dehydration synthesis. During the reaction, the hydroxyl (-OH) group from...
149.7K
02:17Synthesis and Decomposition Reactions
38.2K
Synthesis and decomposition are two types of redox reactions. Synthesis means to make something, whereas decomposition means to break something. The reactions are accompanied by chemical and energy changes.
38.2K
02:59Biological Effects of Radiation
17.9K
All radioactive nuclides emit high-energy particles or electromagnetic waves. When this radiation encounters living cells, it can cause heating, break chemical bonds, or ionize molecules. The most serious biological damage results when these radioactive emissions fragment or ionize molecules. For example, α and β particles emitted from nuclear decay reactions possess much higher energies than ordinary chemical bond energies. When these particles strike and penetrate matter, they...
17.9K
01:59Lagging Strand Synthesis
61.3K
During replication, the complementary strands in double-stranded DNA are synthesized at different rates. Replication first begins on the leading strand. Replication starts later, occurs more slowly, and proceeds discontinuously on the lagging strand.
There are several major differences between synthesis of the leading strand and synthesis of the lagging strand. 1) Leading strand synthesis happens in the direction of replication fork opening, whereas lagging strand synthesis happens in the...
There are several major differences between synthesis of the leading strand and synthesis of the lagging strand. 1) Leading strand synthesis happens in the direction of replication fork opening, whereas lagging strand synthesis happens in the...
61.3K
02:36Transfer RNA Synthesis
13.3K
One of the unique features of tRNA is the presence of modified bases. In some tRNAs, modified bases account for nearly 20% of the total bases in the molecule. Altogether, these unusual bases protect the tRNA from enzymatic degradation by RNases.
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
13.3K