近日從南開大學(xué)獲悉，該校元素有機(jī)化學(xué)國家重點(diǎn)實驗室陳弓教授課題組開發(fā)了一種強(qiáng)力環(huán)狀多肽化合物的化學(xué)合成方法，讓困擾化學(xué)界多年的“高難度多肽成環(huán)”反應(yīng)實現(xiàn)了高效、可控。作為環(huán)肽類分子合成化學(xué)領(lǐng)域的重要突破，該研究還為藥物多肽開發(fā)提供了一種新穎的設(shè)計“工具”。相關(guān)研究成果發(fā)表在最新一期《自然·化學(xué)》上。

　　據(jù)介紹，與傳統(tǒng)的小分子化合物相比，由多種氨基酸單元串聯(lián)而成的多肽類化合物在構(gòu)建體積更大的分子構(gòu)架上有著獨(dú)特的優(yōu)勢和潛力，已知的環(huán)肽類化合物具有包括抗腫瘤、抗HIV、抗菌、抗瘧、安眠、抑制血小板聚集、免疫抑制等多方面的生物活性。既有研究表明，讓鏈狀的多肽“成環(huán)”可以在結(jié)構(gòu)堅固性、細(xì)胞跨膜性、代謝穩(wěn)定性等多個方面顯著提高多肽的成藥性。盡管在過去的幾十年里，環(huán)肽的合成化學(xué)已有了長足的發(fā)展，但仍有很大局限，如何讓這些“大個頭”的多肽分子“定形”為理想的三維結(jié)構(gòu)(環(huán)肽)并具有良好的藥理性質(zhì)還有著巨大的挑戰(zhàn)。

　　受環(huán)肽天然產(chǎn)物生物合成的啟發(fā)，陳弓團(tuán)隊通過金屬催化對鏈狀多肽底物上原本非常惰性的烷基碳?xì)滏I進(jìn)行選擇性活化，并和帶有碘取代的芳香氨基酸側(cè)鏈進(jìn)行分子內(nèi)偶聯(lián)從而生成了各種環(huán)狀產(chǎn)物。該方法把鈀催化烷基碳?xì)滏I的活化反應(yīng)巧妙地運(yùn)用在復(fù)雜多肽的合成中，能“馴服”很多難以成環(huán)的鏈狀多肽前體，讓它們“乖乖”地關(guān)環(huán)。由于該方法采用了非常規(guī)的“碳?xì)滏I活化”合成策略，方法簡潔、高效，底物適用范圍廣，不僅克服了長期困擾“多肽成環(huán)”反應(yīng)的底物依賴性，還可高效制備了具有獨(dú)特“苯環(huán)支撐架”結(jié)構(gòu)的三維環(huán)肽骨架，為構(gòu)建體積各異的環(huán)肽化合物提供了一條嶄新的通用途徑，也為發(fā)現(xiàn)更多具有良好先導(dǎo)藥物活性新型環(huán)肽化合物，推動靶向多肽藥物研發(fā)打下了堅實基礎(chǔ)。

Recently learned from Nankai University, Professor Chen Gong of the State Key Laboratory for organic chemistry has developed a chemical synthesis of a powerful cyclic polypeptide compound, which has made the "highly difficult peptide ring" reaction in the chemical industry more efficient and controllable. As an important breakthrough in the field of synthetic chemistry of cyclic peptides, the study also provides a novel design tool for the development of polypeptide drugs. Relevant research results are published in the latest issue of nature chemistry.

It is said that, compared with the traditional small molecule compounds, the polypeptide compound, which is made up of a variety of amino acid units, has unique advantages and potential in the construction of a larger molecular structure. The known cyclo peptides include anti-tumor, anti HIV, antiseptic, antimalarial, hypnotic, inhibition of platelet aggregation and immunity. Inhibition of many aspects of biological activity. Previous studies have shown that the chain like polypeptide "ring" can significantly improve the polypeptide drug resistance in many aspects, such as structural strength, cell transmembrane, metabolic stability and so on. Although the synthetic chemistry of cyclin has made great progress over the past few decades, it still has great limitations. How to make these "big" peptide molecules "shape" as ideal three-dimensional structure (ring peptide) and have good pharmacological properties still have great challenges.

Inspired by the biosynthesis of natural products of cyclic peptides, the Chen bow team selectively activates the originally very inert alkyl hydrocarbon bonds on the chain polypeptide substrates by metal catalysis, and produces intramolecular coupling with the aromatic amino acid side chains with iodine substituted amino acids to produce various annular products. The method uses palladium to catalyze the activation of alkyl hydrocarbon bonds in the synthesis of complex peptides, which can "tame" many chain polypeptide precursors that are difficult to ring, so that they are "good" to close the ring. Because of the unconventional "hydrocarbon activation" synthesis strategy, the method is simple, efficient, and has a wide range of substrates. It not only overcomes the substrate dependence that perplex the "polypeptide ring" reaction for a long time, but also produces a three-dimensional cycP skeleton with a unique "benzene ring support frame" structure, which is for the construction of different volumes. The cyclic peptide compounds provide a new general approach, and also provide a solid foundation for the discovery of more good lead drug activity novel cyclic peptide compounds and the development of targeted peptide drugs.