Bio-orthogonal association of Janus-face fluorocyclohexyl rings for PET tumour imaging and delivery of drugs to cancer cells

该项目将涉及David O'Hagan教授的实验室和阿伯丁大学医院的临床前成像中心（由Sergio Dall'Angelo博士领导）和爱丁堡大学医院（由Adriana Tavares博士领导）之间的合作。该项目将探索分子识别的一个全新概念，并将其应用于癌症的诊断和治疗。如果成功，它可以更广泛地应用于任何靶向疾病细胞类型。该项目建立在最近发现的环己烷环上，环的一面是氟，另一面是氢，具有非凡的极性性质[1]。这些被称为“双面神”戒指。这些环的极化面具有很强的自结合性，在自然界中没有类似物，因此它们构成了一种与生物化学“正交”的新型分子基序。在化学生物学中，与生物化学正交的化学在控制细胞内的分子精度方面受到广泛关注。有机结合氟只形成非常弱的氢键，因此预计这些环不会与蛋白质和其他细胞成分形成氢键，并且自结合将比细胞环境中的其他相互作用更强[2]。我们希望通过制备这类放射性标记分子用于正电子发射断层扫描（PET）和癌细胞成像来探索这一概念。为了促进这一点，与阿伯丁大学和爱丁堡大学医院的临床前成像中心建立了合作关系，在那里他们可以随时获得放射性同位素18f -氟化物和异种移植小鼠模型。该项目将合成Janus环标记的RGD肽和标记的5'-氯脱氧腺苷，用C-F键形成酶（氟酶）[3]进行[18F]放射性标记。环状RGD肽与乳腺癌细胞表面丰富的特定蛋白基序（表位）结合，因此它们被用于靶向此类细胞。然后，氯腺苷结构将使用该酶用[18F]-氟化物进行放射性标记。随着化学和放射化学的到位，小动物研究将在PET成像实验中使用爱丁堡的异种移植小鼠模型进行调查。

The project will involve a collaboration between Professor David O'Hagan's laboratory and the pre-clinical imaging centres at the University hospitals in Aberdeen led by Dr Sergio Dall'Angelo and in Edinburgh led by Dr Adriana Tavares. The project will explore a fundamentally new concept in molecular recognition and apply it to cancer diagnosis and treatments. If successful it could be applied more widely to any targeted disease cell type. The project builds on the recent discovery that cyclohexane rings which have fluorines on one face of the ring, and hydrogens on the other face have extraordinarily polar properties [1]. These have been termed 'Janus face' rings. The polarised faces of the rings strongly self-associate and have no counterpart in Nature and thus they constitute a novel molecular motif that is 'orthogonal' to biochemistry. Chemistry that is orthogonal to biochemistry is of wide current interest for controlling molecular precision within cells in chemical biology. Organic bound fluorine forms only very weak hydrogen bonds, so it is anticipated that these rings will not hydrogen bond to proteins and other cellular components, and that self-association will be stronger than other interactions in the cellular environment [2]. We wish to explore this concept by preparing radiolabelled molecules of this class for positron emission tomography (PET) and cancer cell imaging. To facilitate this, collaborations are established with the pre-clinical imaging centres at Aberdeen and Edinburgh University hospitals, where they have ready access to the radio-isotope 18F-fluoride and to xenograft mouse models. The project will synthesise Janus ring tagged RGD peptides and tagged 5'-chlorodeoxyadenosine for [18F]-radiolabelling with a C-F bond forming enzyme (fluorinase) [3]. Cyclic RGD peptides bind to specific protein motifs (epitopes) that are abundant on the surface of breast cancer cells, and therefore they are used to target such cells. The chloro-adenosine construct will then be radiolabelled with [18F]-fluoride using the enzyme. With the chemistry and radiochemistry in place small animal studies will be investigated in PET imaging experiments using xenograft mice models in Edinburgh.