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

该项目将涉及大卫奥黑根教授的实验室和临床前成像中心在阿伯丁大学医院由塞尔吉奥Dall'Angelo博士领导和在爱丁堡由阿德里安娜塔瓦雷斯博士领导。该项目将探索分子识别的全新概念，并将其应用于癌症诊断和治疗。如果成功，它可以更广泛地应用于任何靶向疾病细胞类型。该项目建立在最近的发现基础上，即环的一面上有氟，另一面上有氢的环己烷环具有非常强的极性[1]。这些被称为“两面神面”环。环的极化面强烈自缔合，在自然界中没有对应物，因此它们构成了一种与生物化学“正交”的新分子基序。与生物化学正交的化学在化学生物学中用于控制细胞内的分子精确度具有广泛的当前兴趣。有机结合的氟仅形成非常弱的氢键，因此预计这些环不会与蛋白质和其他细胞组分形成氢键，并且自缔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，与阿伯丁和爱丁堡大学医院的临床前成像中心建立了合作，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，用于用C-F键形成酶（氟化酶）进行[18 F]-放射性标记[3]。环状RGD肽结合乳腺癌细胞表面上丰富的特定蛋白基序（表位），因此它们被用于靶向此类细胞。然后使用酶用[18F]-氟化物放射性标记氯腺苷构建体。随着化学和放射化学的到位，将在爱丁堡使用异种移植小鼠模型在PET成像实验中研究小动物研究。

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.