Cytosine substituted calix[4]pyrroles: Neutral receptors for 5′-guanosine monophosphate

The synthesis and characterization of two cytosine-substituted calix[4]pyrrole conjugates, bearing the appended cytosine attached at either a β- or meso-pyrrolic position, is described. These systems were tested as nucleotide-selective carriers and as active components of nucleotide-sensing ion-selective electrodes at pH 6.6. Studies of carrier selectivity were made using a Pressman-type model membrane system consisting of an initial pH 6.0 aqueous phase, an intervening dichloromethane barrier containing the calix[4]pyrrole conjugate, and a receiving basic aqueous phase. Good selectivity for the Watson–Crick complementary nucleotide, 5′-guanosine monophosphate (5′-GMP), was seen in the case of the meso-linked conjugate with the relative rates of through-membrane transport being 7.7:4.1:1 for 5′-GMP, 5′-AMP, and 5′-CMP, respectively. By contrast, the β-substituted conjugate, while showing a selectivity for 5′-GMP that was enhanced relative to unsubstituted calix[4]pyrrole, was found to transport 5′-CMP roughly 4.5 times more quickly than 5′-GMP. Higher selectivities were also found for 5′-CMP when both the β- and meso-substituted conjugates were incorporated into polyvinyl chloride membranes and tested as ion selective electrodes at pH 6.6, whereas near-equal selectivities were observed for 5′-CMP and 5′-GMP in the case of unsubstituted calix[4]pyrroles. These seemingly disparate results are consistent with a picture wherein the meso-substituted cytosine calix[4]pyrrole conjugate, but not its β-linked congener, is capable of acting as a ditopic receptor, binding concurrently both the phosphate anion and nucleobase portions of 5′-GMP to the calixpyrrole core and cytosine “tails” of the molecule, respectively, with the effect of this binding being most apparent under the conditions of the transport experiments.

本文报道了两种胞嘧啶取代的杯[4]吡咯（calix[4]pyrrole）缀合物的合成与表征，该类缀合物的胞嘧啶侧链分别连接于β-位或中位（meso-）吡咯环位置。上述两种缀合物体系被用作核苷酸选择性载体，以及pH 6.6条件下核苷酸传感离子选择性电极的活性组分。载体选择性的研究采用普雷斯曼（Pressman）型模型膜体系，该体系由初始pH 6.0的水相、夹隔其中的含杯[4]吡咯缀合物的二氯甲烷阻隔相，以及接收用碱性水相三部分构成。对于中位连接的缀合物，其对沃森-克里克（Watson–Crick）互补核苷酸5′-鸟苷单磷酸（5′-GMP）表现出优异的选择性，其跨膜运输相对速率依次为5′-GMP:5′-腺苷单磷酸（5′-AMP）:5′-胞苷单磷酸（5′-CMP）=7.7:4.1:1。与之形成对照的是，β-取代缀合物虽较未取代的杯[4]吡咯对5′-GMP的选择性有所提升，但对5′-CMP的运输速率约为5′-GMP的4.5倍。当将β-取代与中位取代的缀合物掺入聚氯乙烯（polyvinyl chloride, PVC）膜中，并在pH 6.6条件下作为离子选择性电极进行测试时，二者均对5′-CMP表现出更高的选择性；而未取代杯[4]吡咯对5′-CMP与5′-GMP的选择性则近乎相等。这些看似相悖的实验结果与如下模型相符：中位取代的胞嘧啶杯[4]吡咯缀合物（而非β-连接的同类物）可作为双位点受体，分别同时将5′-GMP的磷酸阴离子部分与核苷碱基部分结合至杯吡咯核心与分子的胞嘧啶“尾”部，该结合效应在运输实验条件下最为显著。