Design of 4-(4-dialkylaminostyryl) -pyridinium dyes for fluorescent detection of amyloid fibrils

• DOI: 10.7124/bc.00092b
• Publication Date: 2016-11-01T14:19:42Z
• Authors: D. I. Inshyn; S. V. Chernii; V. B. Kovalska; S. M. Yarmoluk

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QSAR ?????? ???????????????????????? ???????????????????????????????? ?????????????????? ?? ??????????????????, ????????????, ???????????????????????? ????????????????????????. ????????????????????. ???? ?????????????????????? ???????? ???? 1500 ???????????????????????????? ???????? ?????????????? ???????????? ???????????????? ?? ?????????????? ???????????????????????????????? ????????????????????????????. ?????? ???????????????????? ???????? ??????????????????????????, ???? ??????????????????????-???????????????????????????? ???????????????? ???????? ?????????????? ?? ?????????????????????? ?????????????????????????????? ?????????? ????????????????. ?????????????????? ???????????????? ???????????? ?????????????????????? ?????????????????????????? ?? ???????????? ???????????????????????????????? ?? ?????????????????????? ????????????????. ?? ?????????????????????? ?????????????????????????? ???????????????? ?????? ?????????? ?????????????????????? ?????????????????????????? ?????????????????????????? ???? ???????????????? ?????? ?? ?????????????????????? ???? ?????????????? ?????????????????? ?????????????????????? ?? ???????????????? ??????????????????. ?????????????????? ?? 4-???????????????????????????????? ???????????????????????? ???????? ?????????? ?????????????? ???????????????????????????? ?????????? (???? 23 ??????) ?? ?????????????? ???????????????? ???????????????? ???????????????????? ???????????? (1???40 ?????? / ????). ????????????. (4-(4-????????????????????????????????????)-?????????????????????? ?????????????????? ?? ???????????????????????? ???????????????????????????? ?????????????????? ?????????????????????????? ?????????????????????????? ?????????????????????????? ???????????????? ?????? ???????????????????????????? ?????????? ?????? ???????????????? ???????????????????? ??????????????. ?????????????????????????? ???????????? ???????????????? ?????????????? ???????????????? ???????????????????????? ?????? ?????????????????????? ????????????????????????????, ???? ?????????????????????? ???????????????????? ???????????????????? ?????????????????????????????? ?? ???????????? ?????????????????????????? ??????????????????????.<br/>?????????????????????? ?????????????????? ??????????????. ????????. ???????????? ??????????????-???????????????? ?????????????????????????????????? ???????????????????????????? ??????????????????. ????????????. ?????????? QSAR ?????? ???????????????????????? ???????????????????? ?????????????????? ???? ???????????????????? ????????????, ???????????????? ????????????, ?????????????????????? ?????????????????????? . ????????????????????. ???? ?????????????????????? ???????? ???? 1500 ???????????????????????????? ???????? ???????????? ??????????????? ???????????????? ???? ???????????????? ???????????????????????? ????????????????????????. ???????????? ?????????????? ???????? ??????????????????????, ???? ??????????????????????-?????????????????????????? ?????????????????????? ???????? ?????????????? ?? ?????????????????????? ?????????????????????????????? ?????????? ????????????????. ???? ???????????????? ?????????? ???????????? ???????????? ?????????????????????????? ???? ???????????? ???????????????????? ???? ?????????????????????? ????????????????. ?? ?????????????????????? ???????????????????????? ???????????????? ???????? ???????????? ?????????????????????? ?????????????????????????? ?????????????????????????? ???? ???????????????? ?????????? ?????????????? ?????? ?????????????? ?????????????????? ?????????????????? ?? ???????????????? ????????????????. ?????????????? ???? 4-???????????????????????????????? ???????????????????? ?????? ?????????????? ?????????????????????????? ?????????????????? (???? 23 ??????????) ?? ?????????????? ???????????????? ???????????????? ?????????????? ?????? ???????????? (1???40 ?????? / ????). ????????????????. (4-(4- ????????????????????????????????????) -???????????????????? ???????????????? ?? ???????????????????? ???????????????????????? ?????????????????? ?????????????????????? ???????????????????????? ???????????????????????? ?????????????????????? ???? ?????????????????????????? ?????????? ?????? ???????????????? ???????????????????? ????????????. ???????????????????? ???????????? ???????????????? ???????????? ???????????????? ???????????????????????? ?????? ?????????????????? ??????????????????, ?????????????????????? ?? ??????????????????????????, ???? ?????????????? ?????????????????????????????? ???? ???????? ???????????????????? ??????????????????.<br/>The pathological proteins aggregation into the fibrillar structures is common to a large group of amyloid-related disorders, such as neurodegenerative diseases. Accordingly, there is a need for development of analytical tools, particularly fluorescent probes for detection of amyloid fibrils. Aim. To design amyloid-sensitive styrylpyridinium fluorescent dyes. Methods. QSAR model for the prediction of the dye efficiency followed by the synthesis and spectral-luminescent studies. Results. Nine structures with the highest predicted efficiency were selected from the virtual database of 1500 styrylcyanines; these compounds were synthesized and their spectral-luminescent properties in the presence of amyloidogenic protein insulin were studied. The dyes are weakly fluorescent when free and have a low sensitivity to native insulin. In the presence of insulin fibrils, they increase the fluorescence intensity up to dozens of times depending on the nature of the terminal substituent. The dye with a 4-methylpiperidinyl substituent demonstrated the highest fluores-cence response (up to 23 times) and a wide range of fibril detection (1???40 ??g/ml). Conclusion. (4-(4-dialkylaminostyryl) -pyridinium dyes with cyclic aliphatic terminal substituent have the properties of fluorescent probes for sensing the amyloid fibrils. The prediction accuracy of the regression model is suitable for the majority of the styrylcyanines but poor in the case of the dyes with piperazinyl substituent or those containing additional aromatic substituents.<br/>