TY - JOUR
T1 - Folding fan mode counter-current chromatography offers fast blind screening for drug discovery. Case study
T2 - Finding anti-enterovirus 71 agents from Anemarrhena asphodeloides
AU - Liu, Mengshun
AU - Tao, Ling
AU - Chau, Siu Leung
AU - Wu, Rong
AU - Zhang, Hong
AU - Yang, Yifu
AU - Yang, Dajian
AU - BIAN, Zhaoxiang
AU - LYU, Aiping
AU - HAN, Simon Q B
AU - Xu, Hongxi
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (Grant No. 81303289 ), the Major Application Development Project of Chongqing ( cstc2014yykfc10002 ), the Science Foundation for the Excellent Youth Scholars of Shanghai (No. ZZszy13059 ), and Hong Kong Baptist University ( FRG2/13-14/026 ). We thank Dr. Long Song from the School of Pharmacy, Shanghai University of Traditional Chinese Medicine for identification of A. asphodeloides; and Professor Hanzhong Wang from the Wuhan Institute of Virology, Chinese Academy of Sciences, for providing the BrCr strain of EV71.
PY - 2014/11/14
Y1 - 2014/11/14
N2 - A new application of counter-current chromatography (CCC) in drug discovery, called folding fan mode (FFM), is designed to eliminate the extensive and time-consuming calculation of the partition coefficients of some preset compounds in conventional CCC separation. Careful reading of reports in the literature reveals that, when two-phase solvent systems are listed in a polarity-increasing sequence, the isolates also show a similar trend in polarity. The relationship between the two-phase solvent system and the isolates is like that between the folds and the picture of a folding fan. We can directly select a two-phase solvent system to separate fractions having similar polarity, just as opening a fan reveals a picture. The solvent ratio of two-phase solvent systems can be adjusted according to the polarity and weight ratio of active fractions rather than the partition coefficients. Without preset compounds, FFM-CCC not only requires no measurement of partition coefficients, but also achieves true blind screening. This paper reports the method's first success in drug discovery: six anti-EV71 saponins were found from the mixture (9.13g) of ethanol extract and water extract of Anemarrhena asphodeloides after a total of four CCC separations, using hexan/ethyl acetate/methanol/butanol/water as the model solvent system. Among these saponins, timosaponin B-II displayed a comparable IC50 (4.3±2.1μM) and a 40-fold higher selective index (SI=92.9) than the positive control (IC50=361.7±104.6μM, SI=2.4), ribavirin. The structure-activity relationship (SAR) of these compounds was also studied.
AB - A new application of counter-current chromatography (CCC) in drug discovery, called folding fan mode (FFM), is designed to eliminate the extensive and time-consuming calculation of the partition coefficients of some preset compounds in conventional CCC separation. Careful reading of reports in the literature reveals that, when two-phase solvent systems are listed in a polarity-increasing sequence, the isolates also show a similar trend in polarity. The relationship between the two-phase solvent system and the isolates is like that between the folds and the picture of a folding fan. We can directly select a two-phase solvent system to separate fractions having similar polarity, just as opening a fan reveals a picture. The solvent ratio of two-phase solvent systems can be adjusted according to the polarity and weight ratio of active fractions rather than the partition coefficients. Without preset compounds, FFM-CCC not only requires no measurement of partition coefficients, but also achieves true blind screening. This paper reports the method's first success in drug discovery: six anti-EV71 saponins were found from the mixture (9.13g) of ethanol extract and water extract of Anemarrhena asphodeloides after a total of four CCC separations, using hexan/ethyl acetate/methanol/butanol/water as the model solvent system. Among these saponins, timosaponin B-II displayed a comparable IC50 (4.3±2.1μM) and a 40-fold higher selective index (SI=92.9) than the positive control (IC50=361.7±104.6μM, SI=2.4), ribavirin. The structure-activity relationship (SAR) of these compounds was also studied.
KW - A. asphodeloides
KW - Bioassay-guided counter-current chromatography
KW - Enterovirus 71
KW - Folding fan mode
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84908210397&partnerID=8YFLogxK
U2 - 10.1016/j.chroma.2014.09.064
DO - 10.1016/j.chroma.2014.09.064
M3 - Journal article
C2 - 25441347
AN - SCOPUS:84908210397
SN - 0021-9673
VL - 1368
SP - 116
EP - 124
JO - Journal of Chromatography A
JF - Journal of Chromatography A
ER -