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The Complexity of Natural Products at the Chemistry‒Biology Interface
thesisposted on 2013-06-28, 00:00 authored by Feng Qiu
The chemical and biological complexity associated with bioactive natural products (NPs) leads to significant challenges for mining these molecules. This dissertation developed new or enhanced methods to expedite the separation, structural elucidation, and biological evaluation of NPs. Two powerful tools, countercurrent separation (CS) and nuclear magnetic resonance (NMR), were used extensively for unraveling the chemical and biological complexity of NPs from exemplified plants, including Actaea racemosa, Camellia sinensis, Ginkgo biloba, Humulus lupulus, and Oplopanax horridus. Initially, sample-cutting was applied as a pre-separation procedure to concentrate the target compounds from the complex mixtures. In order to provide a rapid approach to optimize the CS conditions, a “K-by-NMR” method was developed for simultaneous measurement of partition coefficients (K) of multiple components in mixtures. As selectivity is important for resolving NP congeners which exhibit similar chemical properties, the orthogonal chromatography was explored for the design of efficient fractionation procedures. The basic application of NMR was expanded to further enhance the separation and characterization of NPs. For example, qHNMR was used as an offline detector for monitoring the chromatographic process. The COSY spectra were used for evaluation of the residual complexity of purified fractions. Differential analysis of HSQC spectra facilitated the identification of minor new compounds in complex mixtures. Furthermore, pattern recognition of HMBC spectra enabled rapid dereplication of multiple NP congeners in residually complex samples. A 1H NMR-based computational model was also developed for dereplication of NPs by taking advantage of easily discernible methyl 1H NMR signals. In order to correlate the chemical and biological complexity of NPs, a preliminary study was carried out for establishing quantitative purity‒activity relationship of NPs based on the foregoing NMR-based analysis of residual complexity. Finally, a biochemometric approach was employed by using a combination of CS, GC-MS dereplication and statistical analysis. This facilitates the evaluation of potential synergistic effects originating from multiple components in the crude plant extracts. The results demonstrate that these methods are helpful to resolve the complexity of NPs at the chemistry‒biology interface, and, thus, enable the efficient separation and characterization of NPs.
AdvisorPauli, Guido F.
DepartmentMedicinal Chemistry and Pharmacognosy
Degree GrantorUniversity of Illinois at Chicago
Committee MemberOrjala, Jimmy Chen, Shaonong Friesen, J B. McAlpine, James B. Ferreira, Daneel Seigler, David S.