Isolation, Structure Determination of Sesquiterpenes from Neurolaena lobata and Their Antiproliferative, Cell Cycle Arrest-Inducing and Anti-Invasive Properties against Human Cervical Tumor Cells

Abstract

Seven new germacranolides (1–3, 5–8), among them a heterodimer (7), and known germacranolide (4), eudesmane (9) and isodaucane (10) sesquiterpenes were isolated from the aerial parts of Neurolaena lobata. Their structures were determined by using a combination of different spectroscopic methods, including HR-ESIMS and 1D and 2D NMR techniques supported by DFT-NMR calculations. The enantiomeric purity of the new compounds was investigated by chiral HPLC analysis, while their absolute configurations were determined by TDDFT-ECD and OR calculations. Due to the conformationally flexible macrocycles and difficulties in assigning the relative configuration, 13C and 1H NMR chemical shift and ECD and OR calculations were performed on several stereoisomers of two derivatives. The isolated compounds (1–10) were shown to have noteworthy antiproliferative activities against three human cervical tumor cell line with different HPV status (HeLa, SiHa and C33A). Additionally, lobatolide C (6) exhibited substantial antiproliferative properties, antimigratory effect, and it induced cell cycle disturbance in SiHa cells.

Isolation and NMR Scaling Factors for the Structure Determination of Lobatolide H, a Flexible Sesquiterpene from Neurolaena lobata

“…Although NOE correlations work well in smaller rings, for flexible systems or macrolides one should be careful with the interpretations to avoid misassignments [ 24 , 50 , 51 ]. Therefore, we tested a large number of available DFT NMR methods, developed parameters for two combinations and augmented the NMR studies with TDDFT-ECD calculations to verify the stereochemistry of 1 .…”

“…It is a rich source of SLs; previously 24 sesquiterpenes, among them 22 SLs having germacranolide, seco -germacranolide, furanoheliangolide and eudesmanolide skeletons were isolated from the aerial parts of the plant. Several of them possessed remarkable antiproliferative and anti-inflammatory activities [ 20 , 21 , 22 , 23 , 24 ].…”

“…There are, however, a few examples in the literature, where even for rather problematic cases, such as halogen atoms, well performing scaling factors could be prepared [ 40 ]. Exomethylene groups are less problematic than halogen atoms, but still capable of exerting a distortion of several ppm, which is comparable with the difference between the possible stereoisomers and, hence, thwarts a safe assignment [ 24 , 41 , 42 ]. For example, in our previous study on lobatolide derivatives, the 13 C NMR chemical shift data of lobatolide A could be well reproduced, but for most of the other exomethylene containing lobatolides, large differences were found in the vicinity of the exomethylene group preventing utilization of the calculated NMR scaling factors in structure elucidation [ 24 ].…”

“…Exomethylene groups are less problematic than halogen atoms, but still capable of exerting a distortion of several ppm, which is comparable with the difference between the possible stereoisomers and, hence, thwarts a safe assignment [ 24 , 41 , 42 ]. For example, in our previous study on lobatolide derivatives, the 13 C NMR chemical shift data of lobatolide A could be well reproduced, but for most of the other exomethylene containing lobatolides, large differences were found in the vicinity of the exomethylene group preventing utilization of the calculated NMR scaling factors in structure elucidation [ 24 ]. Since a large number of level combinations with NMR scaling factors are already available in the literature [ 27 , 43 ], and for some of them, even exomethylene containing derivatives were considered in the training set [ 41 ], we hoped to find a few well applicable combinations for germacranolides including the novel flexible natural product ( 1 ).…”

Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications

“…Probably plants are the most well-known source of molecules with demonstrated anticancer therapeutic properties. Another set of papers of this Special Issue have investigated the antitumoral properties of plant extracts and plant-derived compounds, revealing interesting antiproliferative and/or pro-apoptotic activities in vitro [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In addition, Huang and coworkers have shown that Ceylon olive leaf extract and its phytochemicals, such as mearnsetin, displayed potent antimelanogenesis effects in a zebrafish model [ 19 ].…”