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Phytochemical profiling of iranian plants, and ECD calculation as tool for establishing the absolute configuration of new natural products

Samad Nejad, Ebrahimi. Phytochemical profiling of iranian plants, and ECD calculation as tool for establishing the absolute configuration of new natural products. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10607

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Abstract

Biosynthesis of secondary metabolites occurs by concerted multistep reactions in a biological (chiral) environment. Therefore, many natural products (NPs) are chiral molecules having one or several stereocenters. The biological activity of NPs and drug like molecules is generally dependent on the stereochemistry of a molecule. Thus NPs are uniquely predestined to interact with biomacromolecules, and this explains their importance as drug leads.
Chiroptical methods such as electronic circular dichroism (ECD) have been used for assignment of absolute configuration since several decades, but were limited in their applicability. The rapidly developing computer technologies and a broad diversity of quantum chemical methods available now permit to study virtually any molecule by selecting the most appropriate method for each particular case, with regard to the desired accuracy, time consumption, and available computer resources. The progress in the areas of conformational analysis and quantum chemical calculation of molecular properties has widened the applicability of ECD in unambiguous determination of chiral molecules. This is especially valuable for the analysis of new molecular entities when chemical synthesis of the compound is not an option. The good agreements between the experimental and simulated ECD curves of these compounds provided the unambiguous configurational establishment.
The aim of the present work was phytochemical investigation of Iranian medicinal plants, in order to identify bioactive compounds responsible for inhibition of Plasmodium falciparum. About 120 plant extracts were prepared from 40 plants traditionally used in Iranian traditional medicine (ITM) to treat malaria and screened for in vitro activity against P. falciparum.
In a preliminary screen, the lipophilic extracts of Artemisia persica, Salvia hydrangea, and Salvia sahendica roots potently inhibited the growth of P. falciparum K1 strain. HPLC-based activity profiling led to localizing and identification of the active constituents of these plant extracts. Their structures were elucidated by a combination of powerful analytical methods such as HPLC-PDA-TOF-MS, and microprobe NMR. In order to determine the absolute configurations of isolated chiral compounds, quantum chemical calculation of ECD spectra in combination with experimental ECD studies were used. This methodology successfully applied to establish the ACs of structurally diverse and conformationally rigid or flexible molecules including sesquiterpene coumarins, bisabolol sesquiterpenes, diterpenoids and complex isoprenoids with novel scaffolds.
Activity profiling of the active n-hexane extract from the roots of Salvia sahendica against malaria resulted in the identification of eight abietane-type diterpenoids. In vitro biological activities of isolated pure compounds were determined against P. falciparum L& strain and Trypanosoma brucei rhodesiense STIB 900 strain, and cytotoxicity in rat myoblast (L6) cells was determined. The IC50 values of the compounds ranged from 0.8 µM to over 8.8 µM against P. falciparum, and from 1.8 µM to over 32.3 µM against T. brucei rhodesiense. The cytotoxic IC50 values ranged from 0.5-15.5 µM. Selectivity indices for P. falciparum were from 0.1 to 18.2, and 0.1 to 1.2 for T. brucei rhodesiense. The absolute configuration of sahandol (3) and sahandone (4) were assigned by comparison of experimental and calculated ECD spectra and optical rotation values.
HPLC based activity profiling of the EtOAc extract of the aerial parts of Artemisia persica resulted in the isolation of a series of bisabolol oxide esters. Relative configurations of cyclohexenone/cyclohexene and tetrahydropyran moieties of 5–9 were established on the basis of 3JH–H coupling constants and NOE difference spectra. Absolute configurations of 5–9 were established by comparison of experimental ECD spectra with simulated ECD data for possible stereoisomers, by TDDFT. Assignment of AC by ECD calculation is possible even though relative stereochemistry cannot establish by NMR techniques due to the flexibility of the molecule. Bisaboloids 5–8 exhibited in vitro antimalarial activity against Plasmodium falciparum, with IC50 values ranging from 2.8 to 20.1 µM, and selectivity indices (SI) in L-6 cells of 3.7–11.9.
Hydrangenone, perovskone and salvadione three new triterpenoids with rare carbon skeletons were isolated from aerial parts and flowers of Salvia hydrangea endemic plant to Iran. These compounds indicated significance in vitro activity against P. falciparum with IC50 values 1.40, 0.18 and 1.43 µM, respectively and acceptable selectivity index in rat myoblast L-6 cells.
Advisors:Hamburger, Matthias Otto
Committee Members:Wolfender, Jean-Luc
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
Item Type:Thesis
Thesis no:10607
Bibsysno:Link to catalogue
Number of Pages:213 p.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:54
Deposited On:09 Dec 2013 12:39

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