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ISOLATION OF ANTIEPILEPTIC CONSTITUENTS AND BIOTRANSFORMATION OF BIOACTIVE NATURAL PRODUCTS FROM SOME MEDICINALLY IMPORTANT PLANTS OF PAKISTAN

Shaheen, Farzana (1998) ISOLATION OF ANTIEPILEPTIC CONSTITUENTS AND BIOTRANSFORMATION OF BIOACTIVE NATURAL PRODUCTS FROM SOME MEDICINALLY IMPORTANT PLANTS OF PAKISTAN. PhD thesis, University of Karachi, Karachi.

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Abstract

This thesis comprises two parts. Part A of the thesis deals with bioactivity-guided isolation and identification of anticonvulsant constituents from a medicinal plant Delphinium denudatum, which has been used traditionally for the treatment of epilepsy in Pakistan. Acute toxicity studies and LD50 of various extracts obtained from dried roots of this plant carried out by Dr. Mohisn Raza of our research group and Dr. R. J. Delorenzo in the Medical College of Virginia, Virginia Commonwealth University, USA, indicated that the chloroform extracts obtained by us extraction at different pH values as well as their diterpenoid alkaloidal constituents were highly toxic to neuromuscular system of mice. In a joint research program with Dr. R. J. DeLorenzo, the anticonvulsant constituents were found to be localized in the least toxic aqueous extract (A.E), since it showed strong anticonvulsant action both in invitro and in invivo experiments. Bioactivity-guided fractionation of the aqueous extract (A.E.) with various solvents yielded an acetone fraction (FS-1) which was ten times more active than the A.E. in in vitro studies. The acetone fraction (FS-1) showed strong limitation of sustained repectitive firing (SRF) of hippocampal neurons as well as also inhibited pentylenetertrazole (PTZ) and bicucculine (BIC)-induced epileptiform activity in a dose-dependent manner. In in vitro experiments, carried out in USA. FS-1 exhibited strong action in subcutaneous pentylenetetrazole (scPTZ), subcutaneous bicucculine (scBIC) and maximal electroshock (MES) tests, suggesting that the compounds present in FS-1 can be effective in therapy of generalized tonic-clonic, partial, absence and myoclonic seizures. Further purification of the acetone fraction by us yielded several sub-fractions (FSS 15-19) that also showed strong limitation of SRF of hippocampal neurons in culture. Two novel compounds named as delphadiencne 1 (21) and delphadienone II (22) were isolated from these sub-fractions (FSS 15-19) Delphadienone 1 (21) Delphaqienone II (22) Part-B of this thesis describes the microbial transformations of three bioactive natural products i.e., E-guggulsterone (29), vindoline (30) and α-santonin (31). Microbial transformation of E-guggulsterone (29), a hypolipacmic compound from Commiphora mukul, with a fungus Cephalosporium aphidicola resulted in the formation of four new metabolites identified as 11 α-hydroxy-Z-guggulsterone (44), 11 α-hydroxy-E-guggulsterone (45), 11 α, 15β-dihydroxy-Z-guggulsterone (46), and 11 α, 15β-dihydroxy-E-guggulsterone (47), whereas fermentation of E-guggulsterone (29) with Aspergillus niger also afforded four new metabolites identified as 7β-hydroxy-Z-guggulsterone (49), 7β-hydroxy-Z-guggulsterone (50), 17, 20-dihydro-7β-hydroxyguggulsterone (51) and 17, 20-dihydro-7β-hydroxyguggulsterone (52). Microbial transformation of vindoline (30) with Aspergillus niger, Fusarium iini and Fusarium moniliforme afforded the same metabolite identified as, 17-deacetylvindoline (35), while transformation of α-santonin (31) with A. niger afforded regiospecific reduction of C-1/C-2 double band to yield 1, 2-dihydro-α-santonin (43) 29 R1=Ch3, R2, =R3=R4=R5=H, 30 R=COCH3, 31, 43, 44 R1=Ch5, R4,=H, R2=CH3, R3=OH, 45 R1=Ch3, R2,=R4, R5=H, R3=OH, 46 R1=R5,=H R2,=CH3, R3=R4=OH, 47 R1=CH3, R2,=R5,=H, R3=R4=OH, 49 R1=R3,=R4,=H, R2=CH3, R5=OH, 50 R1=CH3, R2,=R3=R4=H, R5 =OH,

Item Type:Thesis (PhD)
Uncontrolled Keywords:antiepileptic constituents, bioactive natural products, medicinal plant, delphinium denudatum, epilepsy, e-guggulsterone, vindoline, α-santonin, diterpenoid alkaloids
Subjects:Physical Sciences (f) > Chemistry(f2)
ID Code:1320
Deposited By:Mr. Muhammad Asif
Deposited On:27 Jan 2007
Last Modified:04 Oct 2007 21:05

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