Synthesis and Insecticidal Activity and Fluorescent Spectral Properties Study of 4-deoxypodophyllotoxin Derivatives Modified in the D-ring and E-ring

Author:Wang Juan Juan

Supervisor:xu zuo

Database:Doctor

Degree Year:2014

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Pages:163

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The thesis is comprised of two parts on 4-deoxypodophyllotoxin study:Part Ⅰ:insecticidal activities of 4-deoxypodophyllotoxin derivativesUsing natural products as the lead compounds for further structural modifications has recently become a significant way to develop new pesticides.Podophyllotoxin is an important antitumor drug precursor as well as a promising leading compound for insecticidal agents.In order to understand the relationships between structure and insecticidal activities of podophyllotoxin and to develop some novel botanical insecticides with high activity,in this article we designed and synthesized three series of new 4-deoxypodophyllotoxin derivatives based on conjugating pharmacophore protocol.Phenazine,pyrrolidyl,piperidyl and aromatic sulfonyl were introduced to 4-deoxypodophyllotoxin through being modified in the D-ring and E-ring.The synthesized compounds were evaluated on the insecticidal activity against the third-instar larvae of Mythimna separata Walker in vivo.Meanwhile,the structure-activity relationships were also discussed which will provide a cornerstone for new podophyllotoxin-baesed botanical insecticides development.The results are shown as follows:(1)A series of novel 4-deoxypodophyllotoxin-based phenazine analogues were prepared in the E-ring.Their antifeedant activity and insecticidal activity were evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL.All derivatives showed poor antifeedant activity,but with a potent delayed insecticidal activity.Eight compounds showed higher insecticidal activity than toosendanin(48.3%).Especially compound 2-9i,exhibited the most promising insecticidal activity with the final mortality rate of 72.4%.In addition,preliminary structure-activity relationships indicated that insecticidal activity was decreased when introduce quinone motif on the D-ring.Whereas,quinone reacting with phenylenediamine gave the phenazine analogues,the final mortality rate was increased.The proper length of the side chain of alkylacylamino might be important for their insecticidal activity,and introduction of the acylamino groups at the C-9’-position of 4-deoxypodophyllotoxin-based phenazine fragment usually afforded more potent compounds than those containing the same ones at the C-10’-position.(2)A series of 12-(pyrrolidine/piperidine-l-yl)-11-acyloxy-4-deoxypicropodophyllotoxin derivatives were prepared in the D-ring.Their antifeedant activity and insecticidal activity were evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL.All derivatives showed lower antifeedant activity than toosendanin,but majority compounds showed higher insecticidal activity than podophyllotoxin.Especially compounds 3-5a(58.6%),3-51(65.5%),3-6h(55.2%)exhibited good insecticidal activity compared with toosendanin(51.7%);a commercialized insecticide.In addition,preliminary structure-activity relationships indicated that insecticidal activity was decreased when D-ring was opened.But,when acyloxy was introduced at 11-position the insecticidal activity improved.Proper length of the side chain of alkylacyloxy and the electron-donating group and fluorine atom on the 11-benzoate substituent groups might be important for their insecticidal activity.(3)A series of 4’-demethyl-4-deoxypodophyllotoxin sulfonates and ether derivatives were prepared in the E-ring.Their antifeedant activity and insecticidal activity were evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL.All derivatives showed lower antifeedant activity than toosendanin and 4-deoxypodophyllotoxin,but with obvious delayed insecticidal activity.Especially compounds 4-4f(50.0%).4-4g(60.7%),4-5a(67.9%)and 4-5c(67.9%)showed the higher insecticidal activity than toosendanin(46.4%).Preliminary structure-activity relationships indicated that demethylation of 4’-position result a reduced insecticidal activity.The electronic effect of the substituent groups on the 4’-benzenesulfonate’s ring of 4-deoxypodophyllotoxin to insecticidal activity was not obvious.Besides,configuration of D-ring is important for this series of compounds to keep insecticidal activity.2-α,3-β-trans compounds showed better insecticidal activity than that of 2-β,3-β-cis compounds.Part Ⅱ:fluorescence molecular probes based on 4-deoxypodophyllotoxinThe advantages of fluorescent molecular probes for metal ion detection is simple,high sensitivity,good selectivity,short response time,strong in anti-jamming and observation in situ which is widely used in dynamic imaging of the metal ions and the online analysis of the sample in intracellular or in vivo.Deoxypodophyllotoxin-like natural-product-based sensor for recognition of Hg2+ ion based upon the specific mercury-promoted desulfurization reaction was synthesized and measured recognition ability of compond 5a.5a exhibited selective and specific fluorescence decreased property to Hg2+ ion in CH3CN.It is the first probe based on a natural product moiety(deoxypodopnyllotoxin)for recognition of Hg2+ ion.In summary,three series of podophyllotoxin-based bioactive derivatives and one fluorescence molecular probe were synthesized.Their structures were well characterized by 1H-NMR,MS,HRMS,IR and physical properties were also collected.The absolute steric configurations of key intermedi were unambiguously confirmed by X-ray crystallography.The structure-activity relationships showed that the locatone and 4’-methoxyl is the key motif for develop more potent podophyllotoxin-based insecticide candidates.New and highly Hg2+-selective deoxypodophyllotoxim-like natural-product-based sensor may open up a new opportunity for development of natural-product-based probes for selective detection of some specific metal ions.