Azadirachtin structure

Axle and collar molecular structure, 27 60-61 Axokine, 3 97 Azaboranes, 4 170, 204 Azacarbocyanine dyes, 9 257 Aza[18]crown-6, 24 41 Aza[18]crown-6 appended a-helical barrels / rods, 24 58 Azacrown ethers, 24 44 Azacrowns, 24 41 Azacryptands, 24 42 Azadirachtin, 24 474 Azafullerenes, 22 231, 232, 243 Azahomofullerenes, 22 243 Azaindene compounds, 29 197 Azalactone method (for Emphaze supports), for covalent ligand immobilization, 6 396t Azamethiphos (salmosan)... 

However, the acctimulated Information on azadirachtin, while promising, is presently much less than that needed for insecticidal product commercialization (41). The mode of action, structure-activity relationships (SAR s), formulation, and metabolism of azadirachtin are not yet well understood. Furthermore, formulation studies are required prior to product development and commercialization. Consequently, further investigations are needed before the full potential of azadirachtin as an insect control agent or insecticide can be realized. 

Another limonoid isolated from neem seeds and determined to be as potent as azadirachtin as an ecdysis inhibitor has been identified as 3-deacetylazadirachtinol (Figure 15) (57). Both compounds were lethal to 50% of the treated H. virescens larvae (EI5Q) at 0.8 ppm in artificial diet (Table VII). Structurally, there are two differences between the compounds. In 3-deacetylazadirachtinol, the C-ll-O-C-13 ether linkage of azadirachtin is reductively cleaved at the 11 position and the acetoxyl group at C-3 is hydrolyzed to a hydroxyl group. 

Dr. Govindachari has an indefatigable interest in the study of Natural Products and has elucidated the structures of many novel oxygen heterocyclics and terpenoids like polyalthic acid and azadirachtins from the neem kernel extracts. 

HPLC H NMR spectroscopy using an isocratic separation with acetonitrile and D2O in the ratio 7 13 has also been used to study photo-isomerisation of the natural material azadirachtin extracted from the seeds of the neem tree and which is a powerful insect anti-feedant [34], This has a complex structure with an (ii)-2-methylbutyl-2-enoate fragment but which after exposure to UY iradiation is converted to the Z-isomer ... 

The powerful antifeedant and insecticide azadirachtin (213), from the neem tree (Azadirachta indica, Meliaceae), is a highly oxidized limonoid with rings A, B, and D intact.2 It is used as a benchmark against which all other antifeedants can be compared (vide infra). The total synthesis of azadirachtin has recently been achieved in 64 steps.96 This is very unlikely to provide a synthetic source of the compound, but it does allow SAR studies to find maximum activity, and opens up the field to possible simpler synthetics modelled on it. As yet, even slight modifications of the structure tend to decrease activity. Azadirachtin (213) has been available commercially, particularly in the United States, but at present the cost of the seeds and the isolation procedure inhibit its wider use. 

David Morgan is a member of the Chemical Ecology Group at Keele University. He was bom in Newfoundland and had his university education there, at Dalhousie University and University of King s College in Halifax, Nova Scotia, and at Oxford. His doctorate thesis was on the lipids of Mycobacterium tuberculosis. He later worked at the National Institute for Medical Research in London, and for Shell Chemical Company and Shell Research under the direction of Sir Robert Robinson, O.M., Nobel Laureate. From 1966 he has been at Keele in Staffordshire as lecturer, senior lecturer, reader, and professor. He discovered the natural pesticide azadirachtin and collaborated with S. V. Ley for its final structure elucidation. He is the author of over 300 papers and reviews, mostly on insect chemistry, editor, and contributor to several volumes and author of the book Biosynthesis in Insects. ... 

Azadirachtin, which is a tetranortriterpenoid, is an active ingredient of neem Azadirachta indica) seed oil. The structure of azadirachtin is as follows. It controls 200 species of insects, including locusts, gypsy moths, cockroaches, and fall army worms. It has an oral LD50in rats of >5000 mg/kg, making it essentially nontoxic to mammals. 

Figure 3.12 Structure of azadirachtin. Reprinted with permission of Shokabo Publishing Co., Ltd...

The neem tree, Azadirachta indica, is native to tropical Asia but has been planted widely in the warmer parts of Africa, Central and South America, and Asia. Extracts from neem seed kernels act as repellents, antifeedants, and growth disruptants. The main active principle in kernels is azadirachtin (AZ), a limonoid with a very complicated structure. A range of other compounds is also present. These neem substances can repel insects, prevent... 

Use of polymer-bound chlorite 11 was shown to be more efficient for the oxidation of secondary alcohols to the corresponding ketone [23c]. The method was applied to a series of complex synthetic intermediates and gave excellent results. Immobilized chlorite was shown to be also a very efficient co-oxidant in the conversion of primary alcohols into the corresponding carboxylic acid [24]. This method is particularly attractive due to the ease of purification, the excellent yields and purity obtained also on more complex structures. What makes these techniques particularly interesting is that they have found applications in the synthesis of complex molecules. It was the method of choice for the synthesis of intermediate 13, the core of azadirachtin, in studies towards the synthesis of this natural product by the Nicolaou group [25]. This bicyclic aldehyde was obtained very cleanly using this method (Scheme 4.2). 

In this chapter, our recent studies on the Insecticidal constituents from these two plant species will be presented, concentrating first on the volatile organosulfur compounds recently Isolated from neem seeds (, and then on the azadirachtin-type tetranortrlterpenoid limonoids present In both species (22-26). Our recent studies on the Insecticidal mellaclns of the azadirachtin type suggest structure-activity relationships and a mode of action which may be useful In the design of synthetic analogs. 

HPLC methods previously described (22.24.26.42). The cinnamoyl ester-bearing compounds were detected by uitraviolet (UV) monitoring at 280 nm. Structure elucidation of the purified compounds was carried out by means of infrared (iR) and UV spectrophotometry, proton and carbon-13 nuciear magnetic resonance (NMR) spectroscopy, and electron impact (EI-) and fast-atom bombardment mass spectrometry (FAB-MS). The structures of the two new isolates and three of their derivatives were established on the basis of spectroscopic data and spectrai evidence obtained on comparison with azadirachtin (23). 

Structure-Activitv Relationships of Azadirachtin and Its Analogs and Derivatives... 

Kraus, W., M. Bokel, A. Klenk, and H. Pohnl, Structure of azadirachtin and 22,23-dihydro-23p-methoxyazadirachtin, Tetrahedron Lett., 26, 6435-6446 (1985). 

Rembold, H., Azadirachtins Their structure and mode of action, in Insecticides of Plant Origin (Amason, J. T., B. J. R. Philo-gene, and P. Morand, eds.), ACS Symposium Series 387, 150-163, American Chemical Society, Washington, DC, 1989. 

To use a more sophisticated example, we can look to the products of the neem tree (Azadirzchta indica), a tropical plant that is known for its pesticidal properties. The seed of this tree is abundant with limonoids and simple terpenoids that are responsible for its biological activity. One particular limonoid found in the seed is Azadirachtin (2.134). The bioactivity of Azadirachtin potentially leads to a wide range of applications in herbal medicine and healthcare products for the treatment of malaria and tuberculosis and in anti-worm, clotting, and blood-detoxification preparations. These uses of Azadirachtin as a biopesticide or herbal medicine is limited due to solubility constraints in water and its instability as a result of its propensity to undergo complicated, irreversible rearrangements under acidic, basic and photolytic conditions. Consequently, there has been much research in the structural modification of Azadirachtin to overcome its solubility constraints to increase stability. This process normally involves many protection and deprotection synthetic steps and chromatographic separations. 

Hyoscyamine, present in Datura stramonium Atropine, present in Atropa belladonna Cocaine, present in Erythroxylon coca Codeine and morphine, present in Papaver somniferum Terpenoids (come from semiterpene oligomerization) Azadirachtin, present in seeds of Azadirachta indica (neem) Artemisinin, present in Artemisia annua Tetrahydrocannabinol, present in Cannabis sativa Steroids (terpenes with a particular ring structure) Glycosides (heavily modified sugar molecules)... 

Broughton H B, Ley S V, Slawin A M Z, Williams D J, Morgan E D 1986 X-Ray crystallographic structure determination of detigloyldihydroazadirachtin and reassignment of the structure of the limonoid insect antifeedant azadirachtin. J Chem Soc Chem Commun 46-47... 

Butterworth J H, Morgan E D, Percy G R 1972 The structure of azadirachtin the functional groups. J Chem Soc Perkin Trans I 2445-2450... 

Kraus W, Bokel M, Klenk A, Pohnl H 1985 The structure of azadirachtin and 22,23-dihydro-23)ff-methoxyazadirachtin. Tetrahedron Lett 26 6435-6438... 

Zanno P, Miura I, Nakanishi K, Elder D L 1975 Structure of the insect phagorepellent azadirachtin. Application of PRFT/CWD carbon-13 nuclear magnetic resonance. J Am Chem Soc 97 1975-1977... 

Azadirachtin was first isolated as a potent antifeedant against the desert locust by Morgan (24) who also elucidated partid structures (25). A structure was proposed in 1975 by us (Zanno et al.. Figure 8) which was subsequently revised by Kraus (26), Ley (27) and later ourselves 28), Azadirachtin, isolated from the Indian neem tree... 

The most highly oxidized limonoids in neem are modified in both the C and D rings. Azadirachtin, 15, (25, 2d), the most studied member of this structural class, contains 16 oxygen atoms and has 16 chiral centers. In addition to their own unique structural modifications, members of the class have side-chain substitutions similar to those observed in compounds already discussed. Other representative examples of this class are shown in Figure 6 25-27), These compounds, although found in various plant tissues, are predominantly in the neem kernel. Azadirachtin is the most... 

The molecular structure of azadirachtin has been firmly established as 15 by numerous studies. An initially proposed structure (49) of this highly oxidized tetranortriterpenoid was subsequently revised to 15 on the basis of much high-resolution NMR spectroscopic data (see, for example, 40, 50, 58). 

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