Natural Products in Crop Protection

BIOLOGICALLY ACTIVE AGENTS IN NATURE 29 CHIMIA 52 (1998) Nr. 112(JunuarIFcbruur)

Chimia 52 (/998) 29-47 lead structures for the synthesis of opti- © Neue Schweizerische Chemische Gesellschaft mized marketable analogues or as com- ISSN 0009-4293 mercial products per se. Also valuable is the discovery of new natural products Natural Products which operate with novel modes of action. These findings can be used to set up novel in Crop Protection mechanism-based bioassays for the detection of novel lead structures. J. Paul Pachlatko* Whereas synthetic chemicals are being tested as single compounds, natural products start out as crude extracts from Abstract. Nature is a rich source of products with interesting and useful biological organisms. These extracts represent large activity. In the field of crop protection, natural products and analogues have success- libraries of chemically diverse structures fully been introduced to the market to control insect pests, plant diseases, and weeds. of unknown concentration. Very often, The search for new natural products with promising activity continues in academia and the biologically active natural products in industry to initiate and to foster novel, ecologically and economically sound crop- are minor or even trace components. To be protection solutions. able to run a natural products screening efficiently, it is important that the screening tests are sensitive, have a high through- Introduction analogues is considerable. It is estimated put capacity, use small amounts of test that today the total market share of natural sample, allow a simple test sample prepa- The protection of crop plants from products including their analogues is ca. ration, and give fast results. competing plants, insects, and diseases 10%, with a tendency to increase as new has been an issue ever since agriculture products will be entering the market. How- Identification of Novel Leads developed. Whereas in the early days ever, natural products should not be seen Fast detection and identification of manual labour was used to solve the weed as an alternative to synthetic chemicals, novel active extract components is the problem, the manual control of insect in- but as a complement, as a source of chem- primary goal of the natural products chem- festations was in most cases an impossible ical structures from nature's evolutionary ist. It is therefore of utmost importance task. Plant diseases were even more diffi- playground, the secondary metabolism [4]. that known natural products are recog- cult to understand and to take measures The structures of natural products gener- nized and eliminated in the deconvolution against. The first generation of crop-pro- ally show little overlap with those of syn- process as early as possible. This can be tection products consisted of inorganic thetic chemicals, while often being more achieved with an efficient dereplication arsenic, sulfur, copper, and mercury com- complex than the latter. With regard to system. State-of-the-art systems consist pounds. In the first half of the 19th centu- toxicity, natural products have to be exam- of HPLC with UV diode array and mass ry, extracts from Pyrethrum flowers made ined with the same scrutiny as synthetic detection coupled with on-line data analy- their debut as household insecticides [2], chemicals [5]. However, mechanisms for sis and databases. HPLC-NMR is emerg- and shortly after, the application of nico- biodegradation by soil microorganisms ing as a valuable additional tool. If the tine-containing insecticidal tabacco ex- and reintegration into the environment active components seem to be novel, a tracts marked the first use of an organic already exist for natural products, so no bioassay-guided extract deconvolution is pesticide in crop protection [3].After 1930, long-term accumulation effects are to be carried out using efficient chromatographic a broad search for new organic crop-pro- expected. techniques. The structures of the isolated tection agents began in industry by screen- pure natural products are then determined ing synthetic chemicals and to a lesser with spectroscopic methods, mainly with extent natural products. It was the start of Screening for Biologically Active NMR and mass spectrometry. an unprecedented success story, in which Natural Products industry learned to understand more and Sources of Biologically Active Natural more the delicate and complex interplay in In contrast to a pharma primary screen Products ecology and to use this knowledge for the which for obvious reasons cannot test on Is there a best source for new biologi- development of safe and ecologically the actual target, but has to rely on mech- cally active natural products, and for crop- sound products for the control of weeds, anism-based assays, a primary screening protection indications in particular? This insects, and microbial plant pathogens. in crop protection can start in the 'clinic'. question is difficult to answer, even when Although the share of natural products Miniaturized agronomically relevant test using available statistical data. At Novar- in today' s crop-protection market is small, arrangements indicate activity based on tis Crop Protection, we tend to include in their impact as lead structures spawning all possible modes of action, known or not our screening as many different types of the synthesis of economically successful yet known. To find potent lead structures organisms as possible, unicellular and fil- at a reasonable rate, the search for new amentous bacteria, fungi, and also plants. crop-protection agents has to tap all sourc- The procaryotic actinomycetes with their es of chemicals, the ingenuity of the chem- active and highly variable secondary me- ists, and that of nature. Mechanism-based tabolism have been and still are an excel- assays used in parallel help to rank the lent source, and so are the myxobacteria. leads. Anaerobic organisms, yeasts and organ- *Correspondence: Dr. J.P. Pachlatko Novartis Crop Protection AG [1] The main goal of a natural product isms which do not allow a supply of gram R-1040.P.73 screen is to identify novel, biologically quantities of acti ve natural product for CH-4002 Basel active metabolites which serve either as extended biological evaluation, have so BIOLOGICALLY ACTIVE AGENTS IN NATURE 30

CHIMIA 52 (1998) Nr. 1/2 (Januar/Fcbruar) far been excluded. The same applies to tribute to the enormous efforts put into organisms which are exceedingly difficult synthesis and into studies of very complex to grow. structure-activity relationships would by I HX.H A~ ~ It is the task of the microbiologists to far exceed the size of a general review. R~O"L{~ contribute to the screening by providing Three recent reviews, excellently written microbiologically diverse and highly tal- by firsthand authors, cover this field in o ented strains. To comply with this require- detail [7-9]. In this summary, the practical 1 pyrethrin I R = CH ment, a serious effort has to be made in the results which emerged from the research 3 careful selection of the strain sources as programs in academia and in industry are 2 pyrethrin II R = COOCH3 well as in the development and application highlighted. Powdered heads of the flow- of strain isolation techniques, and of ade- ers of Tanacetum cinerariifolium (also quate cultivation methods. If microbiolo- known as Chrysanthemum c. or Pyrethrum gy has to feed a high-throughput screen- c.) or an extract thereof have long been ing, there is the latent danger, that number used and are still popular as household crunching will prevail over innovative insecticides. Of the six insecticidal com- strain isolation with the result, that only a ponents of pyrethrum extract, 1is mainly ~O~ fraction of the potential source will actual- responsible for kill, whereas 2 exerts main- o ly be tapped. ly knockdown activity. The insecticidal metabolites in pyrethrum are all unstable 3 allethrin USDA when exposed to light and air. Therefore, Development and Production these natural products are not suited for agricultural application. The pioneering The relatively low market value of work by Staudinger and Ruzicka, carried ~O'.~ agricultural products sets a limit to the out during 1910-16 [10], led to the correct final price of a crop-protection agent. Treat- structural assignment of the acid part of 1, o ment costs of25-50 USD/ha are typical. If trans-( IR)-chrysanthemic acid and of 2, 4 bioallethrin USDA an application rate of 250 g ai/ha is as- trans-(1R)-pyrethric acid. The same au- sumed, this would amount to a price of thors also synthesized a number of ana- 100-200 USD/kg active ingredient (= ai). logues of the natural esters by varying Needless to say that the actual production both the acid and alcohol parts. They no- costs will have to be lower [6]. An impor- ticed, that both the acid and the alcohol tant criterion for commercialization is the part can be replaced by structural mimics ratio of biological activity to production with retention of some insecticidal activi- 5 tetramethrin Sumitomo costs. The task of natural product research ty [10], although none of the active ana- is therefore twofold, to identify novel nat- logues came close to the activity of the ural products which can be used as lead natural products. Nevertheless, this early o ~ II structures for an economical synthesis of work was a valuable source for future research which aimed at highly active, highly active analogues, and to detect those ~O ~ Ib natural products whose high intrinsic ac- photostable pyrethroids. The topic was o tivity allows production via a more elabo- picked up at the US Department of Agri- rate chemical or biological process. culture and at the Rothamstead Experi- 6 resmethrin Rothamstead mental Station in the UK. Then Sumitomo and Roussel-Ucla! joined in, while other Commercial Successes and Interesting companies followed later. Leads The first effort concentrated on replac- ing (S)-pyrethrolone, the photolabile alco- Insecticides hol part of 1and 2. Allethrin (3), which is ~O~ The worldwide efforts in the search for structurally closely related to pyrethrin I o natural products and analogues for the (1), was the first synthetic pyrethroid to 7 bioresmethrin Rothamstead crop-protection market have been remark- reach the market [11 ][12]. Its most active ably successful, foremost in the field of isomer, (S)-bioallethrin (4), was later com- insect control. It is interesting to note, that mercialized by Roussel-Ucla! In Sumito- in this indication higher plants contributed mo's tetramethrin (5), the natural pyre- significantly to this success as sources for throlone is replaced by a much simpler highly active agents. isosteric substructure [13]. A major achievement was the synthesis of res- 8 phenothrin Sumitomo Pyrethroids methrin (6) and bioresmethrin (7) which The pyrethroids are a prime example had a distinctly higher insecticidal acti vity how a biologically active natural product than the natural pyrethrins [14]. Despite served as a template for the creation of their high activity, bioresmethrin (7) and economically and ecologically sound hy- also phenothrin (8) are by an order of giene and crop-protection insecticides by magnitude less toxic towards mammals chemical synthesis. To adequately sum- than the natural product [15]. The intro- 9 cyphenothrin Sumitomo marize this fascinating topic and to pay duction ofthe 3-phenoxybenzyl ester in 8 BIOLOGICALLY ACTIVE AGENTS IN NATURE 31

CHI MIA 52 (1998) Nr. 1/2 (Januar/Fcbruar) and of an additional a-cyano group in cyphenothrin (9) by chemists at Sumitomo [16] [17] marked a very important step towards future development of photostable 'HHyOl~ CF ~ 0 ~ oA)l pyrethroids. Until that point, however, 3~ these synthetic pyrethroids 3-9 were still 10 fenvalerate Sumitomo o CN too photolabile to be used in crop protec- (racemate) tion, but they found use as hygiene and 17 A.-cyhalothrin ICI (now Zeneca) household insecticides. Now that excellent replacements for the labile pyrethrolone were at hand, the focus in the search for photostable pyre- 11 esfenvalerate Sumitomo IH H ~;1 throids shifted towards improving the acid CF ~ 0 ~ F 3~ part. The Sumitomo research group made ro (YBr o F another breakthrough, when they found F ';::, o~o~ (racemate) that chrysanthemic acid can be replaced .--l I ~ 0 CN by a-substituted phenylacetic acids. Fol- F 0 m 18 tefluthrin Zeneca lowing up on this finding, the Sumitomo 12 ZXI 8901 Shanghai Zhong-Xi group synthesized fen valerate (10), the first truly photostable pyrethroid which appeared on the market [18]. The most ?I active enantiomerically pure isomer is also X 0 0 CI CIyO JJ CI~O~O~ o :::,...I :::,... I marketed under the common name esfen- ~ 0 o valerate (11) [19]. Recently, researchers l 1 h 0 CN of1! from Shanghai Zhong-Xi Pharmaceuti- 13 permethrin Rothamstead cals presented a new fen valerate analogue, 19 cycloprothrin CSIRO, Allstralia ZXI 8901 (12), a broad-spectrum insecticide/acaricide with much improved mam- I :::,... 0 ~ ~ CI PI~10 CF Y malian, fish, and bee toxicology [20]. ~ 3y:::,...1 "1(' ayOJJ:::,...1 :::,...1 o CN N 0 Already in 1958, a Czech research H CI 0 CN group had found that replacement of the 3- 14 cypermethrin Rothamstead (dimethyl vinyl) side chain in the chrysan- 20 't-tluvalinate Sandoz [1] themic-acid part of trans-allethrin by 3- (dichlorovinyl) did not cause loss of activ- ~rHHPI0 ~ ~ ~ ity [21]. More than ten years later, this Br 0 ~ o CN replacement was studied in more detail by Elliot's Rothamstead group. This led to IS deltamethrin Rothamstead another breakthrough in the discovery of photostable pyrethroids [22], to permethrin 21 etofenprox (13), cypermethrin (14), and to delta- I :::,... 0yCCIF0~ ~ methrin (15) [23], one of the most active CI 0 Mitsui Toatsu ~ insecticides, which is applied in crop pro- o eN tection at rates of only 2.5-12.5 g/ha [24]. 16 cytluthrin Bayer ~F 0TF It is interesting to note, that the cis- (lR, 'a'S)-isomers of the products 14-17 c:X)'x~o~ exert the highest activity of all possible programs. 'l'-Fluvalinate (20) is virtually isomers. Ofthis structural class, only 15 is nontoxic to honeybees, so that it is also being produced as a single enantiomer. used to control the bee parasite mite, Var- 22 CyfIuthrin (16) [25] and ?-cyhalothrin (17) roa jacobsoni [31 ][32]. Zeneca [26] are two examples of developments A major discovery in the field of pyre- based on the structure of cypermethrin throids was made by scientists of Mitsui The pyrethroids in general and the (14). All these products are highly active Toatsu, when they found the non-ester photostable representatives in particular broad-spectrum insecticides and acaricides pyrethroids [33]. Etofenprox (21), which were very well received by the market. In which are used in many crops, with cotton has excellent safety features for mammals 1996, the total market volume of pyre- being the largest market. TefIuthrin (18) is and fish [34], was the first representative throids was 1.61 billion USD, with fen va- the first pyrethroid which was especially of this class to be commercialized in 1987. lerate (10), esfenvalerate (11), cyper- developed for the use in soil [27][28]. The structure of 21 has little resemblance methrin (14), deItamethrin (15), cyfIuthrin Two commercial pyrethroids which to that of the pyrethrins 1 and 2, and yet it (16), and ?-cyhalothrin (17) being the can be structurally placed in the vicinity of is the result of a consequent activity-guid- best-sellers [28]. fenvalerate are cycloprothrin (19), with an ed abstraction of the structure of the natu- The mode of action of the pyrethroids extremly low toxicity to mammals and ral products. The same applies to the imi- has been intensively studied. Interference fish [29][30], and 'l'-fIuvalinate (20), an date 22, a member of a new class of pyre- with some of the sodium-ion channels in excellent insecticide and acaricide, which throids recently described by Zeneca re- nerve membranes leads to prolonged chan- fits well into integrated pest management searchers [35]. nel opening. This causes a blockage of the BIOLOGICALL Y ACTIVE AGENTS IN NATURE 32

CHIMIA 52 (1998) Nr. 1/2 (Jo"unr/Fehruar) nerve signal which eventually results in tenpyram (26) [46]. Acetamiprid (27) [47], and pharaoh ants [59]. Due to their insta- the death of insects and mites [36-38]. which was developed by Nippon Soda bility under field conditions, these two against sucking insects, is also active products are not suitable for crop protec- Nicotine and Neonicotinoids against certain lepidoptera, like Plutella tion. In the research laboratories of Ciba- The alkaloid nicotine (23) has long xylostella. Compounds 24-27 all act by Geigy [1] and of Maag [1], independent been used in crop protection as a natural binding to nicotinic acetylcholine recep- efforts were made to overcome the inher- insecticide in the form of aqueous tabacco tors [48][49]. One can expect that the ent instability of the juvenile hormones extracts [3]. Nicotine (23) acts as an ace- neonicotinoids will establish themselves and their close analogues. Further abstrac- tylcholine receptor agonist and is highly as an important new class of safe insecti- tion of the juvenile-hormone structure toxic, also to mammals. Industry has strug- cides, and it is very likely that more prod- through introduction of a 4-phenoxyphe- gled long to make use of this potent tem- ucts of this class will appear on the market. noxy group as in 36 and 37 greatly contrib- plate and to create structurally related nic- Compounds 28, 29 [50], and 30 [51] are uted to the solution of the problem. Both otinoids which have the same mode of promising lead structures, the latter of action, but which are specifically active which shows aninteresting biological spec- against insects. This task turned out to be trum of activity which includes lepidopter- not an easy one [39]. It was only after Shell an pests. 0""'" researchers had published [40] the high insecticidal potential of nithiazin (24), that Juvenile-Hormone Mimics 31 juvenilehormoneI researchers of Nihon Bayer, building on Due to observed effects on the devel- this information, were able to create insec- opment of insects, the existence of juve- 0 ticidal analogues of 24 which can also be nile hormones was postulated by biolo- regarded as analogues of nicotine (23) gists [52] some time before they were 0""'" [41]. Imidacloprid (25), the first commer- isolated and their structures elucidated cial neonicotinoid [42], emerged from this [53-55]. The juvenile hormones form a 32 juvenilehormoneII program in 1984 [43-45]. This new sys- family of closely related compounds of temic insecticide was developed by Bayer which 31-33 are the main representatives. and put on the market in 1991 for the Whereas lepidoptera synthesize all three treatment against sucking insect pests. hormones 31-33, other insects seem to Aiming at the same target, Takeda fol- rely just on 33 [56]. Juvenile hormones "'~o""'" lowed in 1995 with the neonicotinoid ni- playa crucial role in the regulation of the o molting and metamorphosis processes. 33 juvenile hormone III Their presence or absence in the insect hemolymph during the molt determines, if a larger juvenile state is formed or if con- 0 eNN version to the fertile adult state is initiated. oj Fertile adults are produced only if the 23 nicotine 24 nithiazin (Shell) concentration of juvenile hormone drops 34 hydroprene to almost zero before the last molt [57]. Application of juvenile-hormone-active compounds to an insect population essen- 0 tially prevents the formation of viable ~ o~ adults. When the structures of thejuvenile 2S imidacloprid 26 nitenpyram hormones became known around 1970, 35 methoprene Bayer Takeda Zoecon's [1]research group pioneered the N~CN industrial search for insecticides with ju-

~N~ venile-hormone activity. Much ofthis work ~ •.) I is described in an excellent review by CI N Henrick [58]. Zoecon [1] developed hy- 27 acetamiprid droprene (34) for indoor cockroach con- Nippon Soda trol and methoprene (35) for the control of mosquitoes in still waters, horn flies, fleas,

o NJ6 37 fenoxycarb I I I ..-:; R 1 R2 CIfNf

R::; H. alkyl R,. R2 = H, alkyl o~D I ION 28 lead structure 29 lead structure 30 lead structure QbObO Novartis Navartis Nihon-Bayer 38 pyriproxyfen BIOLOGICALLY ACTIVE AGENTS IN NATURE 33

CHIMIA 52 (1998) Nr. 1/2 (Januar/Fcbrunr)

'N/ 'N/ 0 (j 5-5 0y5 SyO R3

NH2 NH2

39 nereistoxin 40 cartap Takeda R,

milbemycins R, Rz R3 in development or marketed b ~ 43 milbemectin H, (3-0H H,H CH3:CH2CH3= 7:3 Sankyo S...... 5 5 44 LL-F 28249 = H, (3-0H H, u-OH (Z)-C(CH3)=CH-CH(CH3h American Cyanamid nemadectin

41 bensultap 42 thiocyc1am derivatives R, Rz R3 in development or Takeda Sandoz [I] marketed b 45 milbemycin =NOH H,H CH3:CH2CH3= 7:3 Sankyo, Novartis oxime 46 moxidectin H,(3-0H =NOCH3 (Z)-C(CH3)=CH-CH(CH3h American Cyanamid 36 [60] and 37 [61] are excellentjuvenoid insecticides. The latter was developed by Maag [1] for the control of lepidopteran pests in orchards and vineyards as well as / / for a variety of other applications includ- ° 0 ing the control offire ants [61]. Pyriproxy- fen (38), another stable j uvenoid, was sub- =r?--op--o--- "~ sequently developed by Sumitomo [62] I for the control of public health and agricultural insect pests. Due to their specific I mode of action, all the juvenoid insecticides show extremely low toxicity to mammals and vertebrates in general [63]. avennectins R, Rz R3 X in development or Nereistoxin Analogues marketed b The observation that feeding on dis- 47 abamectin- (R)- Bu OH H CH=CH Merck, Novar/is eased marine worms Lumbriconereis het- avermectin Bla eropoda is lethal to flies led to the isola- 48 doramectin Cyclohexyl OH H CH=CH Pfizer tion and identification of a new insecticidal natural product, nereistoxin (39) [64- X 66]. The natural product and a large num- derivatives R, R2 R3 in development or marketed b ber of analogues were synthesized and 49 ivermectin (R)- Bu OH H CHrCH2 Merck checked for insecticidal activity [67] [68]. It was found, that only those compounds 50 emamectin (R)-'Bu H NHCH3 CH=CH Novar/is were active which could revert to the natural product 39 after uptake by insects. Two such products were developed for the Milbemycins/ Avermectins milbemycins 44 with an unsaturated side market by Takeda against coleopteran and No other family of natural products has chain at C(25) was isolated at American lepidopteran pests, namely cartap (40) [69], had a comparable impact in the field of Cyanamid from a culture of Streptomyces a broad-spectrum insecticide with good animal health as agents against worms, cyanogriseus [81]. In the same year, re- activity against the rice stem borer [70], ticks, and flies like the milbemycins 43- searchers from Glaxo described the same and bensultap (41) [68] for the control of 46 and the closely related avermectins 47- compounds as metabolites of Streptomy- the Colorado beetle and other insect pests 50 [75-78]. The family of milbemycins ces thermoarchaensis [82]. [71]. Sandoz [I] developed the nereistox- was detected in 1972 by researchers of In an in vivo screening fornatural prod- in analogue thiocyclam (42) [72] for the Sankyo in the culture broth of a strain of ucts with anthelmintic activity, reseachers control of a broad spectrum of coleoptera Streptomyces hygroscopicus [79]. It was at Merck [83] found the avermectins in and lepidoptera pests in several crops [73]. the broad acaricidal and insecticidal acti v- 1976 in the culture filtrate of a strain of The mammalian toxicity of the prodrugs ity of this group of compounds which was Streptomyces avermitilis which had been is lower than that of the natural product. recognized by the discoverers. The struc- supplied by the Kitasato Institute in Japan. Nereistoxin (39) acts on nicotinic acetyl- tures of the milbemycins were also deter- The structures of the avermectins were choline receptors, as partial agonist at low mined at Sankyo [80], with X-ray diffrac- elucidated by the Merck researchers using concentration and as channel blocker at tion analysis and other spectroscopic meth- spectroscopic methods and Sankyo's mil- higher concentration [74]. ods. In 1984, the LL-F 28249 group of bemycin X-ray data [84]. The first total BIOLOGICALLY ACTIVE AGENTS IN NATURE 34

CHIMIA 52 (1998) Nr. 1/2 (JanuarlFebmur)

synthesis of avermectin B la (47) was re- channel opening [88][89]. A number of Spinosyns ported in 1986 by Hanessian and cowork- total syntheses of simpler analogues of the The spinosyns, a new class of highly ers [85-87]. The extensive literature on natural products were undertaken with the active natural insecticides, were discov- this topic has been reviewed in detail [75] hope to get access to constructs containing ered in 1989 by researchers at Eli Lilly [76]. the pharmacophore which would be bio- [103]. From a culture of the actinomycete Avermectins and milbemycins have logically active, but more economical to Saccharopolyspora spinosa, they isolated the same mode of action, they potentiate prepare. None of these attempts led to a spinosyn A (55) and D (56) as well as 21 glutamate- and GABA-gated chloride- compound with high activity [77]. On the minor analogues [104][105]. The struc- other hand, the search for derivatives of ture elucidation of all these components the natural products with improved bio- was carried out by the same research group, logical properties such as 45, 46, 49, and mainly with NMR and X-ray diffraction 50, turned out to be very successful. The analysis [104]. The mode of action of the prime example is ivermectin (49), today a spinosyns is reported to be novel [106], standard tool against animal parasites, with with no cross-resistance to known insecti- CI worldwide sales in 1995 of an estimated cides. Spinosyns cause excitation of mo- 665 million USD [77]. Researchers from tor neurons. A persistent activation ofnic- 0 0 Pfizer showed that directed biosynthesis otinic acetylcholine receptors with a pro- 51 dioxapyrrolomycin is a very interesting way to get to new, longed acetylcholine response by a yet highly active avermectins as, e.g., dora- unknown mechanism isobserved. The total EWR X, mectin (48) [90-92]. synthesis of 55 has been accomplished by In crop protection, abamectin (47) and Evans and Black [107]. Spinosad (57), a X 7' \ 2 milbemectin (43) are being marketed as mixture of spinosyn A (55) (85%) and D HN I ~ X acaricides. Abamectin (47) also finds ap- (56) (15%), is being produced via fermen- %~ J plication against insects like leaf miners tation and was introduced to the market by and certain lepidoptera. Its market volume DowElanco in 1997 for the control of CN, N02• S02CFJ in 1996 was 160 million USD [93]. Ema- lepidoptera pests in cotton [106]. CI, Sr, CFJ mectin (50) [94], which was discovered 52 by Merck chemists, will be introduced to Bacillus thuringiensis the market by Novartis as an efficient Bacillus thuringiensis has been known

CN sr insecticide against lepidoptera. as an insect pathogen for almost a century [108][] 09]. The major insecticidal princi- CF If \ 3 Dioxapyrrolomycin Analogues ple is the protein 8-endotoxin. During ~ I ~ In 1987, researchers of American Cy- sporulation, Bacillus thuringiensis forms ~ CI anamidreported the isolation of dioxapyr- crystalline parasporal inclusion bodies % rolomycin (51) from a strain of Strepto- which contain 8-endotoxin, either free or 53 myces fumanus and described its insecti- as part of a larger protein. After uptake by

CN sr cidal activity [95][96]. Independently and feeding, the parasporal bodies dissolve in at about the same time, two other groups at the insect gut and 8-endotoxin is liberated. CF 3 1 \ Meiji Seika [97] and at SS Pharmaceutical It then docks onto epithelial cells and N I ~ [98] discovered the same Streptomyces causes them to swell and burst which leads 0.J ~ metabolite due to its antimicrobial activi- to the death of the insect. Today, several .-1fuCI ty. Despite the relatively high toxicity of different strain types are known with ac- 51, the Cyanamid researchers undertook tivityeither againstlepidoptera and diptera, 54 chlorfenapyr the difficult task of creating less toxic against diptera alone, or against coleoptera. analogues with improved insecticidal ac- The size of the active 8-endotoxin is in the American Cyanamid tivity. By simplifying the structure of the range of 60-70 kDa, depending on the lead compound, they found that members bacteria] strain and its spectrum of activity of the 2-aryl-pyrrole group 52 had excel- [110][] 11]. Due to its highly insect-spe- lent activity, with compound 53 having cific mode of action, 8-endotoxin is not I the highest potential [96][99]. However, toxic to other living organisms [109]. Its /N~ 53 and others of this group showed intol- first use as an insecticide was reported in .··l....0)9 0 erable phytotoxicity [100]. This problem 1938 [112], and commercialization start- , was overcome by converting 53 into the ed in 1957 [113]. Today insecticidal prod- prodrug 54 [101] which is metabolized by ucts based on BT 8-endotoxin are being insects back to the active compound 53. produced and marketed by Abbott, Caffa- Chlorfenapyr (54) is a potent insecticide ro, Ecogen, Mycogen, and Thermo Trilo- and less toxic than 51. It has been devel- gy. In 1996, the market volume of Bacillus oped by American Cyanamid for a variety thuringiensis products worldwide was 160 spinosyn R of crops [100]. Dioxapyrrolomycin (51) million USD [114]. Recently, the gene for and 53 are both uncouplers of the oxida- Bacillus thuringiensis 8-endotoxin has 55 A H tive phosphorylation in mitochondria, been used to create transgenic crop plants 56 D whereas the prodrug 54 does not show any which express 8-endotoxin and thus be- such activity [102], as long as it is not come insect-resistant. Such insect-resis- 57 spinosad H:CHJ = 85:15 converted back to 53. tant maize was introduced to the market by BIOLOGICALLY ACTIVE AGENTS IN NATURE 35 CHIMIA 52 (1998) Nr. 1/2 (Janu,uiFcbruar)

Novartis [115], and Monsanto is commer- were commercially available from S.B. cializing insect-resistant transgenic cot- Penick & Co. [139], but the product never ton [116]. found wide application.

AzadirachtiniNeem Pheromones Seed kernels from the neem tree, Aza- Insect sex pheromones are being used dirachta indica (Meliaceae), contain a to control insect pests mainly in three cocktail of insecticidalli monoids, ofwhich ways. The mating disruption technique azadirachtin (58) is the most active [117- uses the pheromone to confuse the attract- 119].The elucidation of itsstructure proved ed partner such that it does not find its way 58 azadirachtin to be difficult and was finally achieved by to a mate. A disadvantage of this approach Kraus and coworkers in 1985 [120]. The is that relatively large amounts of expen- total synthesis, an even more demanding sive pheromone are needed. The second task, is being tackled by Ley and cowork- method uses physical traps to which the ers [121]. Azadirachtin (58) has a com- insects are lured by the pheromone. Exam- plex mode of action. It is a strong feeding ples are the bark-beetle traps in European deterrent, but causes also metamorphosis forests. In attract and kill, as the third disorders by interference with ecdysteroid method is called, small viscous droplets of synthesis and action [122] [123]. Further- a slow release formulation, which con- 59 rotenone more, 58 seems to be specifically toxic to tains both a pheromone and a contact insect cells [124]. Insecticides prepared insecticide, are placed with a special ap- OH OH OH from neem kernels have long been used in plication tool on cotton leafs for instance, HO HO India [125]. In the USA, two neem insec- or on non-vegetative parts of fruit trees. ticides were developed, Azatin® by Agri- Attracted by the pheromone, the insects 0~ 0 Dyne [126] and Margosan O® by W.R. fly to a droplet. Upon touching it, they HO Grace & Co. [127]. Both products are pick up a tiny but lethal amount of insec- 60 extracts enriched in azadirachtin (58) and ticide, and mating never happens. Com- ~ NH contain several other limonoids [119] mercial products based on this ecological- which add to the activity and reduce the ly sound approach have been developed 60 ryanodine risk that resistance develops. by Novartis [140][141]: SfREN£® PBW for the control of the pink bollworm Pec- OH OH OH Rotenone and Ryania tinophora gossypiella in cotton using the HO HO Preparations from several plant spe- pheromone gossyplure (62), and SIREN£® cies of the genus Derris, Lonchocarpus CM for the control of the codling moth o ~ OH (Leguminosae), and of a number of other Cydia pomonella in apples with the pher- HO closely related genera have long been used omone codlemone (63). Permethrin (13) in Asia as fish poisons and insecticides and cypermethrin (14) function as the con- 61 ryanodol [128]. The active principle was isolated tact insecticides. around 1900 by Geoffrey [129] and by Nagai [130], who called it 59. The eluci- Tetranactin dation of the structure was accomplished The macrotetrolide tetranactin (64) was AcO by USDA researchers, LaForge et al., in discovered by scientists of Chugai Phar-

1933 [131]. The synthesis and biosynthe- maceuticals who isolated it as the main AcO sis of rotenone (59) has been reviewed by insecticidal component from a culture of Crombie [132]. It acts as a mitochondrial Streptomyces aureus S-3466 [142][143]. complex-l respiration inhibitor. Roten- The same research group reported the ex- 1 : 1 one (59) is being commercially used as a cellent acaricidal activity of 64 against broad-spectrum insecticide in the fruit and Tetranychus cinnabarinus and other mites, 62 gossyplure vegetable market as well as for the control and the low toxicity to mammals [144] of fire ants. [145]. Its total synthesis was achieved by h The insecticidal activity of powdered Schmidt and Werner [146]. Tetranactin HO parts of the plant Ryania speciosa was first (64) had no major impact in the crop- 10 described in 1945 [133]. It could be shown protection market, possibly due to the fact, that ryanodine (60) is the main active that it is predominantly an adulticide and 63 codlemone constituent [134][135]. The elucidation of has no effect on eggs. the structure turned out to be a demanding problem which was solved by Wiesner \H. /"11 ~OH H and coworkers [136]. The synthesis of the "" ~ . o ~ 0 0: 0 hydrolysis product ryanodol (61) was o ' , 0 achieved by Deslongchamps and cowork- :o~O ers [137]. Ryanodine (60) interferes with I , "" ~ H H 0 ~H H .• calcium channels in the sarcoplasmic retic- ulum, causing a lethal influx of calcium 64 tetranactin into the cells [138]. Ryania preparations BIOLOGICALLY ACTIVE AGENTS IN NATURE 36

CHIMIA 52 (1998) Nr. 1/2 (JanuarlFebruar)

insecticidal, especially when applied as a mixture [151]. Attempts to improve the ~~~ insecticidal activity and to enhance the 65 pellitorine stability by synthesis of analogues were 0 successful. It is interesting to note that the 0 (2E, 4E)-dienamide structural motif seems to be necessary for insecticidal activity, as < ~~ 0 66 pipercide all efforts to replace it led to inactive compounds [155]. The analogues 69-72 are all very active insecticides, compara- 0 ble with the first generation pyrethroids, and thus much more active than the natu- <0 ~~ 67 dihydropipercide rallead compounds. They exhibit activity 0 against the adzuki-bean weevil, the rice stem borer, the mustard beetle, and the 0 < housefly. However, none was found suit- 0 ~~ 68 gUlneensme able for commercial development. More 0 research is necessary to improve the level and the spectrum of activity as well as the stability for the use under practical conditions [155]. The mode of action of the dienamides is particularly interesting. They are reported to interfere with some of the 69 Sumitomo [152] sodium-ion channels in nerve membranes in a similar manner to the pyrethroids, but when dienamides were tested on pyrethroid-resistant houseflies, no cross-resistance was observed [156]. 70 Wellcome Foundation [153]

Nikkomycins The fungicidal and acaricidal nikkomycins were detected and isolated in 1972 by Ziihner and coworkers as metabolites of Streptomyces tendae [157], with nikkomycin X (73) and Z (74) being the main 71 Rothamstead [154] members of this group. The elucidation of the structures was accomplished in collab- oration with Hagenmaier and Konig et al. [158]. Researchers from Schering-PLough 72 Rothamstead [154] reported the synthesis of nikkomycin Z (74) [159]. Like the related polyoxins (see below), the nikkomycinsinhibitchitin synthase. They are active against spider mites also under field conditions and were therefore investigated by Bayer as a possible Dienamides acaricidal product [160]. Despite the good CHO The unsaturated lipophilic amide pel- field performance of a mixture of 73 and OH NH ..l litorine (65) was the first member of the 74, the project was dropped by Bayer, 2 ~.'COOH (' -NH large group of closely related natural prod- reportedly for cost reasons [161]. I ~ : H~O N-{O ucts of the plant families Compositae, d...,;N (' i0 HO H H Piperaceae, and Rutaceae to be isolated ThiangazoLe HO OH [147], characterized, and synthesized Due to its antiviral properties against [148][149]. Jacobson's review [150] cov- HIV-1, thiangazole (75) was detected and 73 nikkomycin X ers the history and the insecticidal proper- isolated by Hofle and coworkers from a o ties of a number of these metabolites. He culture of the myxobacterium PoLyangium also reported on the early synthesis work sp. P13007 [162]. The same group also OH NH ~ 2 'H COOH (( ;NH and the structure-activity relationships of determined the structure and the abolute I ~ : ~~- 0 N-{ synthetic pellitorine analogues. Pellito- configuration of7 5 [163]. The remarkable ...,;N ' 0 0 rine (65) and close analogues are all too insecticidal activity of 75 against HeLio- HOdY'r H H unstable for practical use as insecticides. this virescens and LuciLia sericata was HO OH Researchers from Sumitomo isolated from found at Ciba-Geigy [1][164]. To pave the 74 nikkomycin Z black pepper, Piper nigrum, the three way to possibly even more active thianga- isobutyl amides 66-68 which are more zole analogues, the total synthesis of 75 stable than pellitorine (65) and strongly was carried out enantioselecti vel y by Ciba- BIOLOGICALLY ACTIVE AGENTS IN NATURE 37 CHIMIA 52 (1998) Nr. 1/2 (Januar/Februar)

Geigy [1][165] chemists. The groups of insecticidal activity in greenhouse tests at Rocaglamide (79), a metabolite of the Pattenden and Heathcock published their Bayer [169], but a commercial develop- plant genus Aglaia (Meliaceae), was re- total syntheses of thiangazole almost si- ment was ruled out, the costly purification ported to exert insecticidal activity against multaneously [166] [167]. of 77 being one of the reasons [161]. The the variegated cutworm Peridroma sau- potential of annonaceous acetogenins as cia, the Asian armyworm Spodoptera Other Insecticidal Leads natural pesticides has been discussed in litura [172], and against the Egyptian cot- Quassin (76) and a number of closely detail by McLaughlin et al. [170]. ton leafworm Spodoptera littoralis, of a related compounds are insecticidal me- Haedoxan A (78), a sesquilignan iso- potency comparable with that of azadirach- tabolites of medium activity, occuring quite lated from the roots of the plant haedoku- tin (58) [173]. frequently in extracts of plants from the sou, Phryma leptostachya, is highly insec- An interesting approach to new insec- Simaroubaceae family. ticidal to houseflies and to lepidoptera, ticides was chosen by FMC chemists who Annonin I (77) [168], a member of a comparable with deltamethrin, when ap- used (X-terthienyl(80), a nematocidal and large family of metabolites from the tree plied together with piperonyl butoxide insecticidal plant metabolite of the Com- Annona squamosa, exhibited remarkable [171]. positae family as a template in the search for new insecticides. (X- Terthienyl (80) acts as a light-driven sensitizer converting triplet oxygen into reactive singlet oxygen [174][175]. F-5183 (81), which evolved Si R from this program, showed excellent anti- HI/, 0>r-f-/7rSrf:~....N ~ ...... N)LN mite activity in the field against Tetrany- chus urticae in cotton and against Phyllo- ° 75 thiangazole coptruta oleivora in orange orchards, at application rates of 30-225 g/ha [176]. The cyclophosphates 82 from Strepto- myces antibioticus Tii-1718 (=DSM 1951) ...... 0 [177][178] have been shown to be very o efficient inhibitors of acetylcholine es- ~(CH2)9 terase, with compound Tii-1718-P (R = propyl) being as effective on the enzyme \J1 and on insects as the commercial insecticide carbofuran [179]. However, this discovery came at a time, when no more 76 qua ssm 77 annonin I organic phosphates were developed for the insecticide market.

o I

0- 78 haedoxan A 79 rocaglamide

80 a.-terthienyl 81 F-5183

O\ .•.0 ....•• o p~ ~ 0 0 ~7H ~N.J:JHNH,

?; 2 o R H N('Y'N) H~0 OH OH 0 = , R CH3 propyl, i-propyl, butyl 82 cyclophosphates TO-1718 83 u\osantoin 84 diabroticin A BIOLOGICALLY ACTIVE AGENTS IN NATURE 38 CHIMIA 52 (1998) Nt. 1/2 (JununtIFebruut)

Another strong inhibitor of acetylcho- gens, protection of the crop plants with Pyricularia oryzae and bacterial Pseudo- line esterase with insecticidal activity on agrochemicals is necessary. With the ex- monas diseases in several crops [189]. cockroaches is ulosantoin (83), isolated ception of kasugamycin (85), which is from the marine sponge Ulosa ruetzleri mainly used as a fungicide (see below), Polyoxins [180]. the natural products and analogues which Polyoxin B (87) and D (88) were iso- The polar insecticidal diabroticin A have so far been developed for controlling lated as metabolites of Streptomyces ca- (84) is produced by Bacillus suhtilis and bacterial plant pathogens are based on the caoi var. asoensis in 1965 by Suzuki and B. cereus. It is highly active against the same modes of action as some of the coworkers [190] as a new class of natural southern corn rootworm Diahrotica un- antibiotics used in medicine. For the con- fungicides. The structures were determined decimpunctata, with an LDso of 2-4 ppm trol of bacterial plant diseases, antibiotics by the same group [191][192]. The mode when incorporated in the diet [181]. like streptomycin and oxytetracyclin are of action of the polyoxins makes them being used in some countries. There is a very acceptable with regard to environ- Fungicides and Bactericides concern, however, that their application in mental considerations. They interfere with To prevent economically unacceptable the environment might cause natural re- the fungal cell-wall synthesis by specifi- losses of yield and quality of agricultural sistance, rendering these antibiotics use- cally inhibiting chitin synthase [193]. Both crops caused by microbial plant patho- less for medical treatment. Compared with 87 and 88 are commercially produced via the economic losses entailed by bacterial fermentation. Polyoxin B (87) found ap- plant diseases, those caused by fungi are plication agai nst a number of fu ngal patho- much larger. The task to find novel bacte- gens in fruits, vegetables, and ornamen- COOH ricides suitable for crop protection turned tals, and polyoxin D (88) is marketed as Zn

A NH2CH3 out to be exceedingly difficult. In contrast, salt by several companies to control rice HN Wlt:$.P OH the search for useful antifungal natural sheath blight Rhizoctonia solani [194]. ~I~ products and analogues was very success- ~o~ ful. Validamycin OH The validamycin family was detected Blasticidin S by Takeda researchers in 1968 in a green- Japanese research has greatly contrib- house assay when screening streptomycete 85 kasugamycin uted to the discovery of new crop protec- extracts for activity against rice sheath tion agents of natural origin. Blasticidin S blight Rhizoctonia solani [195]. Takeda (86), a metabolite of Streptomyces griseo- commercialized 89 by developing a fer- chromogenes [182][183], was discovered mentation process with Streptomyces hy- in Japan in 1958 and found use in the groscopicusvar.limoneus. The same group control of rice blast Pyricularia oryzae. of antibiotics was discovered indepen- This highly active fungicide is applied at dently in China and given the name jing- 10-30 g ailha [184], but due to toxic and gangmycins [196]. The elucidation of the phytotoxic side effects, it has lost ground structure ofvalidamycin A (89) [197] and in the market to other better performing the total synthesis [198] were both achieved products like kasugamycin (85). by Ogawa and coworkers. Validamycin A (89) was found to be a prodrug which is Kasugamycin converted within the fungal cell to vali- Umezawa and coworkers [185] dis- doxylamine A (90), an extremly strong covered kasugamycin (85) as a bactericid- inhibitor of trehalase [199]. This mode of al and fungicidal metabolite of Streptomy- action gives validamycin A (89) a favor- ces kasugaensis. They also determined the able biological selectivity, because verte- structure of 85 [186] and accomplished brates do not depend on the hydrolysis of the total synthesis [187]. Kasugamycin the disaccharide trehalose.

87 R = CH20H polyoxin B (85) acts as an inhibitor of protein biosynthesis in microorganisms but not in mam- Pyrrolnitrin 88 R = COOH polyoxin D mals [188], and its toxicological proper- The biological activity of pyrrolnitrin ties are excellent [189]. Hokko Chem. Ind. (91) was first decribed in 1964 by Arima developed a fermentative production pro- and coworkers [200], who had isolated HO~H OH cess to market the systemically active ka- this antifungal antibiotic from Pseudomo- sugamycin (85) for the control of rice blast nas pyrrocinia. The same authors pub- HO]7;N-H OH O~H OH HO OH OH

89 validamycin A CI h ~ CI h ~ ifld\ ~ CI \ N °~ \ ~ H~ N02 N F-\-O N H H F H HO~HN:H ~OH

Htl Ur OH OH 91 pyrrolnitrin 92 fenpiclonil 93 fludioxonil

90 validoxylamine A Navar/is Navar/is BIOLOGICALLY ACTIVE AGENTS IN NATURE 39

CBlMIA 52 (1998) Nr. 1/2 (lanuar/Febru",)

Iished the structure in 1965 [201]. Pyrrol- tailed information consult the review by X~ nitrin (91) was subsequently synthesized Clough [220). The antifungal activity, es- by chemists at Fujisawa [202] as well as at pecially of strobilurin B (95), in vitro and y~ /O~COOCH 3 Ciba-Geigy [1][203). Although 91 shows in the greenhouse against plant pathogens 94 X = H, Y = H strobilurin A excellent activity in vitro and in the green- like Venturia inaequalis, Cercospora ara- house against the fungal plant pathogens chidicola, Plasmopara viticola, and Phy- 95 X = OCH3, Y = CI strobilurinB Botrytis cinerea and Pyricularia oryzae, tophthora infestans are excellent. Becker its performance in the field was disap- et al. [22]] showed, that the strobilurins pointing, because the natural product rap- strongly inhibit mitochondrial respiration. idly decomposed when exposed to sun- The substructure responsible for the bio- light. The cause of this photo instability logical activity is the ,B-methoxy acrylic was investigated by chemists at Ciba- ester, in short ,B-MAE. This acronym is &~~5~(,Geigy [1], with the aim of eliminating it often used to describe compounds having while conserving the biological activity. It this or a closely related toxophore. In field soon became apparent, that replacement tests, the natural strobilurins were a fail- 96 kresoxim methyl° BASF of the chioro substituent at the 3-position ure, due to their inherent photoinstability. of the pyrrole by a cyano group led to a The half-life of strobilurin A (94) in sim- remarkable enhancement in stability. Thus, ulated sunlight was determined to be only Ql)3,o~ the half-life offenpiclonil (92) in simulat- 12 s [222). Several industrial research ed sunlight is 48 h as compared with liz h groups took up the challenge to design CN /O~O •..•.. for its 3-chloro analogue [204). Finally, photostable analogues of the strobilurins the biological activity was optimized by with equal or even improved antifungal appropriate substitution on the phenyl ring activity. Compounds 96-98 are success- 97 azoxystrobin Zeneca° [204]. Two commercial products emerged ful strobilurin analogues which emerged from these efforts, fenpiclonil (92) [205] from these efforts. Highly active, and with and fludioxonil (93) [206], both excellent the same mode of action as the natural ~o ~ seed treatment agents against fungal patho- strobilurins, they all show a dramatically H gens like Fusarium g raminearum in maize improved photostabili ty. The analogue 96, ~XI/O'N/- N . and Gerlachia nivalis in wheat. Studies of e.g., has a half-life in simulated sunlight of the mode of action of these products and of more than 24 h [223]. BASF introduced 98 SSF 126 Shionogi° pyrrolnitrin concluded, that they inhibit a kresoxim methyl (96) to the market in protein kinase PK-III which is involved in 1996 as a broad-spectrum fungicide in the osmosensing signal transmission path- cereals, apples, and other crops. Zeneca way. It is suggested, that this inhibition recently launched sales of the broadly might lead to an increased concentration active azoxystrobin (97) in the cereal, fruit, of a non-phosphorylated regulatory pro- and vegetable markets [224]. SSF 126 tein, causing a deregulation of a osmo- (98) from Shionogi is expected to appear sensing mitogen-activated protein-kinase on the market, soon. During the search for cascade [207][208]. new fungicides, it was noted that certain strobilurin analogues also exhibit insecti- Strobilurins cidal activity, as, e.g., 99 from AgrEvo The antifungal antibiotic 94 was orig- [225]. inally isolated in 1967 by Musilek, Von- dracek, and coworkers from a culture of Mildiomycin the basidiomycete Oudemansiella mucida The isolation of the antifungal mildio- and given the name mucidin [209][210). mycin (100) from a culture of Streptover- Later, but independently, Anke, Steglich, ticillium rimofaciens was reported by Take- and coworkers isolated 94 and 95 from the da scientists in 1978 [226-228). Mildio- basidiomycete Strobilurus tenacellus [21]] mycin (100) is strongly active against sev- and called them strobilurin A (94) and B eral powdery mildews on various crops 100 mildiomycin (95). On the basis of spectral data, it be- [227][229], acting as an inhibitor of the came apparent that mucidin and strobil- fungal protein biosynthesis [230]. Its low urin A were identical. Both groups con- toxicity in vertebrates would make it an 9, R tributed to the elucidation of the structure environmentally sound crop-protection of the strobilurins which finally could be agent [227], but mildiomycin (100) never proven by synthesis to be (E,Z,E)-config- appeared on the market. Recent publica- urated [2]2]. This class of antifungal com- tions indicate however, that Takeda's ef- pounds is reported to be produced by sev- forts to develop mildiomycin (100) still eral basidiomycetes [213] [214]. At Ciba- continue [231]. Geigy [I], the strobilurins were also found as metabolites of an ascomycete, Bolinia Soraphen A 101 R CH : soraphen A = 3 lutea [215-2]7]. Several stereospecific Soraphen A (101) was discovered by 102 R = CH20CH2CH20CH3 syntheses of the strobilurins have been the research groups of Reichenbach and accomplished [212][218][219). For de- Hofle at GBF (= Gesellschaft fUrBiotech- BIOLOGICALLY ACTIVE AGENTS IN NATURE 40 CHIMIA 52 (1998) Nr. 1/2 (Jonuor/Februor) nologische Forschung mbH) [232][233]. tion program was initiated both at GBF phen A (101) also inhibits the mammalian In their screening of extracts from myxo- and at Ciba-Geigy [1] aiming at an im- enzyme. Due to difficulty of production bacteria, a sample from Sorangium cellu- provement of the already excellent activ- and a flaw in its toxicology profile, sor- losum strain So ce26 showed broad anti- ity ofl01, and a number of derivatives and aphen A (101) never reached the crop- fungal in vitro activity. The new metabo- structural fragments were prepared and protection market. lite soraphen A (101), which was mainly tested [236]. Natural analogues of 101 responsible for the activity, was isolated were isolated in small amounts at GBF Other Fungicidal Leads and fully characterized by NMR spectros- [237] during the preparation oflargerquan- Takeda researchers reported the isola- copy and X-ray crystallography [232]. The tities of soraphen A (101) for field and tion of the antibacterial fumaramidmycin total synthesis of 101 was achieved by toxicology testing. It soon became clear, (103) from Streptomyces kurssanovii Giese and coworkers [234]. Greenhouse that the excellent activity of 101 was dif- [240]. At Ciba-Geigy [1], the structurally tests at Ciba-Geigy [1] soon revealed the ficult to improve on. None of the natural related compound 104 was detected in a high potential of 101 as a plant-protection analogues was better. Most of the many culture of the fungus Sordariasp. F-21223, agent against fungal pathogens [235]. Field derivatives were weaker, but some ether due to its antifungal activity against Pyth- tests met the high hopes generated by the derivatives of the C(ll)-OH group like ium ultimum [241]. From the fungus Co- greenhouse results, and economical appli- 102 showed improved activity. However, niothyrium sp., Krohn and coworkers also cation rates seemed feasible. A derivatiza- this gain did not make up for the increased isolated 104 and called it coniothyriomy- production costs, and further development cin [242]. A number of analogues were was therefore focussed on the natural prod- prepared and tested at Ciba-Geigy [I] for uct soraphen A (101), both as a broad- activity againstoomycetes [243]. Although spectrum seed dressing agent and a fungi- improvements in activity were achieved, cide for foliar application. Mechanistic as in the case of compound 105 with an studies showed soraphen A (101) to be the ECso of 60 ppm against Phytophthora 103 fumaramidmycin first antifungal agent inhibiting acetyl- infestans and Plasmopara viticola and of CoA carboxylase (ACC) [238]. The corre- 106 with an ECso of 6 ppm against Pythi- o sponding enzyme in plants is known to be um ultimum, a competitive level of activ- the target of the aryloxyphenoxy-propi- ity was not reached. I ·OMe CI:crr~-If~~ Jl onate and the cyclohexanedione herbi- From Bacillus subtilis ATCC 6633, ~ 0 0 HO cides [239]. Soraphen A (101), however, Loeffler and coworkers isolated the fungi- has no effect on the ACC of plants and did cidal metabolites, identified them as the 104 fumarimid F-21223 not show phytotoxic effects in the field. Its peptides 107-109 and named them rhizoc- efficacy under practical conditions was tidns [244][245]. In greenhouse tests car- outstanding. As a seed treatment agent at ried out at Ciba-Geigy [1], it became ap- 0.3 g ai/kg seeds, it completely controlled parent that the rhizocticines control grey mildew Erysiphe graminis in barley and mold Botrytis cinerea on apples and vines. snow mold Gerlachia nivalis in rye. Full It could be shown after proteolytic diges- 105 control of apple scab Venturia inaequalis tion, that L-(Z)- 2-arnino-5-phosphonopent- on apples and grey mold Botrytis cinerea 3-enoic acid [246] was the actual active on grapes was achieved with 10-25 gail agent. The corresponding (3E)-compound hectoliter. Apart from fungal ACC, sora- did not show any activity. A mixture of rhizocticine A, B, and D (107-109) was tested in the field against grey mold Botry- tis cinerea on grapes. The result looked 106 promising, however, competing lead structures were given priority for further inves- o tigation. ~-OH Gliovirin (110), a natural fungicide NH2 0 ~ 'OH active against Pythium ultimum, was iso-

HN~~COOH lated from Gliocladium virens [247]. At ..•NH Ciba-Geigy [1], 110 was detected in a R culture of Aspergillus viridinutans F-4464 [241] and tested in the greenhouse against 107 R = H rhizocticine A oomycete pathogens. The good activity 108 R L-val rhizocticine B 111 14, 15~-epoxy-prieurianin = against Pythium ultimum reported earlier 109 R = L-Ieu rhizocticine 0 was confirmed under practical condi tions, when 110 was incorporated into soil at 10 ppm. In other tests and especially against other oomycetes, the performance of gliovirin (110) was insufficient. Many antifungal natural products have been isolated from higher plants. Howev- er, only very few were reported to be tested under practical conditions. The fol- II 0 gliovirin 112 valtrate lowing two compounds are examples of BIOLOGICALLY ACTIVE AGENTS IN NATURE 41

CHIMIA 52 (1998) Nr. 1/2 (Januar/Februar) plant metabolites which were actually active in agronomically relevant greenhouse 0 ~ tests. 14,15j3-Epoxy-prieurianin (111) was QjCOOH HO_~~o R first isolated by Lukacova and coworkers H C..... N 3 H from the bark of the South American tree N H NH2 0 Guarea guidona (Meliaceae) [248]. In the course of Ciba-Geigy's [1] screening of 115 R = L-ala bilanaphos plant extracts for biological activity rele- 113 3-indolyl acetic acid vant to crop protection, a bark extract from o II Pseudocarapa championii (Meliaceae) HO-P COOH from Sri Lanka showed promising activity COOR H3C ..... ~ against the grey mold Botrytis cinerea on CI--r\-r~ 0 NH2 apples and beans [249]. Isolation of the CI active ingredient yielded 111, which con- 116 phosphinothricin trolled grey mold at an EC80 of 60 ppm in R = H, alkyl the greenhouse. Under field conditions its 117 R = L-Ieu phosalacine 114 2,4-D performance did not reach that level. 118 R = L-ala-L-ala trialaphos Valtrate (112) isolated from the plant Valeriana capense (Valerianaceae) by Hostettmann and coworkers [250],showed anti-mildew activity in the greenhouse of AgrEvo) found the excellent herbicidal Ciba-Geigy [1] at an EC80 of 60 ppm. activity of phosphinothricin (116) [255]. Independently, the herbicidal activity Herbicides of 115 was detected in the Meiji Seika Whereas natural products research has laboratories [256]. Following on from this, been very successful in providing lead Meiji Seika developed a fermentation pro- structures and even marketable products cess for the production ofbilanaphos (115) for the control of insect pests and plant as a commercial herbicide. Hoechst went diseases, in the field of weed control, the onto the market with glufosinate, the race- 119 gibberellin A3 ingenuity of the synthesis chemists has set mic form of 116 which is manufactured by the level of competion so high, that only a synthesis. Glufosinate has excellent envi- few natural products have actually con- ronmental properties. In 1996, its market HO~~-f0 tributed to marketable products. share was estimated to be 140 million NH USD [257]. Two peptides closely related H Hormone Weed Killers to 115, phosalacine (117) [258] and trial- OH OH 0 After Kogl had discovered the hetero- aphos (118) [259], were described as me- auxin growth stimulator indol-3-yl acetic tabolites from different species of actino- acid (113) in 1934 [251], programs were mycetes. 120 hydantocidin started in England, Germany, and in the USA for the search of new herbicides Gibberellins o based on excessive growth stimulation. The metabolites of the fungus Gibber- O:;:P-O~~JO This approach proved to be successful. In ella fujikuroi gibberellin A3 (119) and 1- 0 \ 1942, researchers of the Boyce Thompson analogues are being used commercially as o NH H Institute in the USA synthesized 2,4-D plant growth regulators for quality im- (114) [252] which kills broad leafed weeds provement and programmed harvesting in OH OH 0 by the anticipated mode of action, and fruits, vegetables, and other crops [260], 121 hydantocidin-5' -phosphate whose esters and salts are still useful her- e.g., in the production of seedless grapes, bicides today. citrus fruits, and artichokes [261].

Phosphinothricin Peptides Hydantocidin by several groups to devise economical Phosphinothricylalanylalanine (115, Hydantocidin (120) was first discov- syntheses of 120 [267-274] and to search bilanaphos) was discovered independent- ered as a powerful herbicide by Sankyo for herbicidal analogues of 120 which are ly by Zahner and coworkers [253] in a researchers in 1985, who isolated it from more easily accessible. The independent culture of Streptomyces viridochromoge- Streptomyces hygroscopicus SANK 63584 studies of the mode of action of hydanto- nes and by Meiji Seika researchers [254] [262][263]. Two independent discoveries cidin (120) by three groups showed that it as a metabolite of Streptomyces hygro- of 120 from different Streptomyces strains is converted within the plant to hydantoci- scopicus. Both groups described the anti- were reported by Ciba-Geigy [1][264] and din-5'-phosphate (121), the actual herbi- microbial properties of 115 without rec- by Mitsubishi [265]. Hydantocidin (120) cide which efficiently inhibits adenylo- ognizing its herbicidal potential. Ziihner is a nonselective herbicide of at least the succinate synthase [275-278]. Now that and coworkers identified phosphinothricin same potency as the commercial products the crystal-structure data of adeny losucci- (116) as the biologically active agent and glyphosate and bilanaphos (115) [266]. nate synthase with the bound inhibitor 121 elucidated its mode of action as inhibition For a new product to be successful in this are at hand [277][278], the search for of the glutamine synthase [253]. Some market segment, the production costs have chemically more accessible inhibitors has time later, researchers from Hoechst (now to be low. Therefore, an effort was made gained a new dimension. BIOLOGICALL Y ACTIVE AGENTS IN NATURE 42 CHIMIA 52 (1998) Nr. 1/2 (JanuarIFehrunr)

OH Cornexistine Cornexistine (126), a phytotoxic fun- : HO~"n° gal metabolite, was first isolated in 1990 ~,,~6 O~COOH from a culture of Paecilomyces variotii SANK 21086 by Sankyo researchers, who OH also determined its structure and its herbi- 122 pseudomonic acid cidal potential [286]. Although 126 con- trols both mono- and dicotyledonous weeds, it gives good protection for maize. From the identical strain, researchers at DowElanco isolated hydroxycornexistin (127). This analogue is even more potent than 126, especially against broad-leafed weeds, giving good control at rates as low as 32 glha, with excellent selectivity for 123 monic acid use in maize and sorghum [287]. The mode of action of cornexistine (126) has been studied [288] and seems to be novel.

OH Other Herbicidal Leads The herbicidal activity of the strepto- : HO~"n° mycete metabolite vulgamycin (128) was ~,,~6 o~o~ detected by Bayerresearchers [289]. Post- emergent application of 128 at a rate of OH 250 g/ha gives excellent control of several 124 Zeneca weeds without damaging cotton, barley, or maize [289]. Phosphonothrixin (129), isolated at Kureha from a culture of Saccharothrix sp., induces chlorosis in a nonselective way when applied to plant leaves [290- 292], but the mode of action is not yet known. Several mono- and dicotyledonous weeds are controlled by 129 at an application rate of 500 glha. While screening extracts of higher plants for biological activity relevant for 128 vulgamycin crop protection at Ciba-Geigy [1],wefound 125 AT-265 that an extract from the bark of Aglaia congylos (Meliaceae) exhibited quite po- R tent herbicidal activity. The metabolite responsible for the activity proved to be HO., JX'j,~~H HO""'" OH 0 rocaglamide (79), which is also described o as insecticidal [172][173]. Rocaglamide 129 phosphonothrixin (79) showed postemergent and good o preemergemactivity atO.5-1 kglhaagainst a range of mono- and dicotyledonous 126 R = H cornexistine weeds. 127 R = OH hydroxycornexistine There is no information on the mode of Another strongly herbicidal plant me- action of 124, but the parent compound tabolite was recently reported. The quass- 122 is reported to act as an inhibitor of inoid ailanthone (130) from Ailanthus al- isoleucyl-tRNA synthase [282]. tissima (Simaroubaceae) shows pro- Monic-Acid Derivatives nounced postemergent activity against In 1993, researchers from Zeneca re- AT-265 several weeds when applied at ca. ] kglha ported on the herbicidal activity of monic- Several nucleoside-type metabolites [293]. acid derivatives [279]. Pseudomonic acid have been reported to be phytotoxic [283]. Herboxidiene (131) was isolated from A (122), a bactericidal metabolite of Pseu- From a strain of Streptomyces albus, the a culture of Streptomyces chromofuscus domonas fluorescens [280], was hydro- metabolite AT-265 (125) [284] was iden- A7847 by Monsanto researchers [294], lyzed to monic acid (123) which subse- tified at Ciba-Geigy [1] as a potent post- who also reported on the remarkable her- quently was reesterified to the derivative emergent herbicide. A number of weeds bicidal potency of this metabolite [295]. 124. In the greenhouse and in the field, are controlled by 125 at less than 100 g/ha At 70 glha, 131 fully controlled several 124 proved to be a very potent postemer- [285]. However, the mammalian cytotox- weed species, while having no effect on gent herbicide against broad-leafed weeds icity of12S and of its herbicidal analogues wheat and soybean. In the Takeda labora- at application rates of 50-250 glha [281]. precluded a commercial development. tories 131 was isolated from a yet uniden- BIOLOGICALLY ACTIVE AGENTS IN NATURE 43

CHI MIA 52 (1998) Nr. 1/2 (Januar/Febnmr)

~J.. COOH ...•...0 H

o I 131 herboxidiene

79 rocaglamide OH 0

132 phthoxazolin A o

of insecticidal, fungicidal, or nematocidal natural products from other organis ms wi 11 "')4, be constructed. Novartis' insect-resistant 130 ailanthone maize expressing the 8-endotoxin gene of o 0 Bacillus thuringiensis is a first-generation example [115]. This will certainly intensi- 133 moniliformin fy the search for active natural products suitable for transgenic expression in plants. tified Streptomyces species. Mode-of-ac- Such transgenic crop plants certainly rep- tion studies showed that 131 induces apo- ~O O-..r-/ resent excellent solutions to important ptosis in the G2 phase of the cell cycle crop-protection problems. However, in a [296]. Independently, researchers at San- g dynamic field like crop protection, it can be expected that chemical crop protection doz [1] also discovered herboxidiene (131) o 0 and published the absolute configuration will remain to be a strong pillar. There- of this natural product [297]. 134 eGA 49445 fore, the search for conventional crop- Phthoxazolin A (132) was found by protection agents will continue. Omura and coworkers in a screening geared to yield inhibitors of the cellulose NJCOOH Received: December 4, 1997 biosynthesis [298]. Independently, two \ h o []] The company Novartis International Inc. was other groups also discovered 132 [299] formed by the merger of Ciba-Geigy Ltd. and [300] which shows postemergent activity 135 isoxazole-4-carboxylic acid Sandoz Ltd. Prior to this merger, the compa- against broad-leafed plants [298][299]. ny Dr. R. Maag AG had become part of Ciba- Moniliformin (133), a phytotoxic me- Geigy Ltd., and Zoecon Corp. part of Sandoz tabolite of Fusarium moniliforme served OH Ltd. 1 [2] G.A. McLaughlin, in 'Pyrethrum, The Natu- as a lead structure in an optimization project O~ .....N~COOH at Ciba-Geigy [I]. The analogue 134 had 'N I ral Insecticide', Ed. J.E. Cas ida, Academic Press, New York, 1973, p. 3. much improved activity, yielding chloro- NH 2 [3] I. Schmelz, in 'Naturally Occurring Insecti-' sis and desiccation at 1-2 kg/ha [301]. cides', Eds. M. Jacobson and D.G. Crosby, However, it was not selected for further 136 homoalanosine Marcel Dekker, New York, 1971, p. 99. development. [4] H. Zaehner, H. Anke, T. Anke, Mycol. Ser. Isoxazole-4-carboxylic acid (135), a 1983,5, ]53. metabolite of Streptomyces sp., has been [5] B. Fugmann, F. Lieb, H. Moeschler, K. Nau- reported to exert herbicidal activity in pot Outlook mann, U. Wachendorf, Chemie in unserer Zeit 1991, 25, 317. tests [302]. [6] H.-P. Fischer, 'Synthesis of Natural Products Homoalanosine (136) had been known In the future, many more new natural for Plant Protection', in 'Org. Synth. High- as a synthetic chemical with insecticidal products useful for crop protection will be lights II', Ed. H. Waldmann, YCH, Wein- and antimicrobial activity, when research- identified from diverse natural sources. It heim, Germany, ]995, p. 261. ers at Sumitomo isolated it from a culture is foreseeable, that biotechnology will [7] M. Elliott, in 'Crop Protection Agents from of Streptomyces galilaeus due to its phyto- expand its influence on crop protection Nature: Natural Products and Analogues', toxic properties. Homoalanosine (136) acts significantly. Techniques like directed bio- Ed. L.G. Copping, Royal Soc. Chem., Cam- bridge, ]996, p. 254. as an antimetabolite ofL-aspartic acid and synthesis and random gene shuffling will [8] C.A. Henrick, in 'Agrochemicals from Natu- L-glutamic acid. In the paddy field, 136 produce new 'natural' products with inter- ral Products', Ed. C.R.A. Godfrey, Marcel was found to give full control of weeds at esting biological activity. To render crop Dekker, New York, ]995, p. 63. a rate of 4 kg/ha, without impairing the plants resistant to their pests or pathogens, [9] N. Matsuo, J. Miyamoto, ACS Symp. Ser. rice crop [303]. transgenic varieties expressing the genes 1997,658, 183. BIOLOGICALLY ACTIVE AGENTS IN NATURE 44

CHIMIA 52 (1998) Nr. 1/2 (Januar/Febnmr)

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