22-2 NATURAL PRODUCT REPORTS 1991 Table 1 Isolated drimanes Compound R1 R2 Ref. Warburganal (5) PCHO OH H2 17 Polygodial (Tadeonal) (6) PCHO H H2 30 31 Isotadeonal (Isopolygodial) (7) aCHO H H 31 28 Polygonic acid (8) PCOOH H H 27 Cinnamodial (Ugandensidial) (9) PCHO OH POAc H 14 15 Mukaadial (10) PCHO OH aOH H 22a Pu'ulenal (1 1) (E)-CH(OAc) H2 57 p-Coumaroyloxypolygodial (1 2) PCHO H H2 20 Capsicodendrin (1 3)b PCHO OH POAc H 18 Cinnamolide (14) H2 H 14a Cinnamosmolide (15) POAc H OH 14a Bemarivolide (1 6) POAc H H 15 Pereniporin B (17) POH €3 OH 50 11-Ethoxycinnamolide (1 8) H2 H 27 9-Hydroxycinnamolide (19) H2 OH 22b 1I-Hydroxy- I-p-coumaroyloxy H2 H 20 cinnamolide' (20) Confertifolin (2 1) H2 H2 12 Valdiviolide (22) aOH H H2 13 Fuegin (23) aOH H aOH H 13 Fragrolide (24) H2 H2 15 Winterin (25) 0 H2 13 Purpuride (26) H H 41 Bemadienolide (27) H2 H A 15 Drimenin (28) H 0 12 3-Acetoxydrimenin (29) H 0 19 Isodrimeninol (30) H aOH H 29 Drimeninol (3 1) H POH €3 34 --e (32) H aOAc 54 Di(7-drimen-1l-oxy)-I 1,12-epoxy-7-H Cf 9c drimene (33) Olepupuane (34) aH aOAc 54 Acetoxyolepupuane (35) aH aOAc H 53 --(36) aH aORg 52a Euryfuran (37) A 55 Isodrimenin (38) H2 H2 12 Ugandensolide (39) aOH H POAc H 15 Acetoxyisodrimenin (40) H2 POAc H 18 Futronolideh (41) aOH H H2 18 Epoxyisodrimenin (42) H ,O ,H-32 Hydroxyisodrimenin (43) H2 POH H 26b Ketodihydrodrimenin (44) 0 H 43 Hydroxydihydrodrimenin (45) POH H H2 43 Dihydroxydihydrodrimenin (46) POH H aOH H 43 Drimanol (47) PCH, H PCH, OH 40 Drimanediol (48) PCH,OH H PCH, OH 40 Drimanetriol (49) PCH,OH H aCH, OH 48 Albicanol (50) PCH20H H CH 56b Albicanylacetate (5 1) PCH,OAc H CH 566 Cryptoporic acid A (52) PCH,OR Hi CH 45a Drim-9(1l)-en-8P-ol (53) CH aCH, OH 46 Drim-9( 1 l)-en-8a-o1 (54) CH PCH3 OH 46 Isoalbrassitriol (55) PCH,OH OH aCH, OH 49 Uvidin D (56) PCH,OH H PCH, H 44b Drimenon (57) CH3 As CH 39 Drimenol (58) PCH,OH H H 9a Albrassitriol (59) PCH,OH OH aOH H 49 Deoxy uvidin B (60) PCH,OH H 0 49 Drim-7-enyl-glyceride (6 1) PCOR Hj H2 56c Drim-7-enyl-glyceride acetate (62) PCOR Hk 56c t2 Uvidin E (63) PCH,OH H 44b Uvidin A (64) PCH,OH H 0 44a Uvidin B (65) PCH,OH H 0 44a Uvidin C (66) PCH20H,H POH 44b Dihydrocinnamolide (67) H H 34 Pebrolide (68) POBz H1 CH,OAc 42a Altiloxin A (69) H -51 Altiloxin B (70) c1 -51 Astellolide A (71) CH,OAc OBzl 47a Astellolide B (72) CH,OAc O-p-OH-Bzl 47a Parasiticolide A (73) CH,OAc OBz' 476 Periniporin A (74) 50 Cryptoporic acid B (75) 45a Cryptoporic acid C (76) 45b Cryptoporic acid D (77) 456 Cryptoporic acid E (78) 45b ent-Drimanes NATURAL PRODUCT REPORTS 1991-B.J. M. JANSEN AND A. DE GROOT 31 1 Table 1 (cont.) Compound R‘ R2 R3 Ref. Iresin (79) Isoiresin (80) Dihydroiresin (8 1) PH PH A PH A H H 6 7 7 8 nor-Drimanes Compound R1 Ref. Polygonone (82) Polygonal (83) Isopolygonal (84) 0 aOH H POH H 27 29 27 Rearranged drimanes Compound Ref. Muzigadial (85) 4,13-a-Epoxy muzigadial (86) Coloratadienolide (87) 21 24 21 10 -0,CCH = CH-C,H,OH.*Isolated as a tetramer. The authors named it (erroneous)-valdiviolide. N-acetyl-L-valinyl= O,CCH(i-C,H,) NHCOCH,. R acyl residues from several fatty acids of different unsaturated degree. The ‘Presumably obtained by allylic methanolysis of olepupuane (30). 7-drimene-11-oxy. = structure for this compound in ref. 13 is incorrect. * R = -CH(COOCH,)-CH(COOCH,)-CH,-COOH (ether of isocitric acid). OCH,-CH(0H)-CH,OH. *OCH,CH(OH)CH,OAc. Bz = benzoyl. PHO @O / / / R2 / R’ (5) -(13) (14) -(20) ($2Rl R2 (38) -(43) (44)-(46) R’ @OH t>.-(691 (70) (71) -(73) O-C-C-CH,-COOH COOCH3\COOCH3 / f OH HO’ (74) (75) NATURAL PRODUCT REPORTS 1991 0-\ C02R' c=o I I 0 I (76)R = R' = H (78)R =OH R' = H 2 Biosynthesis Most cyclizations of farnesyl pyrophosphate (FPP)58a are initiated by an enzyme-mediated solvolysis of the pyrophosphate group59 whereby an incipient or actual carbocation is formed at the tail position of the farnesyl chain.A small number of bicyclic sesquiterpenes including drimanes arise from a cyclization which is initiated by an electrophilic attack mostly by a proton on the double bond at the head position of FPP or onto the corresponding epoxide (see Scheme 1).60 The relative positions of the double bonds in the con-formation assumed by the FPP chain determines the structure and the stereochemistry of the final product. The trans ring junction is consistent with the stereoelectronic requirements of a concerted mechanism in which the sequential addition of the non-conjugated double bonds takes place.The chair-chair conformation of the polyenic chain during the cyclization can in principle exist in two enantiomeric forms from which the two enantiomeric drimane skeletons are derived. Examples of both are found in nature although not in the same plant. The hydroxyl group at C-3 probably originates from proton attack on an epoxide. It is reasonable to assume that protonation of this hydroxyl group followed by dehydration and rearrangement of the resulting carbocation accounts for the biogenesis of the rearranged drimanes (see Scheme 2). The co- occurrence of bicyclic nor-sesquiterpenes of the drimane class in some plants may arise through decarboxylation of drimanic carboxylic acids28 (see Scheme 3).3 Biological Activity of Drimanes Drimanes possess a wide variety of biological activity including antibacterial antifungal anticomplemental antifeedant plant- growth regulatory cytotoxic phytotoxic piscicidal and molluscicidal properties. Moreover the very hot taste of several biologically active drimanes to humans and their skin- irritant properties have attracted much attention. X = H Hal epoxide OPP x* PP H H ent-drimanes (iresi n) drirnanes (polygodial) Scheme 1 313 NATURAL PRODUCT REPORTS 1991-B. J. M. JANSEN AND A. DE GROOT JpR2-<+ Ho)'yH @& PR2-mR2 O) H' ' H+. Scheme 2 Scheme 3 Table 2 Antimicrobial activity of drimanic dialdehydes MIC Cug/ml) Microorganisms tested Polygodial (6) Warburganal (5) Muzigadial (85) Isotadeonal (7) Staphylococcus aureus > 100 > I00 > 100 > 100" Escherichia coli > 100" > 100 > 100 > 100" Pseudomonas aeruginosa Saccharomyces cerevisiae Hansenula anomala > 100 0.78 1.56 > 100 3.13 12.5 > 100 25 1.56 > 100" > 100 > 100 Candida utilis 1.56 3.13 3.13 > 100 Sclerotinia liber t iana 1.56 3.13 3.13 > 100 Mucor mucedo 6.25 25 25 > 100 Rhizopus chinensis Aspergillus niger 12.5 25 100 50 100 50 > 100 > 100 Penicillium crustosum 25 50 50 > 100 Trichophyton mentagrophytes 2 3 > 100 Bacillus subtilis > 100" > 100 > 100 > 100 An earlier research stated a somewhat lower value for the minimum inhibitory concentration.26 3.1 Antifungal and Antibacterial Activity In screening East African plants used in folk medicine Taniguchi et af.found several possessing antimicrobial activity.lb The plant materials were collected mainly on the basis of in-(85) (86) formation gathered from native people especially from the 'Bwana Mganga ' Swahili for 'medicine man '.61 In particular the species of the genus Warburgia (Canellaceae) showed broad activity. The extracts were fractionated and bioassayed62 leading to the isolation of the antimicrobial principles which were identified as the sesquiterpene dialdehydes polygodial (6) warburganal (5) muzigadial (85) and isotadeonal (7). The results of several bioassays are gathered in Table 2."-24 26 63-66 Polygodial (6) proved to be the most potent antifungal compound tested.It killed the cells of S. cerevisiae within ten (87) minutes when treated with a fungicidal concentration of 50,4m1.65 The related synthetic compounds (88) and (89) were also (OH tested but they were devoid of activity. Pereniporin A (74) a metabolite of Perenniporia meduffaepanis showed a remarkable effect on the growth of B. subtifis (MIC 6.25 ,ug/ml) but it was inactive against Gram-negative bacteria (MIC > 100 ,~g/ml).~O Cinnamolide (14) was active against T. rubrum (MIC > 20 ,ug/ml) T. menthagrophytes (MIC < 10pg/ml) and M. (88) (89) gypseum (MIC 20 ,~g/ml).~~~ 3.2 Plant-growth Regulatory Activity A few drimanes were examined for plant-growth regulatory properties.Polygodial (6) completely inhibited the germination of rice in husk at a concentration of ca. 100 ppm.2gj 33 .34 It also inhibited the root elongation of rice plants at a concentration of 100 ppm but at a concentration of less than 25 ppm a dramatic promotion of root elongation was observed.33' 34 Rice seed (Oryza sativa) germination was also inhibited by cryptoporic acid A (52) which produces the characteristic bitterness of the fungus Cryptoporous volvatus at 200 ppm con~entration.~~~ Polygonal (83) is also active but at a much higher concentration of 500 ~pm.~' The influence of drimenol (58) and confertifolin (21) was investigated on cuttings of Tradescantia virginiana L.f.albzjlora B. with regard to the elon- gation and increase in dry weight of adventitious roots.67. A lo-' molar solution of drimenol (58) proved as active as indole-3-acetic acid (auxin) or N-furfuryladenine (kinetin). Confertifolin (2 1) showed a somewhat higher production and elongation of the roots but it was not significant compared with exogenous auxin or kinetin. The root elongation of lettuce was completely inhibited by pereniporin A (74) at 100 ppm., Altiloxin A (69) and B (70) also had little effect on the root elongation of lettuce.51 The root production of asparagus on the other hand was diminished by 50 percent at a concentration of 10 ppm.jl The germination of wheat seed (Triticum aestivum var. Norman. Graminaceae) was only slightly reduced by polygodial (6) and warburganal (5) at a concentration of 0.1 %.A higher concentration improved the inhibition but the germinated seeds had twisted leaves instead of normal 3.3 Cytotoxic Activity Some drimane-type sesquiterpenes showed cytotoxicity in anti- cancer screens. Cinnamodial (9) and capsicodendrin (1 3) a tetrameric conjugate of cinnamodial had an ED, of 2.2 and 2.9 pg/ml respectively in the P-388 lymphocytic leukaemia test system in vitro. Cinnamosmolide (1 5) possessed an ED, of 1.2 pg/ml in the Eagle's 9KB carcinoma of the nasopharynx cell culture system. However these compounds were devoid of in vivo activity in the P-388 test system.l* The drimanic dialdehyde warburganal (5) was active at a concentration of 0.01 pg/ml against KB.28 The metabolites of Perenniporia medullaepanis pereniporin A (74) and B (17) were cytotoxic for Friend leukaemia cells (F5-5) at 130 and 3.91 pg/ml respectively in the bioassay reported by Morioka." As part of a general attempt to study structure-activity relationships for unsaturated dialdehydes from natural sources several compounds were investigated in the Salmonella-microsome assay (strains TA 98 TA 2637 and TA 100).Polygodial (6) and isotadeonal (7) showed no mutagenic activity at the highest non-toxic concentration. Unfortunately other drimanic compounds were not tested.?l 3.4 Taste Skin-irritant Properties and Anticomplemental Activity The leaves of Warburgia species are sometimes used locally as spices in food in East Africa.'" The fruit of Drimys lanceolata are said to have been used as a substitute for pepper in Tasmania.'2 In Japan the pungent hot tasting tade-jiru is made from squeezed Polygonum hydropiper L.leaves.66 Some liverworts are also known for this pungency.33' 36 It turned out that the drimanic aldehydes polygodial (6) warburganal (5) muzigadial (85) cinnamodial (9) and polygonal (83) a nor- drimane were responsible for this phenomenon. 28 73 The nor- drimane is fairly weak in comparison with the other compounds.2s The bitterness of the fungus Cryptoporous volvatus is caused by cryptoporic acid A (52) an albicanyl-ether of iso-citric acid.45Q Polygodial (6) has been reported on several occasions to display skin irritant properties.23% 30.36 NATURAL PRODUCT REPORTS. 1991 When guinea pigs were sensitized to polygodial (6) by using intradermal injections in Freund'si4 complete adjuvant they showed a high response when the skin was treated with polygodial (6) the primary sensitizer. Moreover related compounds e.g. warburganal (5) having the same configuration also showed an allergic contact dermatitis (ACD); and it was observed that the reaction was halved when a racemic mixture of warburganal was used so the allergenic response was stereospecific to enantiomers.' Several constituents of P.hydropiper L. leaves and seeds were tested for their anticomplemental properties. Polygodial (6) and polygonic acid (8) showed an IC, of 10pg/ml and 250 pg/ml respectively. It is surprising that the usually active drimanes like warburganal (5) and muzigadial(85) showed no activity.27 3.5 Piscicidal and Molluscicidal Activity Muzigadial (85) and warburganal (5) were tested as potential helicocides (snail-killers) because the extract of the bark of Warburgia ugandensis had been known for some time to have molluscicidal activity.A simple snail test was chosen because it could give a lead to agents useful for controlling the dangerous schistosomes and bilhar~ia.?~ Biomphalaria pfeifleri and B. glabratzis are killed within two hours by a 5 ppm solution and LjJmnaca natalensis is killed within two hours by a 10 ppm solution of these two cornp~unds.'~ Treatment of killie fish Oryzia latipes with polygodial (6) at 0.4 ppm killed them within 30 69 After an injection of 2 mg of polygodial (6) into the hepatopancreas of the nudibranch Dendrodoris limbata suffering of the animal was evident and death occurred between 3 and 16 hours.52c 3.6 Antifeedant Activity The insect antifeedant properties of the drimanes has been reviewed recently and will not be repeated here in detail.?* Seed treatment with appropriate chemicals to protect crops against pests is preferred to foliar or soil treatments as it is generally cheaper than soil application and since the pesticide is confined to the small area where it is needed it has less effect on other soil organisms.Polygodial (6) was used in laboratory and field tests to control slugs (Deroceras reticulatum) and wheat bulb flies (Delia coarctata) in winter 8o where its effect was marginal on clay loam soil but obvious on peaty loam soil though still inferior to commercial pesticides.It showed no toxicity towards slugs. Nudibranchs softbodied and apparently unprotected molluscs employ some drimanes as defensive chemicals to escape from predators. These drimanes are often derived from a dietary source predominantly if not exclusively of sponges. However the biosynthetic activity of a nudibranch to elaborate its own chemical defence has been shown by incorporation experiments with [2-14C]-mevalonic acid dibenzylethylene- diamine On injection into the hepatopancreas it gave rise to labelled polygodial (6) and labelled sesquiterpenoid esters (36).j2'-j3 The latter are products of further metabolism of polygodial (6) as a result of a detoxication process.j2' Polygodial (6) and olepupuane (34) inhibited feeding of the Pacific damsel fish (Dascyllus aruanus) with ED,,s of 15- 20 pg/mg of pellet.51 Polygodial(6) also inhibited feeding of the marine fish Chromis chromis and the fresh water fish Carassius carassius (ED,, 10 pg/mg of pellet)."2" The glyceride (61) found in some British Columbia nudibranchs was active against the tide pool sculpin Oligocottus rnaculosus at a level of 18 pg/mg of pellet.56L Albicanylacetate (51) and 6p-acetoxyolepupuane (35) showed antifeedant properties in a standard goldfish (Cnrassius auratus) bioassay with ED, of 5-10 ,ug/mg of pellet.52b On Chinese cabbage leaves treated with polygodial (6) or warburganal (9,at a concentration of 0.05 YO,ca.125 ppm compound/leaf few Myzus persicae settled and few nymphs NATURAL PRODUCT REPORTS 1991-B. J. M. JANSEN AND A. DE GROOT active inactive CHO warbu rganal //I CHO I I P\\ Ho+ I polygodI ial \ I ci nnarnod ial I I I I I I CHO 1 I I 4 I I I muzigad ia I I Scheme 4 were depo~ited.~~ 'I The transmission of potato virus Y,beet yellow virus and barley yellow dwarf virus was therefore three times with polygodial (6) at 50 g/ha in early autumn showed diminished damage caused by BYD virus and an improved yield of 136 YO. Warburganal (5) and muzigadial(85) inhibited the feeding of larvae of two species of African armyworm the monophagous Spodopteru exempta and the polyphagous S.littoralis at a concentration of 0.1 ppm in a regular leaf disk ~ethod.~' Polygodial (6) and ugandensidial (9) were also antifeedants for these insects but less active.1e* 17 84 The drimane dialdehydes turned out not to be uniformly active against all insects but showed some species specificity. Activity was also observed against S.Jrugiperda Heliothis armigera and H. virescens."* 85 brassicae at a concentration of 200 ppm.86 3.7 Phytotoxicity in the chemoreceptor membranes of insects thus an interference Some drimanes are potentially valuable crop protecting agents due to their aphid antifeedant activity. For that reason polygodial (6) warburganal (5) and cinnamolide (14) were further investigated because primary studies had suggested a possible phytotoxicity.82b When treated with a concentration of 0.1 O/O the leaves of Chinese cabbage (Brassica campestris var.scorched and yellowed but the leaves of sugar beet (Beta vulgaris) were ~nharmed.~~ The earlier claim of phytotoxicity for unnatural polygodial was not confirmed so the racemates reduced even by aphid variants highly resistant to insecticides.**. 83 Field trials with winter-sown barley treated which are more readily available by synthesis can be employed in the development of drimane-type antifeedants.82b Altiloxin A (69) and B (70) isolated from the culture filtrate of Phoma asparagi Sacc. are phytotoxic metabolites responsible for the stem blight disease on a~paragus.~~ 3.8 Mode of Action of Biologically-active Drimanes Since the drimanic dialdehydes are among the most active drimanes they are frequently used to investigate the mode of action at the molecular level Ma has studied the influence of warburganal (5) on the receptor response of Spodoptera exempta to the stimulant activity of sucrose or meso-inositol ~olutions.~~ Brief treatment with warburganal greatly reduced Polygodial(6) was active against diamond moth larvae down to 0.1 Yoand it inhibited food intake by fifth-instar larvae of Pieris the excitability of the receptors but when it was mixed with L-cysteine or dithiothreitol no decrease in excitability was 0bser~ed.l~M a suggested that the enal moiety of warburganal (5) may act as an -SH acceptor; thiol groups have been detected of warburganal with the stimulus transduction process in the chemoreceptor cell seemed likely.88 Additional evidence for this hypothesis was derived from the fact that the mercaptide forming organomercurial p-(chloromercuri)-benzoate gave a qualitatively similar reaction to ~arburganal.~~ Further investigations revealed that the active antifeedants all taste hot and spicy to the human tongue whereas all inactive derivatives Chinensis) showed slight pitting over the entire surface with some dry patches.Potato leaves (Solanum tuberosum) were are devoid of hot taste (see Scheme 4).le. 77739 NATURAL PRODUCT REPORTS 1991 CH,NH pH -9 Scheme 5 Scheme 6 From Scheme 4 it can be concluded that an enal and a 9P- aldehyde group are required for activity.Mild treatment with base inverted the 9P-aldehyde into a 9a-aldehyde group with concomitant loss of activity and hotness. The enhanced activity of the 9a-hydroxy compounds suggested an involvement of this functionality with the best fit of the molecule on the sensilla. Similar conditions were found by Sterner et al. in a structure-activity relationship study with regard to the mutagenicity of unsaturated dialdehydes. ’l The antifungal activity of polygodial (6) was studied by Taniguchi et al.63* 64 The yeast Saccharomyces cerevisiae was the most susceptible organism among those tested so the made of action on this yeast was carefully investigated. A variety of physiological effects due to polygodial (6) e.g.inhibition of growth alcohol fermentation and papain activity appeared to result from its irreversible reaction with sulfhydryl groups. However in a biomimetic reaction the inactive isopolygodial (7) also had a high reactivity with the sulfhydryl group of L-cysteine. Based on kinetic data Sodano et al. proposed that the biological activity of the enal-aldehydes is primarily related to their ability to form adducts with amino groups rather than sulfhydryl groups on the receptor^.^^ Similar reactivity was observed for both polygodial (6) and iso-polygodial (7) in a reaction with thiols while the reaction with substrates possessing both amino and sulfhydryl groups was dependent upon the stereochemistry of the 9-aldehyde group the 9P- isomer exhibiting the higher reactivity.With amines or amino acids a remarkable difference in reactivity was observed the 9a- isomer was practically unreactive. They were able under biomimetic conditions to obtain NMR evidence for their proposed mechanism (Scheme 5).’O After reaction with a model amine i.e. methylamine one single product the pyrrole (91) was observed which because of its instability was only examined by NMR spectroscopy. The inactive 9a-isomer cannot form intermediates of type (90) due to the greater distance between the C-9 axial aldehyde and the enal Several other suitable enal aldehydes were also investigated and gave rise to the same observation^.^^ The biological mechanism of hot tasting and antifeedant activity of 1,4-dialdehydes may also result from covalent binding to primary amino groups of the chemoreceptive sitesa4* rather than from Michael addition of membrane sulfhydryl groupsa7 even though both are available at the receptor site ;93 a model study of the reaction of muzigadial (85) with L-cystine methyl ester in vitro is in agreement with thisg2 (see Scheme 6).Cell permeability studies revealed that polygodial (6) preferentially damaged the cell membrane and caused an appreciable amount of leakage of cellular constituents e.g. proteins and saccharides. A decrease in cellular dry weight was also observed. 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