Triazolide Strigolactone Mimics Influence Root Development in

Article pubs.acs.org/jnp

Triazolide Strigolactone Mimics Influence Root Development in Arabidopsis Marcela Dvorakova,† Petr Soudek,† and Tomas Vanek*,† †

Laboratory of Plant Biotechnologies, Institute of Experimental Botany, Academy of Sciences of the Czech Republic, v.v.i., Rozvojova 263, Prague 6 16502, Czech Republic S Supporting Information *

ABSTRACT: Strigolactones are the most recently recognized class of phytohormones, which are also known to establish plant symbiosis with arbuscular mycorhizal fungi or induce germination of parasitic plants. Their relatively complex structures and low stability urgently calls for simple derivatives with maintained biological function. We have prepared a series of triazolide strigolactone mimics and studied their ability to affect root development of Arabidopsis thaliana. The strigolactone mimics significantly induced root elongation and lateral root formation while resembling the effect of the reference compound GR24.

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predominantly in plant roots from where they are transported to other plant parts and to the rhizosphere.10 A protein, PRD1 (member of the ABC transporter family), responsible for strigolactone transport was identified recently.11 The biosynthesis starts with oxidative cleavage of all-trans-β-carotenoids formed by the methylerytritol pathway in cell plastids. Carotenoid isomerase DWARF27 (D27) and carotenoid cleavage dioxygenases CCD7 and CCD8 are the enzymes involved in the first biosynthesis steps. Only one stereoisomer, (11R)-carlactone (Figure 1A), is thus formed as a precursor of all strigolactones.10 The enzymes which further transform (11R)-carlactone to strigolactones were only recently identified. In Arabidopsis, cytochrome P450 enzyme, CYP711A1, encoded by MAX1 (more auxiliary growth1) protein was identified to metabolize (11R)-carlactone to carlactonoic acid (Figure 1B).12 The carlactonoic acid metabolite, methyl carlactonoate, was identified in Arabidopsis roots and shown to directly interact with AtD14 (Arabidopsis DWARF14) protein.12 In rice, two homologues of the CYP711A enzyme encoded by MAX1 homologues were identified. One homologue, Os900, was shown to oxidize carlactone to (−)-(3aR,4R,8bR,2′R)-5deoxystrigol (also called ent-2′-epi-5-deoxystrigol, Figure 1C), whereas the other, Os1400, oxidized (−)-5-deoxystrigol to (−)-orobanchol (Figure 1D).13 Other strigolactones are then formed by further enzymatic oxidation/dehydration reactions. Strigolactone biosynthesis in plants is extremely stimulated under phosphate deprivation.2c Enhanced strigolactone biosynthesis ensures plant adaptation to suboptimal nutrient availability and drought. Increased strigolactone production

trigolactones are the youngest class of phytohormones initially confirmed to repress axillary but outgrowth in pea and Arabidopsis branching mutants.1 Since then, strigolactones were found to affect shoot branching, root architecture (e.g., root-hair elongation, lateral root length, primary root length, adventitious rooting), stem elongation, lateral bud outgrowth, stimulation of cambium activity, nodule formation, photomorphogenesis, resistance to drought stress, among other effects.2 Strigolactones interact with other phytohormones, and evidence suggests that their phytohormone function is related to their ability to modulate auxin transport through the regulation of PIN (PIN-FORMED proteins, auxin transporters) protein activity.3 Originally, strigolactones were identified as stimulators of seed germination of the parasitic weeds Striga and Orobanche.4 These parasitic plants cause massive damage to crops in subSaharan Africa and the Mediterranean region.5 It is estimated that Striga alone has infested around two-thirds of arable land in Africa, thus affecting more than 100 million people6 and causing a financial loss in crop production of approximately US $7 billion every year.7 Thus, strigolactones and their derivatives are intensively studied for their ability to regulate parasitic plant seed germination through so-called suicidal germination.8 In 2005, strigolactones were also identified to induce plant symbiosis with arbuscular mycorhizal (AM) fungi.9 Strigolactones elicit spore germination and hyphal proliferation to allow root colonization.10 This symbiosis is as old as 400 million years It is formed by 80% of terrestrial plants and is highly profitable for both fungi and plant as it provides fungi with carbohydrates and the plant with optimal nutrient uptake.2a,b Chemically, strigolactones are sesquiterpenoid lactones related to carotenoids. Strigolactone biosynthesis occurs © 2017 American Chemical Society and American Society of Pharmacognosy

Received: September 27, 2016 Published: April 19, 2017 1318

DOI: 10.1021/acs.jnatprod.6b00879 J. Nat. Prod. 2017, 80, 1318−1327

Journal of Natural Products

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Figure 1. (A) (11R)-Carlactone, strigolactone precursor; (B) Carlactonoic acid, carlactone metabolite formed by oxidation with CYP711A1; (C) (−)-5-Deoxystrigol, strigolactone formed from carlactone by Os900 enzyme; (D) (−)-Orobanchol, strigolactone formed from carlactone by Os1400 enzyme; (E) (+)-Strigol, first isolated strigolactone; (F) GR24, strigolactone derivative used as a reference molecule in biological tests.

Arabidopsis and rice2h as well as in pea.2g In addition, strigolactone analogues with the D-ring connected to an acyclic unsaturated system via an enol ether bridge were able to inhibit bud outgrowth and shoot branching in pea as well as inhibit adventitious root development and lateral root formation in Arabidopsis.16b The importance of other structural features on phytohormonal activity is not clear. For instance, the significance of the natural (2′R) configuration was found to be indispensable in one study,2h whereas in another study, it was not.2g Moreover, studies on the effects of the enol ether bridge on activity also revealed contradictory results. Initially, it was established that the enol ether bridge is not necessary for the phytohormonal activity.2f This assumption stemmed from the preserved activity of strigolactone mimics, so-called debranones, which are phenoxy furanone derivatives. They retained the ability to inhibit tiller bud outgrowth in rice d10 mutant. From these, the most potent compound, 4-bromodebranone (Figure 2A) was

was shown to directly affect plant architecture (e.g., repress shoot branching and primary root elongation and promote lateral root growth and roothair elongation).2d,e,14 Structurally, strigolactones are formed by a tricyclic lactone (A, B, and C-ring) which is connected to an α,β-unsaturated furanone moiety (butenolide D-ring) via an enol ether bridge (Figure 1E). To date, around 20 natural strigolactones have been identified in root exudates and fully characterized, with the list still growing. 15 The first strigolactone was (+)-(3aR,5S,8bS,2′R)-strigol isolated from cotton root exudates in 1966 (Figure 1E).4 The strigolactones are divided into two structural families based on the absolute configuration of the BCD portion with the family representatives being (+)-strigol, with a β-orientation of the C-ring (Figure 1E) and (−)-orobanchol, with an α-orientation of the C-ring (Figure 1D).15a,b Strigolactone synthesized derivatives may be divided into two groups: (a) synthesized analogues, in which the enol ether bond is maintained, and (b) synthesized mimics, which lack the enol ether bond. Various synthesized strigolactone derivatives have been prepared with a majority being tested for their ability to influence parasitic seed germination.2f,16 From these, derivative GR24 (Figure 1F) developed for suicidal germination is currently used as a reference molecule in biological tests because of its stability and ready availability.17 Comparison of the structure of synthesized derivatives with the results of their biological tests allowed the establishment of structure−activity relationship (SAR) requirements for each biological activity. Thus, the most important part of the molecule is the CD bicyclic part with a 4′-methyl group (for the numbering, see Figure 1E).2g,5 Other structural moieties are either necessary or not required for biological function. For example, the presence of A- and B-rings is not necessary for the stimulation of parasitic seed germination, and substitution of these two rings has a negligible effect on bioactivity.16a,18 On the contrary, Aand B-rings are indispensable for the stimulation of symbiosis with AM fungi, and their substitution pattern affects the bioactivity strikingly.10 In the case of phytohormonal function of strigolactones, information about structural requirements are limited and need further examination. Nevertheless, it seems that the activity resides solely in the CD bicyclic portion of the molecule with the A- and B-rings being redundant.2f,g For example, the absence of the A- and B-rings of the GR24 molecule had no effect on the shoot branching activity in

Figure 2. (A) 4-Bromodebranone; (B) thia-3′-methyl-4-chlorodebranone.

further tested for its phytohormonal function in Arabidopsis as well as for its seed germination stimulation ability on Striga and was found almost as active as GR24.19 Similarly, the debranonelike molecule, thia-3′-methyl-4-chlorodebranone (Figure 2B), inhibited shoot branching and bud outgrowth in pea and adventitious root formation in Arabidopsis at nanomolar concentrations.16b On the other hand, four compounds with preserved D-ring and altered enol ether bridge were found to be inactive in the same assays.2g Likewise, four dihydro GR24 derivatives (with reduced enol ether double bond) were unable to affect tiller bud outgrowth in rice, and two imino GR24 derivatives were only weakly active.2h However, all these studies employed only a limited number of compounds with an enol ether bridge modification and tested in various biological assays, and thus, it is difficult to determine the precise effect of an enol ether bond on activity. 1319



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Herein, the synthesis of simplified strigolactone mimics devoit of an enol ether bond and evaluation of their ability to affect root architecture of Arabidopsis thaliana plants are reported.

Table 1. A Set of Triazolides as Strigolactone Mimics

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RESULTS AND DISCUSSION Chemistry. In order to find simple strigolactone mimics which would be easily synthesized, stable against hydrolysis, and with maintained phytohormonal function, a series of triazolide compounds was designed. From the known SAR requirements, it was assumed that the triazolide mimics may resemble the activity of the reported debranone compounds (Figure 2) and thus may be effective as phytohormonal regulators. A concise three-step synthesis and the stability of these compounds introduced by the absence of the enol ether bridge are the striking benefits of these compounds. The synthesis started from the commercially available furanone, 3-methyl-2(5H)-furanone (1), which was converted to its 5-bromo derivative (2) using N-bromosuccinimide (NBS) (Scheme 1).20 The 5-bromo derivative (2) was reported to be Scheme 1. (i) NBS, CCl4, Benzoyl peroxide, 78°C, 2 h; (ii) sodium azide, DMF, 1.5 h

obtained as a racemic mixture16c and is employed as a D-ring precursor in a vast majority of syntheses of strigolactone derivatives. The feasibility of the one-step addition of the Dring makes this approach so attractive. On the other hand, its instability was reported.16c It is thus recommended to utilize it directly in the next reaction step. 5-Bromo derivative (2) was thus converted into the corresponding 5-azido derivative (3) by the reaction with sodium azide (Scheme 1). The instability of the 5-bromo derivative (2) may have contributed to the moderate yield of the 5-azido derivative (3) and thus of the final compounds. However, such moderate yields are often reported in the syntheses of strigolactone derivatives.16d−h Finally, the employment of a high-yielding “click chemistry” approach generated a set of triazolides as strigolactone mimics (4a−i) (Table 1). The “click chemistry” mechanistically involves the 1,3-dipolar cycloaddition of copper(I) acetylides with organic azides to produce solely 1,4-disubstituted triazolides.21 Thus, appropriate ethynylbenzenes reacted with 5-azido derivative (3) in H2O/t-BuOH (1/1) mixture in the presence of a Cu(I) catalyst generated in situ from CuSO4· 5H2O and sodium ascorbate. The triazolide strigolactone mimics (4a−i) were obtained as racemic mixtures. Biological Activity. As phytohormones, strigolactones play a pivotal role in the modulation of plant shoot and root architecture. Such activity is predominantly studied on Arabidopsis, Oryza (rice), and Pisum (pea) plants using mainly strigolactone synthesized derivative GR24 because of its availability and stability. Particularly in Arabidopsis, GR24 regulates different stages of root development, with root hair elongation, primary root elongation, and lateral root density being the most studied (reviewed by Matthys et al., 2016).22 Lateral root density is defined as the number of lateral roots on 1 cm of primary root. Lateral root density therefore reflects the effect of GR24 not only on lateral roots but also on the primary root. For example,

under phosphate starvation conditions, Arabidopsis plants displayed shorter primary roots and higher lateral root density even though the absolute number of lateral roots also decreased.2e Similarly, under normal phosphate conditions, lateral root density was shown to decrease in Arabidopsis while lateral-root-forming potential was not effected.2d This lateralroot-forming potential was described as the sum of lateral roots and lateral root primordia. It was argued that the decrease in lateral root density was caused by the inhibition of outgrowth of lateral root primordia. However, the increase in primary root length may also have partly affected the lateral root density. Recently, another study reported that especially an emergence of lateral root primordia near the shoot−root junction is inhibited upon GR24 treatment.2i In our case, the synthesized triazolide strigolactone mimics were tested for their ability to influence the total root length and the number of root tips of Arabidopsis thaliana plants. The compounds were tested at three concentrations (1, 10, and 100 μM) with GR24 as a reference compound. Even though the two assays also reflect the impact on both primary and lateral roots, under our conditions they better evaluated the effect of the compounds on root architecture. The measurement of total root length was carried out because the exact designation of one primary root was impossible in our case (Figure 3A−E). The total root length thus expresses the effect of compounds on elongation of both primary as well as lateral roots. Still, as no elongation of lateral roots upon GR24 treatment has yet been observed, and the total root length may be a function of just primary roots length. On the other hand, the number of root tips function was chosen as an alternative to lateral root density. 1320



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Figure 3. Root morphology of 12-day-old wild-type A. thaliana (Col-0) seedlings: (A) control, (B) 1 μM of GR24, (C) 100 μM of GR24, (D) 1 μM of compound 4b, (E) 100 μM of compound 4b. Bar represents 1 cm.

Upon the assumption that the number of primary roots stays the same, it should represent the impact of compounds directly on the number of lateral roots. The results show that the activity of strigolactone mimics depended on their concentration. At the highest concentration of 100 μM, especially compounds 4b and 4f significantly decreased total root length as well as the number of root tips of Arabidopsis plants with an extent similar to GR24 (compare Figure 3A,C,E; Figure 4; and Figure 5). Slightly lower inhibitory activity was also observed for compounds 4a, 4d, and 4e. Completely different results were obtained at lower concentrations (1 and 10 μM). At 10 μM, none of the compounds including GR24 displayed any significant activity on both total root length as well as the number of root tips when compared to the control. On the contrary, at 1 μM, a majority of synthesized strigolactone mimics significantly influenced Arabidopsis root development. In case of total root length, they activated root elongation, whereas the effect of reference compound GR24 was comparable to control. Compounds 4b and 4c exhibited the highest stimulatory potential. Comparably, these two compounds as well as GR24 also stimulated the increase in the number of root tips at 1 μM. Actually, all tested strigolactone mimics, except for compounds 4e and 4f, increased the number of root tips at least to the extent of GR24. Compounds 4b and 4c, however, were much more efficient. These two compounds, when applied to nutrient medium at 1 μM, induced a 2-fold increase in total root length when compared to control and GR24, and concurrently, they

increased the number of root tips more than 4 times in comparison with control and almost twice when compared to GR24 (compare Figure 3A,B,D; Figure 4; and Figure 5). Previously, it has been shown that GR24 influences primary root length depending on the concentration used.2d At high concentrations (5 and 10 μM), GR24 inhibited primary root elongation, whereas at lower concentrations (1.25 and 2.5 μM), the elongation was induced.2d Therefore, it is not surprising that at high concentration (100 μM) triazolide strigolactone mimics inhibited total root length as well as the number of root tips, but at low concentration (1 μM) they stimulated it. In the case of GR24, the inhibition of primary root length at higher concentrations was suspected to be caused by its toxicity at nonphysiological concentration,2d which we believe is also the case with the strigolactone mimics. The highest toxicity was observed for compounds containing fluorine atoms and a pentyl group, which may be caused by increased lipophilicity and thus enhanced bioavailability of these compounds. On the other hand, compounds with polar substituents (OH, NH2) had no significant toxic effect on plants and even at high concentration did not inhibit root development. At low concentration, alkyl substitution seemed to potentiate the stimulatory effect of strigolactone mimics 4b and 4c on both total rooth length and the number of root tips. Also, the compounds with polar substituents enhanced both root elongation and lateral root formation, even though that effect was not as pronounced as in the case of compounds 4b and 4c. The only nonaromatic compound 4i displayed similar effectivity compared to its aromatic counterparts, and thus, it 1321



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Figure 4. Root length of A. thaliana grown 7 days on nutrient medium in the presence of different strigolactone derivatives. The error bars indicate the standard deviation of analyzed concentrations made in nonuplicate. Statistically insignificant values on the level of probability P < 0.05 are indicated by the same symbol above the columns.

Figure 5. Number of root tips of A. thaliana grown 7 days on nutrient medium in the presence of different strigolactone derivatives. The error bars indicate the standard deviation of analyzed concentrations made in nonuplicate. Statistically insignificant values on the level of probability P < 0.05 are indicated by the same symbol above the columns.

compared to control. It is possible that under the growth conditions, the effect of GR24 on root length could have been more pronounced at even lower concetration. Such suggestion is based on the analogy with root hair elongation studies, where

may be assumed that steric properties play a pivotal role in the activity of synthesized strigolactone mimics. We did not observe any effect of GR24 at 1 μM concentration on total root length of Arabidopsis when 1322



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The current results were obtained on Arabidopsis wild-type (WT) plants. Thus, they are compared with other results acquired on Arabidopsis WT plants because the exact effect of strigolactones may vary between plant species and plant mutants. The are four Arabidopsis max mutants: max1, max2, max3, and max4. Three of them are strigolactone-biosynthesis mutants in which the WT phenotype may be restored upon an exogenous strigolactone supplement. The fourth max2 mutant, is a strigolactone-signaling mutant thus irresponsive to exogenous strigolactone treatment. In addition, GR24 has been shown to be bound and hydrolyzed not only by strigolactone receptor, D14, but also by karrikin receptor, KAI2 (karrikin insensitive 2).24 These two receptors are closely related as both belong to the α/β hydrolase superfamily and both require the F-box protein, MAX2, for signal transduction through either direct or indirect interactions.24 Karrikins are capable of inducing seed germination and are produced during the burning of vegetation. Even structurally, karrikins partly resemble strigolactones by the presence of a methylbutenolide scaffold. Therefore, we cannot completely rule out the possibility that the Arabidopsis response to the strigolactone mimics may be mediated through the KAI2 receptor. Therefore, in the future, to ascertain whether the activity of synthesized strigolactone mimics is induced through the strigolactone signaling pathways, further studies evaluating these compounds on Arabidopsis max mutant plants would be necessary. This was, though, beyond the scope of this study. In conclusion, a series of triazolide strigolactone mimics was synthesized using a concise three-step reaction procedure. Strigolactone mimics were evaluated for their ability to affect Arabidopsis root architecture. The total root length and the number of root tips were measured after treatment with various concentrations of strigolactone mimics and of GR24 as a reference molecule. At high concentration (100 μM), the potential toxicity of the compounds was probably responsible for their inhibitory effect on both root length and number of root tips. On the other hand, at low concentration (1 μM), strong induction of root elongation as well as increase in the number of root tips were observed. Compounds 4b and 4c were found to be especially effective. They induced a 2-fold increase in root elongation when compared to control and GR24 treatment. Concurrently, they elicited more than 4-fold increase in the number of root tips when compared to control and almost 2-fold increase when compared to GR24. Even though further studies are necessary to confirm the direct effect of the strigolactone mimics on strigolactone signaling, the strigolactone mimics resembled GR24 in biological activity, thus indicating the same mode of action.

increasing root hair elongation was observed with decreasing GR24 concentration.2j In addition, the influence of strigolactones on primary root length was previously reported to depend greatly on the growth conditions.2d,22 Considering the reported results on the effect of GR24 on lateral root density, the finding that the number of root tips increases upon treatment with either the strigolactone mimics or GR24 was rather surprising. The opposing results of our study with published data may arise from differences in experimental procedures and lateral root development evaluation. In reality, the experimental procedures vary greatly among the published studies, especially in GR24 concentration and in incubation time. GR24 concentration ranges from as low as 10−11 M2j to as high as 50 μM2e and incubation time ranges from about 6 to 14 days.2d,j As GR24 was reported to display toxicity at concentrations above 10 μM2j and also GR24induced activity was found to diminish with prolonged incubation time (11−14 days),2d the direct comparison of the studies may be challenging. Moreover, high auxin levels were observed to revert the negative effect of GR24 on lateral root density into a positive effect.2d Furthermore, the studies evaluating the effect of GR24 on Arabidopsis lateral root density suggest the inhibition of lateral root outgrowth in a MAX2-dependent manner, whereas the unclear lateral root phenotypes of max3 and max4 mutants indicate that signals other than strigolactones may also play a role in lateral root development.22 In pea, a recent study into the role of strigolactones on photomorphogenesis revealed that only advetitious rooting is directly affected by endogenous strigolactones,23 thus opposing previous studies reporting the effect of strigolactones on shoot branching and bud outgrowth in pea.2g,16b,d In any case, under our experimental conditions, synthesized strigolactone mimics resembled the effect of GR24. Among the strigolactone derivatives synthesized to date, just a few were evaluated for their influence on Arabidopsis root architecture. Fukui et al. (2013)19 selected, from the previous studies on rice,2f the most active strigolactone mimic, 4bromodebranone, and further evaluted its activity in other strigolactone bioactivity assays. In Arabidopsis, the root hair length and the number of lateral roots were measured. Though its effect was less pronounced than that of GR24, a 10 μM concentration of 4-bromodebranone was observed to induce root hair elongation and reduce the number of lateral roots.19 However, the exact experimental procedure defining the number of lateral roots was determined is missing. Other strigolactone derivatives with an acyclic unsaturated system connected to a D-ring were also reported to affect lateral root formation in Arabidopsis. These derivatives reduced lateral root density at 1 μM.16b Even though the number of studies concerning the phytohormonal activity of strigolactones is increasing, to date, there are no other reports studying the effect of synthesized strigolactone derivatives on Arabidopsis primary and lateral roots. From the results obtained, it is obvious that at low concentration the synthesized strigolactone mimics are at least as effective as GR24 in impact on root architecture of A. thaliana. At high concentration, the observed activity of some compounds may be atributed to their general toxicity of applied concentration as was previously reported for GR24.2d Therefore, it may be concluded that the activity of synthesized strigolactone mimics corresponds to that of GR24, thus indicating the same mode of action.

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EXPERIMENTAL SECTION

General Experimental Procedures. All reactions requiring anhydrous or inert conditions were carried out under a positive atmosphere of argon in oven-dried glassware. Solutions or liquids were introduced in round-bottom flasks using oven-dried syringes through rubber septa. All reactions were stirred magnetically using Tefloncoated stirring bars. If needed, reactions were warmed using an electrically heated silicon oil bath, and the stated temperature corresponds to the temperature of the bath. Organic solutions obtained after aqueous workup were dried over MgSO4. The removal of solvents was accomplished using a rotary evaporator at water aspirator pressure. GR24 stands for rac-GR24, which was purchased from Stichting Chemiefonds Paddepoel, The Netherlands. Chemicals for the syntheses were purchased from Sigma-Aldrich (Prague, Czech Republic). Solvents for extractions and chromatography were of

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2.00 (3H, t, J = 1.6 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ 171.1 (CO), 142.2 (CH, C-4), 134.2 (C), 88.6 (CH, C-5), 10.6 (CH3). General Procedure for the Synthesis of Triazolide Strigolactone Mimics (4a−i). To a solution of 5-azido-3-methyl-2(5H)furanone (3) (1 × n) in 15 mL of t-BuOH/H2O (1/1, v/v) was added the appropriate ethynyl compound (1.2 × n), and successively solutions of CuSO4 × 5H2O (0.2 × n) in 0.5 mL of H2O and sodium ascorbate (0.4 × n) in 0.5 mL of H2O. The reaction mixture was stirred overnight at 40 °C and the solvent evaporated. The residue was dissolved in EtOAc, washed with water, and the water phase was extracted with EtOAc (4 × 20 mL). The products were racemic mixtures. The following compounds were prepared using these methods: 3-Methyl-5-(4-phenyl-1H-1,2,3-triazol-1-yl)furan-2(5H)-one (4a). For the reaction, 80.0 mg (0.58 mmol) of 5-azido-3-methyl-2(5H)furanone (3) was used. Purification by column chromatography (gradient 7/3 to 6/4, v/v, hexanes/EtOAc) gave 3-methyl-5-(4phenyl-1H-1,2,3-triazol-1-yl)furan-2(5H)-one (4a) as a white solid (135 mg, 97%). IR (CHCl3) νmax 3136 (triazole), 3095 (Ph), 1779 (CO), 1665 (CC), 1609 (Ph), 1580 (Ph), 1557 (triazole), 1484 (Ph), 1460 (Ph), 1435 (Ph), 1370 (CH3), 1321 (C−O, lactone, 1087 (Ph), 1025 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz): δ 7.85 (1H, s, H-5′), 7.83−7.80 (2H, m, Ar), 7.46−7.41 (2H, m, Ar), 7.38−7.34 (1H, m, Ar), 7.27 (1H, quintet, J = 1.7 Hz, H-4), 7.06 (1H, quintet, J = 1.7 Hz, H-5), 2.13 (3H, t, J 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz): δ 170.5 (CO), 148.8 (C), 141.0 (CH, C-4), 135.0 (C), 129.6 (C), 128.9 (2 × CH, Ar), 128.7 (CH, Ar), 125.9 (2 × CH, Ar), 117.9 (CH, C-5′), 85.0 (CH, C-5), 10.9 (CH3). HRMS m/z 242.09243 (calcd for C13H12O2N3 ([M + H]+): 242.09240). 5-(4-Mesityl-1H-1,2,3-triazol-1-yl)-3-methylfuran-2(5H)-one (4b). For the reaction, 230.0 mg (1.65 mmol) of 5-azido-3-methyl-2(5H)furanone (3) was used. Purification by column chromatography (gradient 7/3 to 6/4, v/v, hexanes/EtOAc) gave 5-(4-mesityl-1H1,2,3-triazol-1-yl)-3-methylfuran-2(5H)-one (4b) as a white solid (395 mg, 84 %). IR (CHCl3) νmax 3138 (triazole), 3093 (Ph), 2953 (CH3), 2923 (CH3), 1738 (CO), 1666 (CC), 1614 (Ph), 1476 (Ph), 1443 (Ph), 1377 (CH3), 1321 (C−O, lactone, 1211 (Ph), 1150 (Ph), 1051 (Ph), 1025 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.56 (1H, s, H-5′), 7.33 (1H, quintet, J = 1.7 Hz, H-4), 7.06 (1H, quintet, J = 1.7 Hz, H5), 6.94 (2H, s, Ar), 2.31 (3H, s, CH3Ph), 2.12 (3H, t, J = 1.7 Hz, CH3), 2.08 (6H, s, CH3Ph). 13C NMR (CDCl3, 100 MHz) δ 170.6 (CO), 146.7 (C), 141.0 (CH, C-4), 138.6 (C), 137.7 (2 × C), 134.9 (C), 128.4 (2 × CH, Ar), 126.1 (C), 121.2 (CH, C-5′), 84.9 (CH, C5), 21.1 (CH3Ph), 20.6 (2 × CH3Ph), 10.9 (CH3). HRMS m/z 284.13937 (calcd for C16H18O2N3 ([M + H]+): 284.13935). 3-Methyl-5-[4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl]furan-2(5H)one (4c). For the reaction, 230.0 mg (1.65 mmol) of 5-azido-3-methyl2(5H)-furanone (3) was used. Purification by column chromatography (gradient 7/3 to 6/4, v/v, hexanes/EtOAc) gave 3-methyl-5-[4-(4pentylphenyl)-1H-1,2,3-triazol-1-yl]furan-2(5H)-one (4c) as a white solid (505 mg, 98%). IR (CHCl3) νmax 3137 (triazole), 3098 (Ph), 2954 (pentyl), 2925 (pentyl), 2873 (pentyl), 2853 (pentyl), 1771 (CO), 1668 (CC), 1563 (triazole), 1617 (Ph), 1498 (Ph), 1445 (Ph), 1382 (CH3), 1325 (C−O, lactone), 1169 (Ph), 1086 (pentyl +Ph), 1057 (pentyl+Ph), 1042 (pentyl+Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.80 (1H, s, H-5′), 7.72 (2H, td, J = 8.2, 1.9 Hz, Ar), 7.26−7.25 (2H, m, Ar), 7.23 (1H, br. s, H-4), 7.05 (1H, quintet, J = 1.7 Hz, H-5), 2.63 (2H, dd, J = 7.9, 7.5 Hz, CH2(CH2)3CH3), 2.13 (3H, t, J = 1.7 Hz, CH3), 1.67−1.60 (2H, m, CH2CH2CH2CH2CH3), 1.35−1.32 (4H, m, CH2CH2CH2CH2CH3), 0.89 (3H, t, J = 7.0 Hz, CH2CH2CH2CH2CH3). 13C NMR (CDCl3, 100 MHz) δ 170.5 (CO), 148.9 (C), 143.8 (C), 141.1 (CH, C-4), 134.9 (C), 129.0 (CH, Ar), 127.0(C), 125.8 (CH, Ar), 117.5 (CH, C-5′), 85.0 (CH, C-5), 35.7 (CH 2 CH 2 CH 2 CH 2 CH 3 ), 31.5 (CH 2 CH 2 CH 2 CH 2 CH 3 ), 31.0 (CH 2 CH 2 CH 2 CH 2 CH 3 ), 22.5 (CH 2 CH 2 CH 2 CH 2 CH 3 ), 14.0 (CH2CH2CH2CH2CH3), 10.9 (CH3). HRMS m/z 312.17070 (calcd for C18H22O2N3 ([M + H]+): 312.17065). 5-[4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran2(5H)-one (4d). For the reaction, 150.0 mg (1.08 mmol) of 5-azido-3-

technical grade and purchased from Penta Chemicals s.r.o. (Prague,Czech Republic) or from VWR (Stribrna Skalice, Czech Republic). Solvents used in reactions were distilled from appropriate drying agents and stored under argon over activated Linde 4 Å molecular sieves. Column and flash chromatography was carried out using Merck silica gel (60−200 μm). Analytical TLC was performed with Merck silica gel 60 F254 plates. Visualization was accomplished by UV-light (254 nm) and staining with a vanillin solution, followed by heating. IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer. 1H, 13C, 19F, and 2D (H−COSY, HMQC) NMR spectra were recorded on a Bruker Avance III HD 400 MHz spectrometer equipped with a Prodigy cryo-probe. TMS (0 ppm, 1H NMR), CDCl3 (77 ppm, 13C NMR), and CFCl3 (0 ppm, 19F NMR) were used as internal references. The chemical shifts (δ) are reported in ppm and the coupling constants are recorded in Hz. The hydrogen and carbon assignments were done according to 1H−1H COSY and 1 H−13C HMQC experiments. The formation of final compounds as racemic mixtures was confirmed by NMR analysis using a chiral agent (R)- and (S)-2,2,2-trifluoro-1-(9-anthryl)ethanol (Figures S21 and S22, Supporting Information). Mass spectra were recorded on a LTQ Orbitrap XL spectrometer. Plant Material. Seeds of A. thaliana var. Col-0 (Columbia) were purchased from NASC (The European Arabidopsis Stock Centre, NASC ID: N1092). Seeds were washed in 70% (v/v) EtOH for 10 min and than surface sterilized in 10% (v/v) NaOCl for 15 min, soaked in sterile water three times for 10 min, and germinated on hormone-free Murashige and Skoog (MS) medium at 25 °C, 16 h photoperiod (irradiance of 115 μmol·m−2·s−1). After emergence of the first pair of leaves (aproximatelly 7 days), the seedlings were used for the tests. Biological Activity Test. Nine seedlings of A. thaliana were placed in nine plastic dishes (one seedling per dish) of 10 × 10 cm dimension with 40 mL of hormone-free Murashige and Skoog (MS) medium with agar supplement with 100 μL of tested strigolactone mimics in solutions at concentrations of 1, 10, and 100 μM. Each treatment had three replicates. The exposure took 7 days under a 16 h photoperiod (irradiance of 115 μmol·m−2·s−1) at 25 °C in vertical position of dishes. Root Measurements. Roots of each plant were scanned on an EPSON PERFECTION V700 PHOTO scanner. The root images were processed by software WinRHIZO (Regent Instruments, Inc., Ville de Quebec, Canada), which calculated the total root length as well as the number of root tips. Statistics. The differences among treatments were tested by oneway ANOVA with the Fisher LSD pos-hoc test. Significance level P = 0.05 was used for both analyses. Each strigolactone treatment (each concentration) was represented by nine biological replicates. STATISTICA 7 (StatSoft, Tulsa, OK, U.S.A.) software was used for all the computations. 5-Bromo-3-methyl-2(5H)-furanone (2). 5-Bromo-3-methyl2(5H)-furanone (2) was synthesized according to a reported procedure.16c To a solution of 3-methyl-2(5H)-furanone (90% technical grade, 339 mg, 3.11 mmol) in CCl4 (4 mL) was added NBS (677 mg, 3.80 mmol) and a catalytic amount of benzoylperoxide (167 mg, 0.69 mmol) as a radical initiator. The reaction mixture was heated under reflux at 78 °C for 1.5 h, cooled to 0 °C, filtered, and the solvent evaporated. The 5-bromo-3-methyl-2(5H)-furanone (2) was used directly in the next step. 5-Azido-3-methyl-2(5H)-furanone (3). Sodium azide (292 mg, 4.49 mmol) was suspended in dry DMF (3 mL) under an argon atmosphere and 5-bromo-3-methyl-2(5H)-furanone (2) dissolved in dry DMF (3 mL) was added dropwise via syringe. The reaction mixture was stirred for 1.5 h at room temperature, and the solvent was evaporated. The residue was dissolved in MeOH and adsorbed on silica gel. Purification by column chromatography (85/15, v/v, hexanes/EtOAc) gave 5-azido-3-methyl-2(5H)-furanone (3) (258 mg, 60%) as a yellow oil. IR (CHCl3) νmax 2964, 2929, 2202 (N3), 2114 (N3), 1792 (CO), 1668 (CC), 1382 (CH3), 1382 (CH3), 1326 (C−O, lactone) cm−1. 1H NMR (CDCl3, 400 MHz): δ 6.88 (1H, quintet, J = 1.6 Hz, H-4), 5.88 (1H, quintet, J = 1.7 Hz, H-5), 1324



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5-[4-(4-Aminophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran2(5H)-one (4h). For the reaction, 258.0 mg (1.85 mmol) of 5-azido-3methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 99.5/0.5 to 99/1, v/v, CHCl3/MeOH) gave 5-[4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran2(5H)-one (4h) as a yellow solid (210 mg, 44%). IR (CHCl3) νmax 3492 (NH2), 3405 (NH2), 3152 (triazole), 3024, 1787 (CO), 1665 (CC), 1624 (NH2), 1503 (Ph), 1370 (CH3), 1317 (C−O, lactone), 1181 (Ph), 1092 (Ph), 1027 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.69 (1H, s, H-5′), 7.61−7.58 (2H, m, Ar), 7.23 (1H, quintet, J 1.7 = Hz, H-4), 7.02 (1H, quintet, J = 1.7 Hz, H-5), 6.74−6.70 (2H, m, Ar), 3.81 (2H, br.s, NH2), 2.11 (3H, t, J = 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz) δ 170.6 (CO), 149.1 (C), 147.0 (C), 141.2 (CH, C-4), 134.8 (C), 127.1 (2 × CH, Ar), 119.9 (C), 116.5 (CH, C-5′), 115.2 (2 × CH, Ar), 85.0 (CH, C-5), 10.8 (CH3). HRMS m/z 257.10334 (calcd for C13H13O2N4 ([M + H]+): 257.10330). 5-[4-(1-Hydroxycyclohexyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran2(5H)-one (4i). For the reaction, 110.0 mg (0.79 mmol) of 5-azido-3methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 1/1 to 0/1, v/v, hexanes/EtOAc) gave 5[4-(1-hydroxycyclohexyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran-2(5H)one (4i) as a white solid (200 mg, 96%). IR (CHCl3) νmax 3453 (OH), 3145 (triazole), 2929 (cyclohexanol), 2854 (cyclohexanol), 1782 (CO), 1664 (CC), 1556 (triazole), 1381 (CH3), 1320 (C−O, lactone), 1031(C−OH) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.54 (1H, s, H-5′), 7.21 (1H, quintet, J = 1.7 Hz, H-4), 7.01 (1H, quintet, J = 1.7 Hz, H-5), 2.31 (1H, s, OH), 2.11 (3H, t, J = 1.7 Hz, CH3), 2.01− 1.94 (2H, m, CH2), 1.88−1.83 (2H, m, CH2), 1.78−1.55 (5H, m, 2 × CH2, 1 × CH2), 1.40−1.32 (1H, m, 1 × CH2). 13C NMR (CDCl3, 100 MHz) δ 170.5 (CO), 156.8 (C), 141.0 (CH, C-4), 134.9 (C), 118.2 (CH, C-5′), 85.0 (CH, C-5), 69.7 (C−OH), 38.0 (CH2), 38.0 (CH2), 25.2 (CH2), 21.8 (2 × CH2), 10.8 (CH3). HRMS m/z 286.11627 (calcd for C13H17O3N3Na ([M + Na]+): 286.11621).

methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 7/3 to 6/4, v/v, hexanes/EtOAc) gave 5[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran-2(5H)-one (4d) as a white solid (238 mg, 85%). IR (CHCl3) νmax 3140 (triazole), 3129 (Ph), 3108 (Ph), 1781 (CO), 1665 (CC), 1612 (Ph), 1563 (triazole), 1498 (Ph), 1441 (Ph), 1367 (CH3), 1317 (C−O, lactone), 1087 (Ph), 1030 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.83− 7.78 (3H, m, H-5′, Ar), 7.28 (1H, quintet, J = 1.7 Hz, H-4), 7.13 (2H, J = 8.8 Hz, Ar), 7.07 (1H, quintet, J = 1.7 Hz, H-5), 2.13 (3H, t, J = 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz) δ 170.4 (CO), 163.0 (C, d, JC−F = 246,2 Hz, Ar), 147.9 (C), 141.0 (CH, C-4), 135.1 (C), 129.6 (C), 128.9 (2 × CH, Ar), 127.7 (CH, d, JC−F = 8.3 Hz, Ar), 125.8 (C, JC−F = 3.4 Hz, Ar), 117.7 (CH, C-5′), 116.0 (CH, JC−F = 21.6 Hz, Ar), 115.9 (CH, Ar), 85.0 (CH, C-5), 10.9 (CH3). 19F NMR (CDCl3, 376 MHz) δ −113.01 (tt, JH−F = 5.3, 8.5 Hz, F). HRMS m/z 260.08303 (calcd for C13H11O2N3F ([M + H]+): 260.08298). 3-Methyl-5-{4-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-1-yl}furan-2(5H)-one (4e). For the reaction, 150.0 mg (1.08 mmol) of 5azido-3-methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 7/3 to 6/4, v/v, hexanes/EtOAc) gave 3methyl-5-{4-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazol-1-yl}furan2(5H)-one (4e) as a white solid (278 mg, 83%). IR (CHCl3) νmax 3138 (triazole), 3111 (Ph), 3089 (Ph), 1776 (CO), 1661 (CC), 1623 (Ph), 1585 (Ph), 1443 (Ph), 1375 (CH3), 1326 (C−O, lactone; C−F), 1105 (C−F), 1085 (Ph), 1066 (Ph), 1032 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 8.00−7.94 (3H, m, H-5′, Ar), 7.72−7.70 (2H, m, Ar), 7.29 (1H, quintet, J = 1.7 Hz, H-4), 7.09 (1H, quintet, J = 1.7 Hz, H-5), 2.15 (3H, t, J = 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz) δ 170.3 (CO), 147.4 (C), 140.9 (CH, C-4), 135.2 (C), 133.0 (C), 130.6 (C, d, JC−F = 32.4 Hz, Ar), 126.1 (2 × CH, s, Ar), 126.0 (2 × CH, q, JC−F = 3.8 Hz, Ar), 123.9 (C, d, JC−F = 269.8 Hz, CF3), 118.7 (CH, C-5′), 85.0 (CH, C-5), 11.0 (CH3). 19F NMR (CDCl3, 376 MHz) δ −63.23 (s, CF3). HRMS m/z 310.07989 (calcd for C14H11O2N3F3 ([M + H]+): 310.07979). 5-[4-(3,5-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran2(5H)-one (4f). For the reaction, 240.0 mg (1.73 mmol) of 5-azido-3methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 85/15 to 1/1, v/v, hexanes/EtOAc) gave 5-[4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-methylfuran-2(5H)one (4f) as a white solid (414 mg, 87%). IR (CHCl3) νmax 3141 (triazole), 3099 (Ph), 1782 (CO), 1665 (CC), 1629 (Ph), 1598 (Ph), 1466 (Ph), 1431 (Ph), 1374 (CH3), 1317 (C−O, lactone), 1238 (Ph), 1120 (Ph), 1033 (Ph) cm−1. 1H NMR (CDCl3, 400 MHz) δ 7.89 (1H, s, H-5′), 7.39−7.33 (2H, m, Ar), 7.28 (1H, quintet, J = 1.7 Hz, H-4), 7.07 (1H, quintet, J = 1.7 Hz, H-5), 6.81 (1H, tt, J = 8.8, 2.3 Hz, Ar), 2.14 (3H, t, J = 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz) δ 170.2 (CO), 163.4 (2 × C, d, JC−F = 246.7 Hz, C−F) 146.8 (C, t, JC−F = 3.2 Hz, C-4′), 140.8 (CH, C-4), 135.2 (C), 132.7 (C, t, JC−F = 10.4 Hz, Ar), 118.7 (CH, C-5′), 108.8 (2 × CH, dd, JC−F = 26.7, 11.6 Hz, Ar), 104.0 (CH, t, JC−F = 25.2 Hz, Ar), 85.0 (CH, C-5), 10.9 (CH3). 19F NMR (CDCl3, 376 MHz) δ −109.27 (m, 2 × F). HRMS m/z 278.07363 (calcd for C13H10O2N3F2 ([M + H]+): 278.07356). 5-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylfuran-2(5H)-one (4g). For the reaction, 250.0 mg (1.80 mmol) of 5azido-3-methyl-2(5H)-furanone (3) was used. Purification by column chromatography (gradient 99.5/0.5 to 99/1, v/v, CHCl3/MeOH) gave 5-{4-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylfuran2(5H)-one (4g) as a white solid (335 mg, 66%). IR (CHCl3) νmax 3131 (triazole), 3096 (Ph), 2808 (CH3), 1785 (CO), 1669 (CC), 1619 (Ph), 1570 (triazole), 1559 (Ph), 1508 (Ph), 1443 (Ph), 1426 (Ph), 1372 (CH3), 1318 (C−O, lactone), 1234 (Ph), 1127 (Ph) cm−1. 1 H NMR (CDCl3, 400 MHz) δ 7.70−7.66 (3H, m, H-5′, Ar), 7.25 (1H, quintet, J = 1.7 Hz, H-4), 7.04 (1H, quintet, J = 1.7 Hz, H-5), 6.78−6.74 (2H, m, Ar), 3.00 (6H, s, N(CH3)2), 2.12 (3H, t, J = 1.7 Hz, CH3). 13C NMR (CDCl3, 100 MHz) δ 170.6 (CO), 150.6 (C), 149.3 (C), 141.2 (CH, C-4), 134.8 (C), 126.8 (2 × CH, Ar), 117.5 (C), 116.1 (CH, C-5′), 112.3 (2 × CH, Ar), 85.0 (CH, C-5), 40.4 (N(CH3 ) 2), 10.9 (CH 3 ). HRMS m/z 285.13467 (calcd for C15H17O2N4 ([M + H]+): 285.13460).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00879. 1 H and 13C NMR spectra of compounds 4a−i (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +420225106832. Fax: +420225106832. ORCID

Marcela Dvorakova: 0000-0002-6664-6870 Petr Soudek: 0000-0002-5298-5978 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support by the grand LD14127 from the Ministry of Education, Youth and Sports of the Czech Republic.

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REFERENCES

(1) (a) Gomez-Roldan, V.; Fermas, S.; Brewer, P. B.; Puech-Pages, V.; Dun, E. A.; Pillot, J. P.; Letisse, F.; Matusova, R.; Danoun, S.; Portais, J. C.; Bouwmeester, H.; Becard, G.; Beveridge, C. A.; Rameau, C.; Rochange, S. F. Nature 2008, 455, 189−194. (b) Umehara, M.;

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