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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2023 , Vol. 35 >Issue 9: 1341 - 1356

DOI: https://doi.org/10.7536/PC221234

Review

Strigolactone and Its Novel Derivatives

  • Zhaoyong Kang 1, 3 ,
  • Xiaoqi Dong 1, 3 ,
  • Shengnan Liu , 1, 2, * ,
  • Qingzhi Gao , 1, 3, *
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  • 1 Frontiers Science Center for Synthetic Biology (Ministry of Education of China), Tianjin University,Tianjin 300072, China
  • 2 Institute of Molecular Plus, Tianjin University,Tianjin 300072, China
  • 3 School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery& High-Efficiency, Tianjin University,Tianjin 300072, China
*e-mail: (Shengnan Liu);
(Qingzhi Gao)

Received date: 2023-01-02

  Revised date: 2023-05-24

  Online published: 2023-08-06

Supported by

The National Key R&D Program Projects of China(2020YFA0907903)

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Abstract

Strigolactones (SLs) are the most concerned endogenous sesquiterpenoid phytohormones.Recent studies have shown that strigolactones play crucial roles in inhibition of plant hypocotyl elongation and crop tillering, regulating root growth and development, stimulation of parasitic weed seed germination, coordinating the symbiotic interaction between parasitic plants and fungi, as well as regulation of plant response to biotic or abiotic stresses. Therefore, it is considered to be a new type of phytohormone with great development value and application potential in the field of agricultural science and plant protection. In addition, SL derivatives have also attracted much attention in the field of innovative drug research as the studies have found that: (1) SLs exhibit inhibitory activities against several tumor cell lines such as liver cancer, breast cancer, prostate cancer, glioblastoma, and colorectal cancers; (2) they possess anti-inflammation and glucose metabolism inhibitory activity. This paper aims to review the latest research progress of strigolactone and its structural derivatives with brief analysis on their biological activity, mechanism of action and structure-activity relationship. We hope this review provide guidance and directions on molecular design, development and utilization of SL natural products.

Contents

1 Introduction

2 Structural features and classification of strigolactones

3 The biosynthetic pathway and signal transduction mechanism of strigolactones

4 Structural characteristics and classification of natural strigolactones

5 Structural characteristics and classification of synthetic strigolactones

5.1 Canonical derivatives of strigolactone

5.2 Non-canonical derivatives of strigolactone

6 Conclusion and outlook

Key words： strigolactones; new phytohormone; green agriculture; biomedicine; molecular mechanism

Cite this article

Zhaoyong Kang , Xiaoqi Dong , Shengnan Liu , Qingzhi Gao . Strigolactone and Its Novel Derivatives[J]. Progress in Chemistry, 2023 , 35(9) : 1341 -1356 . DOI: 10.7536/PC221234

1 Introduction

Natural Strigolactones (SLs) are sesquiterpenoid plant hormones derived from carotenoids, which were first discovered in the root exudates of cotton and named as germination promoters of the root-parasitic plant Striga. The molecular structure of this natural product and its amazing phytohormone activity were first published in Science in 1966[1]. Because the signaling pathway and molecular mechanism of strigolactone regulating plant growth and development are extremely complex, until 2020,Li Jiayang, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, published a research paper in Nature, which systematically revealed the new plant hormone signal transduction mechanism of strigolactone for the first time, and pushed the research of strigolactone to a new climax again[2].
Studies have shown that SLs, as a new plant hormone, can promote the seed germination of parasitic weeds and the hyphal branching of arbuscular mycorrhizal fungi in soil, and effectively coordinate the symbiotic and parasitic interactions between parasitic plants and fungi[3]. In addition, SLs are synthesized in the root and stem of plants, which can be transported upward through the xylem or directly inhibit plant branching in the stem, and act as endogenous signals that can move upward to negatively regulate the growth and development of branches[4]. Recent studies have found that SLs can inhibit hypocotyl elongation, promote leaf senescence and participate in the growth and development of plant roots, such as promoting taproot elongation, reducing lateral root density, and promoting root hair growth[5][6][7][8][9][10]. Therefore, SLs have very rich application potential in the field of agriculture and plant protection. With the development of research on these plant hormones, the scientific community has a more comprehensive understanding of the biosynthesis, transport and signal transduction pathways of SLs. To date, more than 30 SLs have been identified from root exudates of different plant species[11]. However, the low natural yield (25 ~ 30 pg per plant per day) greatly limits its development and utilization. Therefore, many SLs structural analogues with simplified structure and maintained biological activity have been synthesized, among which the synthetic analogues represented by GR24 have become the most widely studied SLs derivatives in plant science[12][10]. At the same time, the latest research results have found that SLs have good anticancer activity, inflammation inhibition and neuroprotection against breast cancer, prostate cancer, liver cancer, colorectal cancer, glioblastoma and other cancers[13]. In this paper, the latest research progress of strigolactones and their derivatives with significant plant and biological activities were reviewed, and their biological activities, mechanisms of action and structure-activity relationships were classified and briefly analyzed, which provided research ideas and directions for the molecular design and further research and development of these natural products.

2 Structural characteristics and classification of strigolactones

SLs can be divided into typical and atypical strigolactones based on their chemical structure (Fig. 1). Typical SLs have similar sesquiterpene carbon skeleton structures, which can be divided into two groups, Strigol and Orobanchol, both of which are composed of a tricyclic (ABC ring) lactone linked to 5-hydroxyfuranone (D ring) through an enol ether bridge[3]. It was found that the enol ether bridge and the D ring were the conserved structures to maintain the SL-like biological activity, and the R stereoconfiguration of the C-2 'of the D ring was an important structural feature to maintain the potent sprouting stimulating activity[14]. Different functional group modifications such as alkyl, hydroxyl or acetoxy were found on the A and B rings of natural isolates, which constituted the structural diversity of natural SLs[15]. At present, more than 30 natural strigolactones are isolated from the root exudates of cotton, rice, red clover, cowpea and tobacco, and are used as germination stimulators of parasitic weed seeds Striga hermonthica (S. hermonthica), Orobanche minor (O. minor) and Phelipanche ramosa (P. ramosa) or mycelial branching inducers of Arbuscular mycorrhizal (AM) fungi. Atypical SLs are a class of derivatives discovered during the study of strigolactone series metabolites, which are characterized by conserved enol ether bonds and D-ring structures, but the classical sesquiterpene ABC ring structure is replaced by aliphatic chains of a diverse skeleton.
图1 天然独脚金内酯及其人工合成类似物的结构

Fig.1 Structural characteristics of strigolactone and its synthetic analogs

Because the content of natural SLs as plant hormones is very low, the structural analogues are difficult to separate, and most chiral structures are difficult to synthesize artificially, the molecular mechanism research and application development of natural strigolactones have been a major challenge in this field for a long time. In order to break through the above scientific problems, researchers have gradually designed and synthesized a series of simplified strigolactone analogues on the basis of confirming that the D ring is a conserved structure that maintains the biological activity of SLs. Compared with the natural structure, the artificially designed SLs derivatives have more abundant structural diversity and are easier to prepare in the laboratory, which not only provide a wide variety of molecular probes for the study of the molecular mechanism of SLs signaling, but also find artificial plant hormone derivatives with higher activity than natural products and potential development value. Table 1 summarizes representative naturally occurring typical and atypical strigolactones reported to date, as well as their biological activities, sources, and biological targets.
表1 天然独脚金内酯的分类和生物活性

Table 1 Classification and biological activity of natural strigolactones

Classification SLs name Plant source Biological activity Action object & biotarget ref
Strigol-tpye SLs
Canonical SLs Strigol (1) Cotton, Menispermum dauricum germination stimulant
hyphal branching inducers
inhibit shoot branching
anti-inflammation, anti-cancer		 Striga, Orobanche
arbuscular mycorrhizal fungi
Rice
Nrf2, NF-κB		 16~18
5-Deoxystrigol (5DS, 2) Cotton, Chinese milk vetch, Sorghum hyphal branching inducers
inhibit shoot branching
liver injury protection		 arbuscular mycorrhizal fungi
Rice
Nrf2		 4,19~21
Strigone (3) Houttuynia cordata germination stimulant
anti-hepatic fibrosis		 O. minor, P. ramosa, S. hermonthica
TGF		 22
Sorgolactone (4) Sorghum germination stimulant Striga, Orobanche 23
Sorgomol (5) Sorghum germination stimulant Striga, Orobanche 24,25
Orobanchol-type SLs
Orobanchol (ORO, 6) Red clover,
Rice, Tobacco		 germination stimulant O. minor, P. ramosa 26,27
4-Deoxyorobanchol (4DO, 7) Rice germination stimulant O. minor 28,29
Orobanchol acetate (8) Cowpea, Soybean,
Red clover		 germination stimulant O. minor, O. ramosa 30,31
7-Oxoorobanchyl acetate (9) Flax germination stimulant O. minor 32
7-Oxoorobanchol (10) Flax germination stimulant O. minor 32
Solanacol (11) Tobacco germination stimulant O. minor 26,33,34
Fabacyl acetate (12) Pea, Faba bean, Alfalfa germination stimulant O. minor 35
Medicaol (13) Medicago truncatula hyphal branching inducers arbuscular mycorrhizal fungi 36
Non-canonical SLs Carlactonate (CL, 14) Sunflower germination stimulant
inhibit shoot branching		 S. hermonthica
Rice		 37
Carlactonoic acid (CLA, 15) Rice, Arabidopsis
thaliana, Selaginella		 inhibit shoot branching Arabidopsis thaliana 38,39
Methyl carlactonate (MeCLA, 16) Sunflower hyphal branching inducers Gigaspora margarita 40,41
Methyl heliolactonate (17) Sunflower germination stimulant S. hermonthica 42
Avenaol (18) Black oat germination stimulant P. ramose, S.hermonthica, O. minor 43
Methyl zealactonate (19) Maize germination stimulant O. minor, P. ramosa, S. hermonthica 44,45
Lotuslactone (20) Lotus japonicus hyphal branching inducers
germination stimulant		 arbuscular mycorrhizal fungi
O. minor, P. ramosa, S. hermonthica		 46
Cannalactone (21) Cannabis sativa germination stimulant P. ramosa 47
Bryosymbiol (22) Marchantia paleacea hyphal branching inducers
germination stimulant		 arbuscular mycorrhizal fungi
O. minor, P. ramosa, S. hermonthica		 48

3 Biosynthetic Pathway and Signal Transduction Mechanism of Strigolactone

SLs are biosynthesized via the carotenoid pathway[49]. In 2012, Al-Babili et Al. Used recombinant iron-containing protein 27 (Dwarf 27, D27), Carotenoid cleavage dioxygenase 7 (Carotenoid cleavage dioxygenase 7, CCD7) and Carotenoid cleavage dioxygenase 8 (Carotenoid cleavage dioxygenase 8, CCD 8) from Arabidopsis thaliana, pea and rice for in vitro biochemical analysis.It was found that the three enzymes sequentially converted all-trans-β-carotene to 9-cis-β-carotene and 9-cis-β-apo-10 '-carotenal, and finally generated an atypical structure of SL caprolactone (CL) (Fig. 2 and Fig. 4)[37]. The CYP711A subfamily of Cytochrome P450 (CYP) enzymes has been found to play a role in converting CL into typical and atypical SLs in vascular plants. Isotope labeling and gene mutation studies showed that CL could be used as a substrate for Arabidopsis SLs mutant MAX1 protein, converting CL to Carlactonoic acid (CLA) and further to Arabidopsis endogenous metabolites 4-deoxyorobanchol (4DO) and Orobanchol (ORO)[50,51]. In rice, CYP711A2/Oryza sativa 900 (Os900) converts CL to 4DO, a natural derivative of SLs, and CYP711A3/Os1400 further catalyzes the hydroxylation of 4DO to ORO, a natural derivative of SLs[28].
图2 SLs在不同植物中的生物合成途径

Fig.2 The biosynthetic pathway of SLs in different plants

In the study of the signal transduction mechanism of strigolactone, Kyozuka et al. First discovered that α/β hydrolase 14 (Dwarf 14, D14) is a strigolactone binding receptor in 2009[52]. Subsequently, many other D14 homologs were found, such as Arabidopsis thaliana D14 (AtD14), rice OsD14, Petunia Decreased apical dominance 2 (DAD2), Pisum sativum Ramosus 3 (RMS3) and Striga hermonthica hyposensitive to light (ShHTL)[53][52][54][55][56]. As shown in fig. 3, after SL binds to the D14 receptor protein, SL is hydrolyzed and releases a non-phytohormone active product ABC-OH, while the lactone structure of the D ring reacts with the nucleophilic group in the receptor protein to form a Covalently linked intermediate mole cule (CLIM), which induces a conformational change in D14.The binding of SLs to the F-box protein D3/MAX2 and the D53/SMXLs family of inhibitors, followed by ubiquitination and degradation of the D53/SMXLs protein complex by the 26 S proteasome, accomplishes the biological activity of SLs in regulating various plant responses, and the D-ring lactone structure of SLs is finally converted into the inactive hydrolysis end product 5-hydroxyfuranone D-OH[57].
图3 SLs与靶点受体D14的结合模式及信号转导机理

Fig.3 Binding mode of SLs with receptor D14 and signal transduction mechanism

Serine (Ser) 97, Histidine (His) 247, and Aspartic acid (Asp) 218 play an important role in the binding mode to D14: the C-2 ′ and C-5 ′ positions of SLs receive nucleophilic attack from Ser97 and His247, respectively, which release the intermediate molecule CLIM covalently bound to His247 and Ser97, resulting in the subsequent phytohormone response (Fig. 3)[58].
With regard to the detailed molecular mechanism of SLs, the latest research results of Li Jiayang et al., published in Nature in 2020, have enabled human beings to have a deeper understanding of this kind of plant hormones from the aspects of gene regulation and transcription factor discovery, but there are still many unsolved mysteries waiting for scientists to explore[2,59⇓ ~61].

4 Structural characteristics and classification of natural strigolactones

So far, more than 30 natural strigolactones and their derivatives have been found in plant root exudates. Fig. 4 lists 22 reported molecular structures. As mentioned above, all natural SLs derivatives contain 5-hydroxyfuranone (D-ring) structural fragments, and this conserved structure plays a decisive role in the phytohormone activity of SLs derivatives. Table 1 summarizes the main biological activities, plant sources, targets and biological targets of the above compounds. It is worth noting that the found natural SLs derivatives act as plant hormones to regulate the whole process of plant development, such as plant height, tillering, leaf shape, root morphology and anthocyanin accumulation. In addition, several SLs derivatives have been found to have biological activities of great value for pharmaceutical development, such as effectively activating Nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibiting Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), so they have good application potential in anti-inflammatory and cancer therapy[16].
图4 天然独脚金内酯结构衍生物及分子特征

Fig.4 Molecular structure characteristics of natural strigolactones

5 Structural characteristics and classification of synthetic strigolactones

5.1 Strigolactone analogs of typical structures

5.1.1 Indolactone derivatives

GR24 is the most representative synthetic analog of indane lactones obtained by replacing the A-ring structure of natural strigol lactone (1) with a benzene ring (Fig. 5). Because of its excellent simulation of natural strigolactone SL-like biological activity, it has been widely used in various studies of strigolactone and as a reference compound. In terms of physiological effects and structure-activity relationship, GR24 can promote the germination of parasitic weed seeds O. minor, and its activity is higher than that of 5DS (2) and comparable to that of 4DO (7)[62]. In GR24-treated wild type, max3-11 and max4-1 mutant Arabidopsis, the auxin efflux mechanism was altered, resulting in an increase in root hair length and a decrease in lateral root density[10]. GR24 inhibits hypocotyl elongation in Arabidopsis, which correlates with light-dependent and kinetic changes in cortical microtubule organization remodeling[63]. In the Arabidopsis branching inhibition assay, GR24 had a significant inhibitory activity on CLA methyltransferase 1/2 (clamt1/2) mutant, which was consistent with the inhibitory effect of MeCLA (16) on the axillary bud branching of clamt1/2 mutant[39]. The results showed that the stereochemical configuration of both natural and synthetic SLs had a significant effect on the activity of inducing mycelial branching of AM fungi, inhibiting stem branching of Arabidopsis thaliana, inhibiting hypocotyl elongation of Arabidopsis thaliana, inhibiting tiller bud growth of rice and stimulating seed germination of parasitic weeds[62,64,65]. In Arabidopsis, the 2'R isoforms of GR24 and 5DS (2) exhibited more potent stem branching inhibitory activity than the 2'S isoforms[62]. It also showed consistent results with Arabidopsis in inhibiting rice tillering[65]. GR24 has four stereoconfigured structures, which are GR245DS(23), GR24ent-5DS(24), GR244DO(25), and GR24ent-4DO(26). Among them, 23 has the best activity of inhibiting hypocotyl elongation, stem branching and rice tillering in Arabidopsis thaliana. Because it is difficult to isolate GR24 with a single configuration, rac-GR24 is widely used in various studies, and its activity of inhibiting hypocotyl elongation in Arabidopsis thaliana is equivalent to that of natural SLs[62,65]. Although GR24 has been tested in the field and can reduce the number of parasitic weed seeds Striga by 50%, the existence of enol ether bond structure makes it unstable, which greatly limits its further development[66].
图5 代表性独脚金内酯类似物

Fig.5 Structures of representative strigolactone analogs

On the basis of GR24, the enol ether bond and D ring were modified to synthesize a new type of strigolactone derivatives. When the enol ether bond was replaced by alkoxy (27 ~ 30), iminoether (31), thioether (32) or other groups (33 ~ 34), the activities of inducing hyphal branching of AM fungi, inhibiting rice tillering, Arabidopsis branching and stimulating seed germination of parasitic weeds were significantly reduced, indicating that the enol ether bond plays an important role in maintaining efficient SL-like biological activities[64⇓⇓⇓~68]. After demethylation of the C-4 'position of the D ring (35), it completely lost the activity of inhibiting stem branching[68]. When a methyl group was introduced at the C-3 'position of the D-ring (36), the inhibitory activity on stem branching exceeded that of GR24, but it was detrimental to the germination of parasitic weed seeds[69]. After further introduction of a methyl group at the C-2 'position (37), its activity of stimulating S. hermonthica germination of parasitic weed seeds was comparable to that of GR24[70]. In addition, after the D ring was replaced by the lactam ring (38), its activity to stimulate seed germination of P. aegyptiaca reached the same level as GR24 at P. aegyptiaca concentrations[71]. To sum up, most of the modifications to the enol ether bond and D ring are not conducive to phytohormone activity, which further confirms that the enol ether bond and D ring are the key conserved structures for GR24 to maintain phytohormone activity.
In order to further improve the phytohormone potency of GR24, scientists have modified its structure, mainly carrying out various substitution reactions on the indane aromatic ring (A-ring) or B-ring, and obtained a large class of synthetic derivatives of strigolactone. The structural modification of A-ring is mainly concentrated at C-7, which accounts for the largest proportion of SLs derivatives, and many new derivatives with higher biological activity and potential development value have been found. Zwanenburg et al. Obtained 39 after the introduction of a methyl group at the C-7 position of the A-ring, and its germination-stimulating activity on S. hermonthica seeds was reduced[72]. Yuan et al. Synthesized 40 by F substitution at the C-7 position of ring A, which could significantly promote the germination of Orobanche cumana (O. cumana) seeds (O. cumana), 5 times stronger than GR24[73]. The binding avidity (IC50=0.189μmol/L) for SLs receptor ShHTL7 is higher than GR24(IC50=0.248μmol/L), which is expected to be an effective herbicide for parasitic weed trapping. In addition, the structural derivatives substituted with nitro (41) or sulfonamide (42) at C-7 of ring A further enhanced the activity of promoting seed germination, and the activity of stimulating seed germination at 1 mg/L was 30% higher than that of GR24[74]. However, when the nitro group was reduced to amino group and protected with t-butyloxy carbonyl (Boc) (43), its germination activity against S. hermonthica seeds at S. Hermonthica concentration reached 90%, which was slightly lower than that of GR24 (100%)[75]. Sugimoto et al. Made a hydroxyl substitution (44) at the C-7 position of the A-ring and found that it did not enhance the germination activity of S. hermonthica seeds[76]. Therefore, the introduction of an electron-withdrawing group on the A-ring would be beneficial to improve the germination activity. In addition, the introduction of hydroxyl group (45) or acetoxy group (46) in the B ring greatly improved the germination stimulating activity on S. hermonthica and O. ramosa seeds, and (47) still had good germination activity after further oxidation of hydroxyl group to carbonyl group, indicating that the hydrogen bond formed by 4-OH is not an important factor restricting the molecular binding mode in the receptor[77].
Recent studies have shown that GR24 has the potential to resist environmental stress and help to improve the adaptability of plants to changes in environmental conditions such as drought, salinity, heavy metals, nutrient deprivation and heat stress, so as to cope with global climate change and achieve sustainable agricultural development[78]. For example, GR24 can protect barley plants from oxidative damage by reducing cadmium content, balancing nutrients, and indirectly eliminating Reactive oxygen species (ROS), thus helping to reduce the potential risk of cadmium pollution[79]. Exogenous application of GR24 can regulate the key gene D14 of phytohormone synthesis and metabolism, and ultimately effectively alleviate the drought symptoms of grape seedlings[80].
In addition, various studies have revealed the effects of GR24 on human cells and its possible applications in medicinal health, demonstrating its critical role in apoptosis- and inflammation-related pathways[12]. In terms of physiological effects on human body, GR24 is mainly manifested in three aspects: regulation of glucose metabolism, anti-inflammatory and neuroprotection, and inhibition of tumor proliferation. For regulation of glucose metabolism, GR24 up-regulates and activates Silencing information regulator 2 related enzyme 1 (SIR2 related enzyme 1,SIRT1), which enhances insulin signaling, Glucose uptake, Glucose transporter type 4 (GLUT4) translocation, and mitochondrial biogenesis in skeletal muscle cells, has emerged as a new treatment for skeletal muscle insulin resistance, the cause of type II diabetes[81]. At the same time, GR24 promotes the activation of Protein kinase B (PKB/AKT) and down-regulates the expression of Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) in insulin-resistant skeletal muscle cells, controlling the rate-limiting step of gluconeogenesis in hepatocytes.
In the prevention and treatment of inflammation, GR24 shows strong inhibitory activity on the release of inflammatory cytokines, including Nitric oxide (NO), Tumour necrosis factor alpha (TNF-α) and Interleukin 6 (IL-6), by blocking NF-κB and Mitogen-activated protein kinases (MAPK) signaling pathways. At the same time, GR24 can significantly inhibit the migration of neutrophils and macrophages in zebrafish larvae labeled with fluorescent protein, and play a good anti-inflammatory effect, and the absolute configuration of enol ether bridge and D ring structure is found to be essential for anti-inflammatory activity[82]. Further mechanistic studies by Kulabas et al. Showed that GR24 treatment induced increased expression of reduced Nicotinamide adenine dinucleotide phosphate quinone dehydrogenase-1 (Nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1, NQO1) and Heme oxygenase-1 (HO-1) by interfering with Kelch-like epichlorohydrin-associated protein 1 (Recombinant Kelch like ECH associated protein 1, K[83]. In addition, GR24 can inhibit the production of NO, inhibit the expression of Inducible nitric oxide synthase (iNOS) induced by Lipopolysaccharide (LPS) at mRNA and protein levels, and significantly reduce the release of IL-1β, the mRNA expression of Cyclooxygenase 2 (COX-2) and IL-1β, and the accumulation of NF-κB in the nucleus. In terms of neuroprotection, a decrease in LPS-induced NO production, a significant decrease in both mRNA and iNOS levels in a dose-dependent manner, and an inhibition of TNF-α and IL-1β production were also observed in GR24-treated SIM-A9 microglial cell line.It shows that GR24 has potential anti-neuroinflammatory and neuroprotective effects, which opens up a new way for the early treatment of neurodegenerative diseases and Alzheimer's disease (Alzheimer's disease, AD)[84].
In the aspect of anti-tumor, GR24 induces apoptosis and DNA damage of breast cancer cells by inhibiting the cell cycle in G2/M phase, and inhibits the growth of breast cancer MCF-7 cell line (IC50=18.8μmol/L), but has little effect on the growth and proliferation of normal cells, which has potential anti-tumor effect. This effect is associated with induction of p38 mitogen-activated protein kinase (P38 MAPK) and Jun N-terminal kinase 1/2 (JNK1/2) -mediated activation of stress responses and inhibition of the Phosphatidylinositide 3-kinases (PI3K)/AKT signaling pathway[85]. In addition, GR24 inhibits angiogenesis both in vivo and in vitro, which is associated with cytoskeletal reorganization, inhibition of Vascular endothelial growth factor 2 (VEGFR2) phosphorylation, and inhibition of downstream Focal adhesion kinase (FAK) activation[86]. Despite these advances in the antitumor potency of GR24, there is still much room for improvement in IC50. Inhibition of autophagy has been found to be a promising strategy to improve the efficacy of existing cancer treatments[87]. Deng et al. Synthesized 36 new GR24 analogues by replacing C-6, C-7 and C-3 'of ring a and changing the size of ring B, and identified that analogue 48 had strong cytotoxicity against colorectal cancer cell HCT116.And selectively increases autophagic flux while blocking autophagosome-lysosome fusion, was confirmed to be a potent autophagy/mitochondria inhibitor that exerts potent anti-colorectal cancer effects by inhibiting autophagy (IC50=0.68 nmol/L)[88]. The structure-activity relationship of GR24 was summarized for the first time: C-6 and C-7 substitution in ring a was beneficial to enhance the antitumor activity, Br or NHBoc substitution in C-6 position significantly increased the activity, free amino group and expansion of ring B were not beneficial to enhance the activity, introduction of methyl group in C-3 'position of ring D could enhance the activity, and R configuration in C-2' position was more favorable than the corresponding S configuration.
Fig. 6 shows the three-dimensional structures of protein-ligand complexes of GR24 with signaling genes Arabidopsis thaliana D14 receptor, mammalian stress-activated protein kinase JNK1, nitric oxide synthase iNOS, and Kelch-like epichlorohydrin-associated protein Keap1, respectively, and the corresponding molecular modes of action.
图6 GR24 23与AtD14 (PDB: 4IH4)、JNK1 (PDB: 4QTD)、iNOS (PDB: 3NW2) 和Keap1 (PDB: 5FZN)的复合结构

Fig.6 GR24 23/AtD14 (PDB: 4IH4), GR24 23/JNK1 (PDB: 4QTD), GR24 23/iNOS (PDB: 3NW2) and GR24 23/Keap1 (PDB: 5FZN) protein complex structure

5.1.2 Lactam derivatives

Strigolactam is a class of derivatives in which the lactone structure of the strigolactone C ring is replaced by the γ-lactam ring (fig. 7). Replacement of the O-1 atom of the lactone ring of GR24 by NH gave strigolactam derivative 49, which induced germination of parasitic weed seeds O. cumana with increased O. cumana compared to GR24[89]. The lactam derivative 50 with C-2 'S configuration showed almost no activity on O. cumana seeds, but its germination activity on O. minor seeds was consistent with that of 49 (49: 57.17%, 50: 41.67%, 1 μmol/L), which was higher than that of rac-GR24 (30.26%, 1 μmol/L), indicating that O. cumana seeds were very sensitive to the stereoconfiguration of lactam derivatives[89,90]. In addition, a series of lactam derivatives with novel structures can be synthesized by substitution derivatization at the N atom of the lactam ring, and the derivative 51 after further N-methylation is also very effective for the germination of O. cumana seeds, but the activity is slightly lower than that of 49[89]. Syngenta has obtained a number of N-derivatized analogues with high germinating activity on sunflower broomrape seeds by substituting phenyl (52), 4-chloro-phenyl (53), acetyl (54) or 2-thiazolyl (55) on the N atom of the lactam ring, and the germinating activity of the N-derivatized analogues on sunflower broomrape seeds is higher than that of GR24 at the concentration of 0.001 mg/L[91].
图7 独脚金内酰胺及其衍生物49~66的结构

Fig.7 Structures of strigolactam and its derivatives 49~66

The second generation lactam derivative 56 was obtained by changing the binding position of the C ring and the B ring of the lactam derivative, and its germination activity on seeds of Orobanche aegyptiaca (O. aegyptiaca) (33.9%) was equivalent to that of GR24 (34.7%) at the concentration of O. aegyptiaca. When different groups were substituted at the C-6 position of the A-ring, the germination-stimulating activity of O. aegyptiaca seeds was enhanced, such as methyl (57), methoxy (58), ethoxy (59) and benzyloxy (60), and the germination activity of 56 was better than that of 56, especially the germination rate of 58 was 73.4%[92]. Similarly, the N-derivatization of the second generation strigolactam can obtain compounds with better activity to promote leaf senescence, such as compounds 61 to 66 in the dark-induced senescence test of maize leaves, through the concentration gradient test of 0.0001 to 100 μmol/L and leaf image analysis,The area of leaf senescence browning was measured as a proportion of the total leaf area, and the concentration of 50% senescence (IC50≤1.55μmol/L) was calculated to be lower than that of the first generation of strigolactam derivative (IC50≥2.47μmol/L), showing superior leaf senescence-promoting activity, and the C-3 'methylation of the D ring further enhanced the efficacy of leaf senescence-promoting[93].

5.1.3 Cyclopentenone derivatives

Cyclopentenone derivatives are a class of derivatives in which unsaturated double bond conjugated system is introduced into the C ring structure of strigolactone. Representative structures published so far include compounds 67 – 75 (Fig. 8). Venturello et al. First reported cyclopentenone derivatives 67 – 70, which were more active (O. aegyptiaca) than GR24(EC50=2.15×10-7mol/L) in promoting seed germination of O. Aegyptiaca, and thus attracted the attention of scientific researchers[94]. Prandi et al. Designed and synthesized a series of cyclopentenone diastereoisomers, and found that 71 and 72 (MEB55) had ideal activities to promote seed germination of Phelipanche aegyptiaca (P. aegyptiaca)[95]. The activity of 71 was comparable to that of GR24 in inducing mycelial branching of Gigaspora margarita (G. margarita) and promoting root hair growth of Arabidopsis thaliana. The cyclopentenone derivatives 73 and 75 with fluorescent groups also have good activities of promoting the germination of P. aegyptiaca seeds and inducing the hyphal branching of G. margarita fungi, which can provide a valuable tool for further studying the receptor location and molecular mechanism in plants and fungi[96,97]. Studies have found that 72 and 74 have good anti-tumor activity, triggering apoptosis by inducing DNA damage and inhibiting DNA repair, and have good synergistic anti-tumor activity with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors[98]. In addition, further molecular mechanism studies showed that the inhibitory effect of 72 and 74 on cancer cells was through activating stress-related MAPKs: p38 and JNK pathways and related genes, specifically inducing G2/M cell cycle arrest and apoptosis of tumor cells, thus showing good anticancer activity against prostate cancer (LNCaP cells, IC50=5μmol/L) and breast cancer (MDA-MB-231 cells, IC50=5.8μmol/L)[85,99,100]. In glioblastoma, 71 can inhibit cancer cell proliferation (IC50≤17.5μmol/L), induce apoptosis, and induce G1 cell cycle arrest at low concentrations, and is a potential anti-glioblastoma lead compound[101]. Fig. 9 is the complex structure and binding mode of 72 with the corresponding anti-tumor biological targets P38 MAPK and JNK1.
图8 独脚金内酯人工合成类似物67~75的结构

Fig.8 Structures of synthetic strigolactone analogs 67~75

图9 化合物72与P38 MAPK (PDB: 6YK7) 、JNK1 (PDB: 4QTD) 的复合结构

Fig.9 Compound 72 / P38 MAPK (PDB: 6YK7) and compound 72 / JNK1 (PDB: 4QTD) protein complex structure

5.2 Atypical strigolactone analogs

5.2.1 Aryl furanone ethers

In order to overcome the scientific problems of many chiral centers in natural SLs and the difficulty of artificial synthesis, researchers have designed and prepared a series of strigolactone analogues with simple aryl structure instead of ABC skeleton, called SL mimics. Fig. 10 lists the representative structures of these derivatives, and different substituent groups on the benzene ring will lead to differences in their SL-like biological activities. Asami et al. Carried out halogen (F, Cl, Br, I) or cyano (CN) substitution at the para-position of the benzene ring, and found that when the para-position was substituted by bromine (76), the growth of the second tiller bud of d10-1 mutant rice was significantly inhibited at a low concentration (0.1 μmol/L), and the growth of the tiller bud was inhibited by activating the SL signal transduction pathway, but the activity of promoting the germination of S. hermonthica seeds was not ideal[102]. The substituent and the substitution position on the benzene ring are changed to obtain the chlorophenyl compound 77, and the activity of the chlorophenyl compound 77 for promoting the germination of S. hermonthica seeds is remarkably improved[103]. Containing an electron-donating group (e.g. Methyl group) and an additional hydroxyl group on the phenyl ring, S. hermonthica seed germination activity was somewhat improved (S. Hermonthica), but still several orders of magnitude lower than that of GR24 (EC50=1.30×10-10mol/L). Compound 78 had a stronger effect than GR24 in promoting root hair growth activity[104]. When the methyl group is at the ortho position (79), the activity of inhibiting the growth of the second tiller bud of rice is equivalent to that of GR24, and the activity of inhibiting the germination of S. hermonthica seeds is also superior to that of other ortho substituted compounds[105]. Yan et al. Introduced different electron-withdrawing groups (CN, O. cumana and CF3) on the benzene ring and substituted them at different positions of 1, 3 and 4, and the obtained 2NOD (80) had good activity to promote the germination of O. Cumana seeds, and could significantly inhibit the elongation of Arabidopsis hypocotyl and promote the growth of root hair (Fig. 10)[106]. After the methyl group of the D ring of the series of compounds was replaced by hydrogen (81 ~ 82), it still had good activity of inhibiting rice tillering, indicating that the methyl group may not be essential for SL activity[107]. In addition, 83 showed dose-dependent and time-dependent hepatoma HepG2 cell inhibitory activity (IC50=85.85μmol/L) in terms of anticancer activity[108]. Fig. 11 shows the complex structure and binding mode of 2NOD with strigolactone classical receptor AtD14 and ShHTL7 protein disclosed by Yan et al.
图10 独脚金内酯模拟物76~88的结构

Fig.10 Structures of strigolactone mimics 76~88

图11 化合物80的结构与分子机制。(A)化合物80的分子结构;(B)化合物80与拟南芥AtD14蛋白的分子结合模式 (PDB: 4IH4);(C)化合物80与拟南芥AtD14蛋白的复合结构;(D)化合物80与ShHTL7蛋白的复合结构 (PDB: 5Z7Y)

Fig.11 Structure and molecular mechanism of compound 80. (A) Molecular structure of compound 80; (B) Molecular binding mode of compound 80 to Arabidopsis AtD14 protein (PDB: 4IH4); (C) Complex structure of compound 80 with Arabidopsis AtD14 protein; (D) Complex structure of compound 80 with ShHTL7 protein (PDB: 5Z7Y)

5.2.2 Furanone ester

Furanone esters are a class of compounds in which the active furanone moiety of the D ring in strigolactone natural products is linked to an alkyl carboxylic acid by an ester bond, as shown in Figure 10 at 84 to 88. Cinnamic acid (CA) is a kind of Cinnamic acid natural product widely found in plants, which has both cis and trans configurations. The trans-SLs analog 84, which connects CA with D ring, showed ideal activity to promote the germination of O. minor and S. hermonthica seeds, and its cis-CA derivative was about 10 times stronger than the trans-form. In the experiment of inhibiting the branching of Arabidopsis max4 mutant, the cis-derivative was more effective than the trans-CA-derived analog in directly interacting with SL receptor protein and promoting the growth of Arabidopsis seedlings[109]. 85, which has a similar structure, has the same germination activity to S. hermonthica seeds as GR24, but its stability in soil is much lower than that of GR24, which greatly limits its further development and utilization[110]. Zwanenburg et al. Coupled auxin to the D loop to obtain 86, which also showed the same level of germination activity on P. ramosa seeds as GR24[111]. Using virtual screening and rational structure optimization strategy, we found that 87 could effectively induce the germination of P.aegyptiaca(EC50=3.39×10-11mol/L)) and S.hermonthica(EC50=1.3×10-17mol/L)) seeds, and was better than rac-GR24(EC50=4.85×10-11mol/L)[61]. Compound 88 (Sphynolactone-7) is an analogue of SLs derived from chemical screening, which can efficiently bind to strigolactone receptor ShHTL7 and stimulate S. hermonthica germination in the fM concentration range, and can be used as a selective Striga suicide germination-inducing stimulator[112].

5.2.3 Cyclopentanolactones and lactams

Cyclopentanolactones and lactams are synthetic analogues of natural strigolactones whose A-and B-ring structures are simplified to cyclopentane or cyclopentene. Zwanenburg et al. Synthesized four stereoisomeric cyclopentanolactone compounds (Fig. 12), and compound 89 (GR7) had the strongest activity in promoting seed germination of parasitic weeds, which was consistent with the configuration of GR24[113]. 90 (GR28) and 91 were obtained by de Mesmaeker et al. By changing the position of the unsaturated bond in the B ring and synthesizing the lactam ring[114]. Compound 90 promoted the germination of O. cumana seeds by 90% (0. 1 mg/L), and C-2's had the same activity, while 92 remained active after saturation of the double bond in the B ring. The activity of lactam ring analog 93 to promote the germination of O. cumana seeds was reduced or almost no activity, but the activity was greatly increased when the acetyl group (94) or the acetoxy group (95) was derived from the N or B ring of amide.
图12 环戊烷并内酯及酰胺类独脚金内酯类似物89~95的分子结构

Fig.12 Structures of Corey lactone type strigolactone analogs 89~95

5.2.4 Other Class

Nijmegen-1 (96), a structurally simplified SL analogue with retained biological activity (Fig. 13), was synthesized and reported in 1997. It was found that Nijmegen-1 (96) had strong germination stimulating activity on Striga and Orobanche crenata (O. crenata) seeds[115]. 96 had good Striga germination trapping activity in the laboratory and in the field, and the occurrence of Striga in pearl millet and sorghum fields was reduced by 43% and 60%, respectively[116]. The emergence rate of Striga reached 89% ~ 99% at the concentration of 1. 0 μmol/L, which paved the way for the incorporation of suicide germination trapping parasitic weed Striga strategy into sustainable agricultural management in Africa[117]. The molecular mechanism of action and the complex structure of compound 96 with the signal transduction gene Arabidopsis thaliana D14 receptor and the biological target ShHTL7 of parasitic weed seed germination are shown in fig. 14. 97, obtained by attaching the D ring directly to the N atom on the diketone structure, showed potent stimulation of P.aegyptiaca(97,EC50=1.72×10-6mol/L) and P.ramose(98,EC50=5.2×10-10mol/L) seed germination activity, as did 98, although both were weaker than GR24[118,119]. By changing the benzene ring structure of SL mimics, 99 and 100 derived from cyclic hydroxyketones have good activities of promoting seed germination of parasitic weeds and inhibiting plant pathogenic fungi[120]. In addition, SL analog 101 derived from tetralone showed stronger activity than GR24 in stimulating seed germination of S. hermonthica and O. crenata[121].
图13 独脚金内酯类似物其他类的代表性分子结构96~112

Fig.13 Structures of other types of strigolactone analogs 96~112

图14 化合物96的分子机制。(A)化合物96与ShHTL7的分子结合模式 (PDB: 5Z7Y);(B)化合物96与拟南芥AtD14的分子结合模式 (PDB: 4IH4);(C)化合物96与ShHTL7的复合结构;(D)化合物96与AtD14的复合结构

Fig.14 Molecular mechanisms of compound 96. (A) Molecular binding mode of compound 96 to ShHTL7 (PDB: 5Z7Y); (B) Molecular binding mode of compound 96 to Arabidopsis AtD14 (PDB: 4IH4); (C) Complex structure of compound 96 with ShHTL7 protein; (D) Complex structure of compound 96 with AtD14 protein

Methyl phenlactonoates (MPs), which are structurally similar to the natural atypical structure of MeCLA (16), are potent inducers of seed germination in root-parasitic weeds (Fig. 13). Among them, 102(EC50=2.98×10-9mol/L) and 103(EC50=2.54×10-8mol/L) inhibited rice tillering in d10 mutant significantly more than GR24(EC50=4.83×10-2mol/L), and 102 accelerated the senescence of rice leaves in the dark and significantly inhibited the elongation of Arabidopsis hypocotyls. This activity result was consistent with the results of the hydrolysis of MPs by ShHTL7 and OsD14, and the introduction of chlorine atom (104) and nitro group (105) accelerated the hydrolysis process, and 105 promoted the germination of S. hermonthica seeds with the strongest activity (S. Hermonthica), but weaker than GR24(EC50=9.1×10-11mol/L)[122]. Although 102 and 105 inhibited the germination of AM fungi G. margarita spores, they positively promoted mycorrhizal colonization at the later stage[123]. The methyl ester and the group attached to the methyl ester had a significant effect on the germination-stimulating activity, and when the ester group was replaced by N, N-dimethylamide (109), the germination-stimulating activity (S. hermonthica) on S. Hermonthica seeds was equivalent to that of GR24(EC50=7.23×10-11mol/L), and the senescence-accelerating effect on rice leaves was significantly enhanced. When the methyl group in the ester group was replaced by phenyl, benzyl and tert-butyl (106 ~ 108), the activity of stimulating P. aegyptiaca germination was also significantly enhanced[124]. It was also found that compounds 102-104 could reduce the viability of HepG2 cells, induce apoptosis, and selectively inhibit cancer cells by targeting microtubules[108]. Cannalactone (21), an atypical structure secreted from Cannabis sativa, has the effect of promoting seed germination of parasitic weed P. ramosa[47]. Boyer et al. Designed and synthesized two types of Cannalactone analogues and tested the germination activity of two P. ramosa seeds (1/2a)[47]. All Cannalactone analogs showed weaker germination activity than GR24 on P. ramosa 1 seeds, but P. ramosa and 111 showed significantly higher germination activity than GR24 on P. Ramosa 2a seeds. In addition, Strigoterpenoid (112), which is derived from the sesquiterpene coumarin ether trianone, potently activates the Nrf2 pathway (EC50=1.2±0.03μmol/L) and can inhibit the NF-κB pathway at lower concentrations (IC50=7.9μmol/L)[16].

6 Conclusion and prospect

SLs are a new class of plant hormones derived from carotenoids, which are considered to be key signaling molecules in plant growth regulation. With the development of isolation and identification techniques, more SLs will be isolated and identified in the future. Natural SLs and synthetic SLs analogs isolated from plant root exudates have a wide range of phytohormone activities, including stimulating seed germination of parasitic weeds, inhibiting plant branching, inducing mycelial branching of AM fungi, and promoting plant root hair growth, among which enol ethers, D-rings, and C-2'R configurations are highly conserved structures for their biological activities. Trapping parasitic weeds through suicide germination, promoting mycelial branching of AM fungi, and regulating drought and salinity stress have great potential in agriculture, which will greatly reduce the annual economic losses of billions of dollars caused by the proliferation of parasitic weeds worldwide[125]. Compound 96 can successfully manage O. ramosa and Striga in the field, but low-cost, highly stable and highly active SLs molecules need to be further developed[116]. When designing SLs molecules, we should selectively consider the target and its relevance to biological functions, reduce the impact on the normal growth of crops, and give full play to the characteristics of green agriculture[126].
In addition, SLs also show significant biological activities in anticancer and anti-inflammatory, which play an anticancer role by arresting the cell cycle in G2/M phase, inducing apoptosis and DNA damage, and play an anti-inflammatory and neuroprotective role by inhibiting inflammation-related factors (NO, TNF-α, IL-6, ROS). However, most of the simplified SLs have low potency in terms of IC50, and their mechanism of action and structural optimization need to be further clarified to pave the way for their application in the field of medical health. The existing research of our group shows that derivatization at the C-7 position of the A-ring of GR24 will change its biological activity, and the substituent with electron-withdrawing will further enhance its phytohormone activity, but its anti-tumor activity has not been significantly improved. With the application of rational drug design and artificial intelligence in drug research, it is believed that more and more SLs analogs will be designed and synthesized to contribute to sustainable agricultural development and human health.

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