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Open AccessCCS ChemistryRESEARCH ARTICLES22 Feb 2024

Discovery and Asymmetric Total Synthesis of Phlegmine A as a Selective Inhibitor of ASIC1a

    https://doi.org/10.31635/ccschem.024.202303585

    Phlegmine A ( 1), a novel type of Lycopodium alkaloid with a unique skeleton, was isolated from the rare and endangered herbal medicinal plant, Phlegmariurus phlegmaria. Spectroscopic methods and X-ray diffraction analysis were employed to unambiguously elucidate the structure of phlegmine A ( 1). Furthermore, we realized the asymmetric total synthesis of the natural product phlegmine A ( 1) in 18 linear steps from commercial ingredients, achieving a 1.3% overall yield. An intramolecular carbene cyclization, dimethyldioxirane (DMDO) enamine oxidation, and Stevens rearrangement were exploited to establish the sterically congested vicinal quaternary centers, and an epimerization/aldol condensation/deacetylation reaction was utilized for the rapid assembly of enone at the final step. During our semisynthesis attempts, a novel transformation was developed to construct α-aminoketone from enamine N-oxide. Moreover, the synthetic sample obtained from this work enabled the successful verification of phlegmine A ( 1) as a new type of highly selective acid-sensing ion channel 1a (ASIC1a) inhibitor, which also exerted an in vivo analgesic effect, rendering it a promising lead compound.

    Introduction

    The rich and complex structures of natural products make them a key source of small-molecule drugs.1,2 However, the discovery and research of novel lead compounds from natural products face great challenges due to their limited availability.3 An integrative approach based on the discovery, synthesis, and biological studies of novel molecules has recently attracted considerable interest, as it could overcome these limitations and enhance the efficacy of the lead compound discovery process.4–10Lycopodium alkaloids, produced by plants of the genus Lycopodium, possess complex ring systems and a wide range of biological properties.3,11–13 To date, more than 400 Lycopodium alkaloids have been identified, including the well-known acetylcholinesterase (AChE) inhibitor, huperzine A ( 6), as shown in Figure 1.14,15 The intricate structures of these compounds, along with limited availability, have posed challenges in targeting and sparked great interest in total synthesis.16–24

    Figure 1

    Figure 1 | Phlegmine A (1) and representative Lycopodium alkaloids.

    On the other hand, acid-sensing ion channels (ASICs) have been regarded as promising, but underexplored pharmaceutical targets for diseases of pain, ischemic stroke, neurological disorders, and cardiac pathologies.25,26 Among the several subtypes of ASICs, ASIC1a stands out as one of the most sensitive and promising therapeutic targets.27,28 The therapeutic potential of ASIC1a inhibitors has been demonstrated by decreased infarct volume in rat models of ischemic stroke.29,30 However, further development of the reported ASIC1a inhibitors is hampered by their lack of significant selectivity or satisfactory bioavailability.31 Therefore, the exploration of new selective lead compounds is of high value in this field. In the research on the isolation and syntheses of natural alkaloids,32,33 1 was isolated from the endangered herbal medicine of the Phlegmariurus phlegmaria plant source.34 This study reports the discovery, structural elucidation, total synthesis, and exploration of the possible biological activity mechanism of phlegmine A ( 1).

    Experimental Methods

    The reactions proceeded under an argon atmosphere using anhydrous solvents, except where otherwise noted. Commercially acquired chemicals were employed as received, except where specified. Supporting Information includes the experimental procedures, nuclear magnetic resonance (NMR) spectral characterization for all synthesized new compounds, comparisons between synthetic and isolated natural products, X-ray crystallographic data with the Cambridge Crystallographic Data Center (CCDC) numbers, and NMR spectral copies. In a mouse model, the analgesic effect of phlegmine A ( 1) was evaluated by measuring the pain response after formalin injection, with statistical analysis conducted to determine significance. Immortalized human embryonic kidney (HEK293T) cells were cultured and transfected with ASIC1a cDNA for whole-cell voltage-clamp recordings to measure ASIC1a currents at various pH levels, followed by data analysis using Boltzmann and Hill equations (see Supporting Information for details).

    Results and Discussion

    Based on the NMR data, the planar structure of 1 was determined (see Supporting Information for details). Refinement on the Cu Kα data resulted in a small Flack parameter of 0.03(14),35 allowing for the unambiguous assignment of the absolute configuration of 1 as 2R,7S,12S,13S,15S. Phlegmine A ( 1) featured five stereogenic centers, two of which are vicinal quaternary carbon stereocenters at their bridgehead positions. This molecule also featured an unusual 10-aza-tetracyclo [7.4.32,9.01,5.01,9] hexadecane moiety formed by an unprecedented C1–C13 linkage. These made 1 distinct from currently known Lycopodium alkaloids (representative examples 2– 7 are listed in Figure 1).33,36 The discovery of phlegmine A ( 1) with an unprecedented scaffold led us to investigate its plausible biosynthetic pathway. Although 1,2-migration of cyclic N-alkyl or N-allyl is extremely challenging and very rarely reported in the literature, it was tempting to consider that the biosynthetic route for phlegmine A ( 1) might relate to fawcettimine at a glance. Particularly, fawcettidine is derived from fawcettimine and then oxidized by an epoxidase to form intermediate ii, which then undergoes acid-catalyzed ring opening to yield the diol derivative iii.37,38 Intermediate iii then goes through dehydration, oxidation, and hydrolysis to form vi. Intermediate vi is subjected to methylation, and Aldol reaction to produce viii. After Isomerization and epimerization, compound viii transforms to xi, which undergoes oxidation to form phlegmine A ( 1) (Scheme 1). To verify the hypothesis, experiments were performed in an attempt to accomplish the key migration of C1-N to C1–C13. Our attempts to synthesize compound viii were fruitless. Alternatively, Fawcettidine ( 8) was oxidized to enamine N-oxide 9, followed by treatment with trifluoroacetic anhydride (TFAA) to give ketone 10 (Scheme 2). Notably, this rearrangement was different from the well-known Polonovski reaction with the generation of the α-aminoketone instead of the amide.39 The smooth conversion of compound 11 to 12 also demonstrated the efficiency of this reaction. After the key intermediates 13 and 15 were generated by methylation, attempts to employ ammonium salts to produce the desired rearrangement products were unsuccessful. Under basic conditions, the quaternary ammonium salt undergoes the well-known Hofmann elimination, product 16 was isolated in 30% yield.

    Scheme 1

    Scheme 1 | A plausible biosynthetic pathway of phlegmine A (1).

    We also tried to convert compound 16 to 17 under base or acid-promoted γ, δ-addition, but proved fruitless. The theoretical difficulty, as well as the practical failure of the migration of C1-N to C1–C13 led us to exploit other possible biosynthetic pathways of phlegmine A ( 1). The phlegmine A skeleton might be constructed in a single step from the phlegmarine skeleton via a Diels–Alder reaction, thus imparting a high degree of novelty to the structure of this novel alkaloid ( Supporting Information Scheme S1).40 In our opinion, the pathway for the biogenic synthesis of this alkaloid type deserves more research to validate it in the future.

    Scheme 2

    Scheme 2 | Semisynthetic attempts of phlegmine A (1).

    The highly attractive skeleton of phlegmine A ( 1) is captivating, but its scarce content has precluded biological studies. Thus, a synthetic program was initiated to facilitate the production of sufficient phlegmine A ( 1). Retrosynthetically, we envisioned that phlegmine A ( 1) was derived from an aldol condensation. The allyl group on quaternary carbon C13 of intermediate 27 could be introduced from the ammonium precursor. The ketone moiety of compound 27 could be installed from an enamide by enamine oxidation. The cyclopropanation reactions represented a convenient approach to the desired tricyclic system 23. The intermediate 22 could be prepared from (−)-enone 20 and a diazo compound via Mukaiyama–Michael addition. Compound 20 could be constructed by organocatalytic Robinson annulation from 19 (Scheme 3). The total synthesis of phlegmine A ( 1) was accomplished, as depicted in Scheme 4. The ketoester derivative 19, which was obtained readily in large quantities (>30 g) from commercially available Meldrum’s acid 18, was subjected to an enantioselective organocatalytic Robinson annulation with α,β-unsaturated aldehydes to afford the desired cyclohexen-3-one product 20.41 A Mukaiyama–Michael reaction between silyl enol ethers and α,β-unsaturated ester, followed by hydrolysis to produce the methyl diazoacetate, which was condensed with the methylamine to furnish enamide 22.42 A cyclopropanation pioneered by Tu, Takemoto, and Carreira groups43–45 was performed to provide compound 23. Lycopodium alkaloids containing a C14-carbonyl group are rare and pose synthetic challenges. The oxidized product 24 was accessed from 23 in the presence of DMDO and p-toluenesulfonic acid. An Iridium-catalyzed reduction of amide carbonyl delivered the desired amine 25 in 70% yield.46 Amine 25 and allyl bromide afforded the product 27 in 55% yield along with 29% of its C12 epimer 26.47 Their structures and absolute configurations were unambiguously confirmed by single-crystal X-ray diffraction analyses. It was impracticable to perform selective oxidation of olefin to terminal alcohol, followed by Heathcock’s sequential Oppenauer oxidation/aldol condensation reaction.48 Alternatively, the diol was obtained via an osmium-catalyzed dihydroxylation condition. Treatment of diol with ethanolic NaOH induced crucial epimerization at the stereogenic center adjacent to the C14 carbonyl group, forming the desired diastereomers 28. Selective oxidation of terminal alcohol 28 by trichloroisocyanuric acid (TCCA) followed by aldol condensation reaction afforded phlegmine A ( 1) but with low yields. Therefore, the primary hydroxyl group was protected with a silyl group and the secondary hydroxyl group was protected with an isopropyl acyl. After the removal of the tert-butyldimethylsilyl (TBS) protecting group, Ley–Griffith oxidation smoothly delivered the aldehyde 29 (d.r. ≈ 1.2:1 at C2).49 Finally, diastereoselective steric-controlled reactions in the last process were envisioned to furnish the desired product. Triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed cascade involving an epimerization/aldol condensation/deacetylation smoothly furnished phlegmine A ( 1) (Scheme 3).50 The synthetic phlegmine A ( 1), was chromatographically and spectroscopically (1H and 13C NMR) identical to the natural source compound. Optical rotation was also consistent with each other (observed: [α]25 D +29.1 (c = 0.10, CH3OH), natural: [α]20 D +28.7 (c = 0.33, CH3OH), confirming the absolute configuration (see Supporting Information for details).

    Scheme 3

    Scheme 3 | Retrosynthetic analysis of phlegmine A (1).

    Biological activity studies

    P. phlegmaria is used in Chinese traditional medicine for the treatment of traumatic injury, rheumatic pain, and snakebite.34 Inspired by these clues, we evaluated the analgesic bioactivity of phlegmine A ( 1) in a formalin-induced pain mouse model.51 Remarkably, phlegmine A ( 1) at 1 mg/kg had little effect on the first-phase acute pain while it significantly alleviated the second-phase inflammatory pain induced by formalin (Figure 2a,b). Blocking ASIC1a channels is an important mechanism to attenuate the perception and transmission of inflammatory pain signals.51 Considering the studies demonstrating that inhibiting ASIC1a reduces pain in a variety of animal pain models,52 we hypothesized that phlegmine A ( 1) might inhibit ASIC1a channels and hence impair the perception of inflammatory pain, thereby exerting an analgesic effect.25 To verify the mechanism of analgesic activity of phlegmine A ( 1), we investigated the inhibitory activity of ASIC1a channels of phlegmine A ( 1). Dose–response studies demonstrated that phlegmine A ( 1) inhibited ASIC1a with the IC50 value and Hill coefficient of 20.32 ± 3.31 μM and 2.42 ± 0.6 respectively. This was comparable to IC50 of the positive drug amiloride, which was used clinically as a diuretic for several decades, as well as a commonly used ASIC inhibitor (Figure 2c).53 When phlegmine A ( 1) was applied to the ASIC1a channel, the pH0.5 SSD of ASIC1a shifted from 7.18 ± 0.2 to 7.236 ± 0.07 (P = 0.001539, Student’s t-test), and exerted little effect on the activation of ASIC1a (Figure 2d,e). Amiloride also changed the pH0.5 SSD of ASIC1a from 7.18 ± 0.2 to 7.238 ± 0.02 (P = 0.000069, Student’s t-test). These results suggested that phlegmine A ( 1) inhibited the currents by modifying the proton affinity during steady-state desensitization (SSD) of ASIC1a.54 The results indicated that phlegmine A ( 1) inhibited the ASIC1a channel and impaired the perception of inflammatory pain, thereby playing an analgesic role. Due to the fact that the selective inhibitory effect of ASIC is of great importance for the treatment of related diseases,27,28 we explored the selectivity of phlegmine A ( 1) by screening a series of ion channels. The results showed that phlegmine A ( 1) selectively inhibited ASIC1a but had little effect on other ion channels (Figure 2f). Hence, Phlegmine A ( 1) exhibited a high selectivity and was distinct among a few examples of natural ASIC1a inhibitors.55–57

    Figure 2

    Figure 2 | Biological activity of phlegmine A (1) in vivo and in vitro. (a) 1 reduces the first (0–10 min) and second (11–60 min) phases of formalin-induced nociception (n = 8). (b) Plantar injection 1 has analgesic effects on mice. Formalin-induced pain behavior was measured every 5 min. (c) Dose–response curves showed that 1 inhibited the peak currents of ASIC1a in a concentration-dependent manner, similar to the positive control amiloride. (d) Scatter plots showed the mean effects of 1 and amiloride on pH0.5 SSD in HEK293T cells expressing ASIC1a channel. (e) Typical pH response curves of activation and SSD of ASIC1a in the control and presence of amiloride as a positive control. (f) Effects of 1 at a concentration of 50 μM on different ion channels. All data are presented as the mean ± SD. An unpaired two-tailed t-test was performed to determine statistical significance: ns P > 0.05, **P > 0.01, ***P > 0.001. ASIC1a, acid-sensing ion channel 1a; SSD, steady-state desensitization.

    Conclusion

    We have discovered and characterized a new Lycopodium alkaloid, phlegmine A ( 1), from the club moss P. phlegmaria. Its structure is unique, featuring a C1–C13 bond that has not been observed before in this class of compounds. A scalable asymmetric total synthesis method of phlegmine A ( 1) has also been developed to overcome supply challenges, and its analgesic activity in an animal model has been demonstrated. Evidently, phlegmine A ( 1) reduced pain, which opens up the possibility of exploring its structure-activity relationship and optimization as a lead compound for pain relief. By exploiting its mode of action, we inferred that the analgesic mechanism of phlegmine A ( 1) possibly involves ASIC1a inhibition.

    Scheme 4

    Scheme 4 | Asymmetric synthesis of phlegmine A (1).

    Supporting Information

    Supporting Information is available and includes detailed experimental methods that include characterization information such as spectroscopic data, NMR spectra, X-ray crystallographic and diffraction data for phlegmine A ( 1) (CCDC 975335), 11 (CCDC 2227131), 24 (CCDC 2227135), 25·HCl (CCDC 2227130), 26 (CCDC 2227129), 27 (CCDC 2227132), 29-(2R) (CCDC 2227133), 30 (CCDC 2227134).

    Disclosures

    Experiments were performed on awake 6- to 7-week-old (18–25 g) C57BL/6 mice following the guidelines of the International Association for the Study of Pain and were approved by the local ethics committee.

    Conflict of Interest

    The authors declare no competing financial interest.

    Funding Information

    This work was supported financially by the National Natural Science Foundation of China (NSFC; grant no. 21837003), the Joint Foundation of NSFC-Yunnan Province (grant no. U1502223), the Yunnan Revitalization Talent Support Program “Young Talent” Project, NSFC (grant no. 81903521), and the Natural Science Foundation of Yunnan Province, China (grant no. 202001AT070067).

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