Synthesis and Cytotoxic Activity of Novel Ergosterol Peroxide Derivatives with Acrylate or Propionate Side Chain

Abstract

A series of novel ergosterol peroxide derivatives with acrylate or propionate side chain were synthesized. All compounds 3a-n were evaluated for their cytotoxicity against four kinds of human carcinoma cell lines (HepG2, MCF-7, HCT-116, and A549). Most of the derivatives displayed stronger cytotoxicity than ergosterol peroxide parent. Among them, compound 3h with the highest potency against HepG2 cell line (IC₅₀ = 2.70 μM), which was 7.47-fold more efficacious than ergosterol peroxide. The results suggested that the introduction of acrylate or propionate side chain at C-3 position of ergosterol peroxide is beneficial to enhance its cytotoxic activity. Compound 3h has potential to become a novel anti-tumor agent through further structural modification.

Keywords

natural products modification synthesis ergosterol peroxide derivatives anticancer activity drug discovery

Introduction

Cancer is a persistent and serious disease that affects nearly one-third of humanity worldwide.1 Chemotherapy is still one of the most effective methods of cancer treatment today, but adverse side effects limit the clinical use of many drugs.^2,3 Therefore, it is an important task to develop new antitumor drugs with high efficiency and low toxicity. Natural products have a long history of medicinal use and are one of the main sources of anti-cancer drugs.^4–8 The discovery and structural modification of natural lead compounds is an important field of natural drug research, and is one of the important directions for the development of new anti-tumor drugs.^9–11

Ergosterol peroxide (5α,8α-epidioxiergosta-6,22-dien-3β-ol, EP), a natural steroid that extracted from Ganoderma lucidum in the early stage of our group ( Figure 1 ), has significant anti-cancer activity and cell selectivity.^12,13 The peroxide bridge on the ergosterol peroxide parent is considered to be an important pharmacophore.^14,15 For the past few years, ergosterol peroxide has been extensively studied for its antitumor activities.^16–20 It could be a valuable lead compound for antitumor drugs development. However, its further development is limited due to limited intracellular accumulation, and poor aqueous solubility. Therefore, appropriate structural modification of ergosterol peroxide is the key to improve its anti-tumor activity. In our previous work, we have found that some C-17 modified derivatives of ergosterol peroxide had significant efficacy against several human carcinoma cell lines.^21‐23 These results provide us with confidence for further structural modification of ergosterol peroxide.

Figure 1.

Structure of ergosterol peroxide and its 3-carbamate derivative (BM-3d) and cinnamic acid and the design of new ergosterol peroxide derivatives 3a-n.

Previously, we reported that the 3-carbamate derivatives of ergosterol peroxide had significant efficacy against several human carcinoma cell lines. Among them, compound BM-3d ( Figure 1 ) exhibited significant in vitro antiproliferative activities against the tested tumor cell lines (HepG2, Sk-Hep1, MCF-7 and MDA-MB231), with IC₅₀ values ranging from 0.85 to 4.62 μM.²⁴ In addition, we also introduced coumarin group into C-3 position of ergosterol peroxide, and the synthesized esterified derivatives also showed significant cytotoxic activity.²⁵ Based on the abovementioned encouraging results, we continued to modify ergosterol peroxide by introducing different types of substituents to the 3-hydroxyl position.

Cinnamic acid is an organic acid isolated from cinnamon or benzoin, contains a ubiquitous α, β-unsaturated acid moiety (acrylic group) presenting potential therapeutic effects in the treatment of cancer ( Figure 1 ).²⁶ Many studies have reported that cinnamic acid and its analogues have desirable antitumor activity.^27‐31 Therefore, in the present work, we try to integrate cinnamic acid and its analogues with ergosterol peroxide, the design strategy is shown in Figure 1 . We firstly synthesized an ergosterol peroxide coupled cinnamic acid derivative 3a. Furthermore, compounds 3b-n were synthesized by replacing the phenyl group of the cinnamic acid moiety with an aryl-fused phenyl group or a five-membered ring. The cytotoxic activity of all derivatives against four human carcinoma cell lines was tested by MTT assay, and preliminary structure-activity relationship analysis was performed by experimental data.

Results and Discussion

The synthesis process of novel ergosterol peroxide derivatives is shown in Scheme 1. Ergosterol peroxides (2) was synthesized by photocatalytic oxidation of ergosterol (1) with high-purity oxygen and phloxine B. Then, using DMAP and EDCI as catalysts, ergosterol peroxide (2) was esterified at C-3 position with different propionic acids or acrylic acid to give the target compounds 3a-n. The structures of fourteen new derivatives 3a-n were confirmed by HRMS, ¹H NMR and ¹³C NMR spectra. Taking compound 3a as an example, its NMR spectrum characteristics were analyzed. In the ¹H NMR spectrum, the downfield chemical shifts of C6-H at 6.40 ppm (d) and C7-H at 6.26 ppm (d) demonstrate a formation of 5,8-peroxy bond and 6-CH = CH-7 bond in compound 3a. The resonances showing of 7.67 ppm (d) and 6.52 ppm (d) demonstrate a formation of C = C bond in 3a for side chain. The resonances showing of 7.51 ppm (d) and 7.39–7.36 ppm (m) demonstrate a formation of benzene ring in compound 3a.

Scheme 1.

Synthetic pathway to compounds 3a-n. Reagents and conditions: (I) O₂, Phloxine B, light, methanol, 0 °C, 1 h, 70%; (II) Propionic or acrylic acids, DMAP, EDCI, dichloromethane, rt, 6–10 h, 80%∼95%.

Compounds 3a-n and ergosterol peroxide (EP, 2) were evaluated for their in vitro cytotoxic activities by MTT assay. Ergosterol peroxide (2) was used as the baseline control. Mitomycin C was selected as positive drug. Human hepatocellular carcinoma cell line (HepG2), human breast cancer cell line (MCF-7), human colon cancer cell line (HCT-116) and human lung cancer cell line (A549) were selected for MTT assay. The cytotoxicity activity data (IC₅₀ values) of compounds 3a-n are summarized in Table 1.

Table 1.

In Vitro Cytotoxicity Activity of Compounds 3a-n in Human Cancer Cells.

Compound	IC₅₀ (μM)¹
Compound	HepG2	MCF-7	HCT-116	A549
3a	8.24 ± 0.65	11.82 ± 0.74	17.45 ± 1.04	10.74 ± 0.65
3b	12.31 ± 0.71	12.73 ± 0.82	19.20 ± 1.10	23.24 ± 1.35
3c	9.48 ± 0.88	12.47 ± 0.84	18.15 ± 1.03	11.17 ± 0.72
3d	10.29 ± 0.80	17.41 ± 1.13	24.00 ± 1.31	16.76 ± 1.18
3e	14.04 ± 0.84	10.38 ± 0.89	15.66 ± 1.14	13.53 ± 0.64
3f	33.35 ± 1.78	42.11 ± 1.96	> 60.00	> 60.00
3g	3.92 ± 0.57	5.62 ± 0.58	10.09 ± 0.65	8.05 ± 0.74
3h	2.70 ± 0.35	4.10 ± 0.56	5.29 ± 0.50	8.82 ± 0.72
3i	16.46 ± 0.41	27.23 ± 1.58	19.51 ± 1.33	33.46 ± 1.83
3j	19.80 ± 1.10	33.37 ± 1.72	32.43 ± 1.74	47.92 ± 2.17
3k	22.32 ± 1.42	22.81 ± 1.26	37.17 ± 1.15	35.22 ± 1.98
3l	26.68 ± 1.88	19.60 ± 1.14	25.61 ± 1.11	40.14 ± 1.93
3m	13.40 ± 0.63	10.97 ± 0.82	20.43 ± 1.24	14.73 ± 0.79
3n	15.25 ± 1.23	18.05 ± 1.44	20.64 ± 1.18	30.15 ± 1.72
EP (2)	20.17 ± 1.37	15.65 ± 0.82	22.68 ± 1.35	17.65 ± 1.23
Mitomycin C	25.48 ± 1.44	15.16 ± 1.03	10.24 ± 0.65	13.62 ± 0.74

IC₅₀: Concentration of the tested compound that inhibits 50% of cell growth. All data in the above table are the mean ± SD of three independent experiments.

For the HepG2 cell line, most compounds of 3a-n showed stronger cytotoxicity than ergosterol peroxide (IC₅₀ = 20.17 μM). The results suggested that the introduction of acrylate or propionate side chain at C-3 position of ergosterol peroxide led to a significant increase in cytotoxic activity. In addition, compounds 3h and 3g, which integrated the acrylate side chain that bearing 3-pyridine or 4-pyridine group, showed significant cytotoxic activities, with the IC₅₀ values of 2.70 and 3.92 μM, respectively. For the MCF-7 cell lines, compounds 3e, 3g, and 3h exhibited stronger cytotoxicity than ergosterol peroxide. Among them, compound 3h (IC₅₀ = 4.10 μM) was also the most active. For HCT-116 cell lines, compounds 3a, 3b, 3c, 3e, 3g, 3h, 3i, 3m, and 3n were slightly more potent than ergosterol peroxide. Among them, compound 3h (IC₅₀ = 5.29 μM) was the most active. For the A549 cell lines, most compounds showed no remarkable cytotoxic activities than ergosterol peroxide, except 3g and 3h.

The above results suggested some structure-activity relationship (SAR) considerations. First, compounds 3m and 3n were synthesized by the insertion of two carbon atoms between the carbonyl group and phenyl ring of compounds 3a and 3b. Notably, compound 3a and 3b were slightly more potent than compounds 3m and 3n against four tested cancer cell lines, indicating that the double-bond was more useful for activity. Second, a phenyl substituent on the cinnamic acid moiety of compound 3a, such as compounds 3b, 3c, 3d, and 3e, led to a decrease in cytotoxic activity. Third, replacing the phenyl group of the cinnamic acid with an aryl-fused phenyl group (3f) or a five-membered ring (3i, 3j, 3k, and 3l) resulted in a remarkable decrease in biological activity. Furthermore, to our surprise, compounds 3g and 3h, which replacing the phenyl group of the cinnamic acid moiety with 3-pyridine or 4-pyridine, resulted in significantly increased the biological activity against all four tested cancer cell lines, with IC₅₀ values range from 2.70 to 10.09 μM. It seems that rerouting the N-atom from the 3-position to the 4-position of the phenyl group could led to a significant increase in biological activity. Taken together, compound 3h was the most potent compound against all four tested cancer (HepG2, MCF-7, HCT-116, and A549) cell lines, with IC₅₀ values of 2.70, 4.10, 5.29, and 8.82 μM, respectively, which deserved further investigation.

Experimental

General

All reagents and solvent were purchased from Energy Chemical (Shanghai, China) and used without further purification. All reactions were monitored by thin-layer chromatography (TLC) silica gel plates (Yinlong, Qingdao, China). The compounds were purified by flash column chromatography (300–400 mesh silica gel, Yinlong, Qingdao, China). HRMS (high-resolution mass spectra) data were carried out by UPLC G2-XS Q-TOF (Waters, USA) and TripleTOF 4600 (AB SCIEX, USA) in a positive ion mode with ESI source. ¹H NMR (600 MHz) and ¹³C NMR (150 MHz) spectra (δ, ppm, J, Hz) were recorded on a AVANCE NEO 600 spectrometers (Bruker, Berlin, Germany). Tetramethylsilane was used as an internal standard.

Synthesis of Ergosterol Peroxide (2)

Ergosterol (1, 1.0 g, 2.52 mmol), phloxine B (10 mg), and methanol (100 ml) were added into a flask and placed the reaction system at 0°C ice-bath. High-purity oxygen was continuously pumping into the mixture and the reaction was carried out under the condition of light (300 W) for 1 h. After completion of reaction, the solvent was evaporated and the crude product was purified by column chromatography (petroleum ether/ethyl acetate, 5:1, v/v) to obtain ergosterol peroxide (2) as white solid (750 mg). Yield: 70%.^18,19

General Procedure for the Synthesis of Novel Derivatives 3a-n

Ergosterol peroxide (2, 100 mg, 0.23 mmol), suitable substituents (1.5 e.q.) and dichloromethane (30 ml) were added into flask in sequence, then DMAP (0.1 e.q.) and EDCI (1.5 e.q.) were added as catalyst. The mixture was reacted with stirring at room temperature until ergosterol peroxide disappeared completely. Then the solvent was evaporated and the crude product was purified by column chromatography to give derivatives 3a-n.

Ergosterol Peroxide-3-Cinnamic Acetate (3a)

White powder. Yield 85%. ¹H NMR (600 MHz, CDCl₃) δ 7.67 (1H, s, H-3’), 7.51 (2H, dd, J = 6.7 Hz, H-Ar), 7.39-7.36 (3H, m, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.40 (1H, d, J = 16.0 Hz, H-2’), 6.26 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-23), 5.16 (1H, m, H-22), 5.13 (1H, m, H-3), 2.22 (1H, d, J = 13.7 Hz), 2.09 (2H, d, J = 13.6 Hz), 2.04 (2H, d, J = 9.8 Hz), 1.96 (1H, s), 1.85 (1H, d, J = 6.7 Hz), 1.73 (2H, d, J = 14.1 Hz), 1.63 (1H, s), 1.59 (2H, d, J = 10.8 Hz), 1.53 (2H, s), 1.47 (1H, d, J = 6.6 Hz), 1.43 (1H, s), 1.37 (1H, s), 1.25 (s, 2H), 1.24 (s, 1H), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.2 (C1’), 144.8 (C3’), 135.4 (C22), 135.3 (C6), 134.6 (Ar-1), 132.5 (C23), 131.1 (C7), 130.4 (Ar-4), 129.0 (Ar-2), 128.2 (Ar-3), 118.6 (C2’), 81.9 (C5), 79.6 (C8), 69.8 (C3), 56.3 (C17), 51.8 (C14), 51.2 (C9), 44.7 (C13), 42.9 (C24), 39.9 (C12), 39.5 (C20), 37.1 (C10), 34.5 (C4), 33.4 (C25), 33.2 (C1), 28.8 (C12), 26.5 (C16), 23.5 (C15), 21.0 (C11), 20.8 (C21), 20.1 (C26), 19.8 (C27), 18.3 (C19), 17.7 (C28), 13.0 (C18); HRMS (ESI) m/z, Calcd. for C₃₇H₅₀O₄ [M + H]⁺: 559.3787, found: 559.3784.

Ergosterol Peroxide-3-(4-Methoxyphenyl)Acrylate (3b)

White powder. Yield 93%. ¹H NMR (600 MHz, CDCl₃) δ 7.62 (1H, d, J = 16.0 Hz, H-3’), 7.46 (2H, d, J = 8.8 Hz, H-Ar), 6.89 (2H, d, J = 8.8 Hz, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.28 (1H, s, H-2’), 6.25 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-23), 5.17 (1H, m, H-22), 5.11 (1H, m, H-3), 3.83 (3H, s, Ar-O-CH₃), 2.22 (1H, d, J = 10.2 Hz), 2.12-2.05 (2H, m), 2.03 (2H, d, J = 15.4 Hz), 1.96 (1H, d, J = 6.6 Hz), 1.85 (1H, d, J = 6.7 Hz), 1.72 (2H, d, J = 13.5 Hz), 1.63 (1H, d, J = 9.9 Hz), 1.61-1.56 (2H, m), 1.52 (2H, s), 1.47 (1H, d, J = 6.3 Hz), 1.42 (1H, d, J = 11.6 Hz), 1.35 (1H, d, J = 10.5 Hz), 1.25 (2H, s), 1.23 (1H, s), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.92 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.82 (9H, dd, J = 9.9, 6.7 Hz, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.5 (C1’), 161.5 (Ar-4), 144.4 (C3’), 135.3 (C22), 135.3 (C6), 132.4 (C23), 131.0 (C7), 129.8 (Ar-2), 127.4 (Ar-1), 116.1 (C2’), 114.5 (Ar-3), 81.9 (C5), 79.5 (C8), 69.5 (C3), 56.3 (C17), 55.5 (Ar-O-C), 51.8 (C14), 51.2 (C9), 44.7 (C13), 42.9 (C24), 39.9 (C12), 39.5 (C20), 37.1 (C10), 34.5 (C4), 33.5 (C25), 33.2 (C1), 28.8 (C12), 26.6 (C16), 23.5 (C15), 21.0 (C11), 20.8 (C21), 20.1 (C26), 19.8 (C27), 18.3 (C19), 17.7 (C28), 13.0 (C18); HRMS (ESI) m/z, Calcd. for C₃₈H₅₂O₅ [M + Na]⁺: 611.3712, found: 611.3710.

Ergosterol Peroxide-3-(4-Fluorophenyl)Acrylate (3c)

White powder. Yield 84%. ¹H NMR (600 MHz, CDCl₃) δ 7.62 (1H, d, J = 15.9 Hz, H-3’), 7.52-7.47 (2H, m, H-Ar), 7.06 (2H, t, J = 8.4 Hz, H-Ar), 6.52 (1H, d, J = 8.4 Hz, H-7), 6.31 (1H, d, J = 16.1 Hz, H-2’), 6.25 (1H, d, J = 8.4 Hz, H-6), 5.20 (1H, m, H-22), 5.16 (1H, m, H-23), 5.12 (1H, m, H-3), 2.21 (1H, d, J = 8.5 Hz), 2.08 (2H, d, J = 13.5 Hz), 2.02 (2H, d, J = 16.6 Hz), 1.95 (1H, s), 1.85 (1H, s), 1.74 (1H, s), 1.65 (1H, s), 1.62 (1H, s), 1.59 (1H, s), 1.58 (1H, s), 1.52 (2H, s), 1.46 (1H, d, J = 6.6 Hz), 1.42 (1H, s), 1.36 (1H, s), 1.24 (2H, d, J = 10.4 Hz), 1.22 (s, 1H), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.6 Hz, H-21), 0.83 (9H, d, J = 10.7 Hz, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.0 (C1’), 163.1 (Ar-4), 143.4 (C3’), 135.3 (C22), 135.2 (C6), 132.4 (C23), 131.1 (C7), 130.8 (Ar-2), 130.0 (Ar-1), 118.3 (C2’), 116.2 (Ar-3), 81.9 (C5), 79.5 (C8), 69.8 (C3), 56.3 (C17), 51.7 (C14), 51.2 (C9), 44.7 (C13), 42.9 (C24), 39.8 (C12), 39.4 (C20), 37.1 (C10), 34.5 (C4), 33.4 (C25), 33.2 (C1), 28.8 (C12), 26.5 (C16), 23.5 (C15), 21.0 (C11), 20.7 (C21), 20.1 (C26), 19.8 (C27), 18.2 (C19), 17.7 (C28), 13.0 (C18); HRMS (ESI) m/z, Calcd. for C₃₇H₄₉FO₄ [M + Na]⁺: 599.3513, found: 599.3519.

Ergosterol Peroxide-3-(4-Chlorophenyl)Acrylate (3d)

White powder. Yield 80%. ¹H NMR (600 MHz, CDCl₃) δ 7.61 (1H, d, J = 16.0 Hz, H-3’), 7.44 (2H, d, J = 8.5 Hz, H-Ar), 7.35 (2H, d, J = 8.5 Hz, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.36 (1H, d, J = 15.9 Hz, H-2’), 6.25 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-22), 5.17 (1H, m, H-23), 5.13 (1H, m, H-3), 2.22 (1H, d, J = 8.4 Hz), 2.08 (2H, d, J = 14.1 Hz), 2.03 (2H, d, J = 16.0 Hz), 1.96 (1H, s), 1.86 (1H, d, J = 6.7 Hz), 1.73 (2H, d, J = 13.9 Hz), 1.65 (1H, s), 1.61 (2H, d, J = 16.9 Hz), 1.53 (2H, s), 1.47 (1H, d, J = 6.6 Hz), 1.43 (1H, s), 1.36 (1H, d, J = 11.6 Hz), 1.25 (2H, d, J = 9.6 Hz), 1.23 (1H, s), 1.01 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21) 0.87-0.79 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 165.9 (C1’), 143.3 (Ar-4), 136.3 (C3’), 135.4 (C22), 135.2 (C6), 133.2 (C23), 132.5 (C7), 131.1 (Ar-1), 129.3 (Ar-2, Ar-3), 119.3 (C2’), 81.9 (C5), 79.6 (C8), 69.9 (C3), 56.4 (C17), 51.8 (C14), 51.3 (C9), 44.7 (C13), 42.9 (C24), 39.9 (C12), 39.5 (C20), 37.2 (C10), 34.5 (C4), 33.5 (C25), 33.2 (C1), 28.8 (C12), 26.6 (C16), 23.6 (C15), 21.0 (C11), 20.8 (C21), 20.1 (C26), 19.8 (C27), 18.3 (C19), 17.7 (C28), 13.0 (C18); HRMS (ESI) m/z, Calcd. for C₃₇H₄₉ClO₄ [M + H]⁺: 593.3398, found: 593.3407.

Ergosterol Peroxide-3-(4-Trifluorophenyl)Acrylate (3e)

White powder. Yield 82%. ¹H NMR (600 MHz, CDCl₃) δ 7.67 (1H, d, J = 16.0 Hz, H-3’), 7.63 (2H, d, J = 8.1 Hz, H-Ar), 7.60 (2H, d, J = 8.3 Hz, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.46 (1H, d, J = 16.0 Hz, H-2’), 6.25 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, d, m, H-22), 5.16 (1H, m, H-23), 5.14 (1H, m, H-3), 2.22 (1H, s), 2.10 (1H, s), 2.07 (1H, s), 2.04 (2H, d, J = 13.2 Hz), 1.96 (1H, d, J = 6.8 Hz), 1.85 (1H, d, J = 6.8 Hz), 1.74 (2H, d, J = 14.3 Hz), 1.65 (1H, d, J = 15.7 Hz), 1.60 (2H, s), 1.53 (2H, s), 1.47 (1H, d, J = 6.6 Hz), 1.41 (1H, s), 1.37 (1H, s), 1.25 (2H, d, J = 10.1 Hz), 1.22 (1H, s), 1.00 (3H, d, J = 6.5 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.85-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 165.5 (C1’), 142.7 (C3’), 137.9 (C22), 135.2 (C6), 135.1 (C23), 132.4 (Ar-1), 131.8 (C7), 131.0 (Ar-4), 128.2 (Ar-2), 125.9 (Ar-3), 124.8 (CF₃), 121.1 (C2’), 81.8 (C5), 79.4 (C8), 70.0 (C3), 56.2 (C17), 51.6 (C14), 51.1 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.3 (C25), 33.1 (C1), 28.7 (C12), 26.4 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₈H₄₉F₃O₄ [M + Na]⁺: 649.3481, found: 649.3473.

Ergosterol Peroxide-3-(Naphthalen-2-yl)Acrylate (3f)

White powder. Yield 92%. ¹H NMR (600 MHz, CDCl₃) δ 8.50 (1H, d, J = 15.7 Hz, H-Ar), 8.19 (1H, d, J = 8.4 Hz, H-Ar), 7.88 (2H, t, J = 8.5 Hz, H-Ar), 7.74 (1H, d, J = 7.2 Hz, H-Ar), 7.57 (1H, d, J = 7.8 Hz, H-Ar), 7.53 (1H, d, J = 7.4 Hz, H-Ar), 7.49 (1H, d, J = 7.6 Hz, H-Ar), 6.53 (1H, d, J = 8.5 Hz, H-7), 6.49 (1H, d, J = 15.7 Hz, H-2’), 6.27 (1H, d, J = 8.5 Hz, H-6), 5.22 (1H, m, H-22), 5.18 (1H, m, H-23), 5.17 (1H, m, H-3), 2.26 (1H, s), 2.14 (1H, s), 2.09 (2H, d, J = 10.5 Hz), 1.96 (1H, s), 1.86 (1H, d, J = 6.7 Hz), 1.76 (2H, d, J = 14.0 Hz), 1.70 (1H, s), 1.61 (2H, s), 1.55 (2H, s), 1.47 (1H, s), 1.44 (1H, s), 1.40 (1H, s), 1.26 (2H, s), 1.23 (1H, s), 1.01 (3H, d, J = 6.5 Hz, H-18), 0.95 (3H, s, H-28), 0.92 (3H, d, J = 6.7 Hz, H-21), 0.83 (9H, t, J = 8.2 Hz, H-26, H-27, H-29); ¹³C NMR (150 MHz, CDCl₃) δ 166.1 (C1’), 141.8 (C3’), 135.4 (C22), 135.3 (C6), 133.9 (Ar), 132.5 (Ar), 131.6 (C23), 131.1 (Ar), 130.6 (C7), 128.9 (Ar), 127.0 (Ar), 126.4 (Ar), 125.6 (Ar), 125.2 (Ar), 123.6 (Ar), 123.6 (Ar), 121.4 (C2’), 82.0 (C5), 79.6 (C8), 70.0 (C3), 56.4 (C17), 51.8 (C14), 51.3 (C9), 44.8 (C13), 43.0 (C24), 39.9 (C12), 39.5 (C20), 37.2 (C10), 34.6 (C4), 33.5 (C25), 33.2 (C1), 28.8 (C12), 26.6 (C16), 23.6 (C15), 21.0 (C11), 20.8 (C21), 20.1 (C26), 19.8 (C27), 18.3 (C19), 17.7 (C28), 13.1 (C18); HRMS (ESI) m/z, Calcd. for C₄₁H₅₂O₄ [M + H]⁺: 609.3944, found: 609.3951.

Ergosterol Peroxide-3-(Pyridin-4-yl)Acrylate (3g)

White powder. Yield 81%. ¹H NMR (600 MHz, CDCl₃) δ 8.77 (1H, s, H-Ar), 8.62 (1H, s, H-Ar), 7.87 (1H, d, J = 7.9 Hz, H-3’), 7.65 (1H, d, J = 16.0 Hz, H-Ar), 7.38 (1H, s, H-Ar), 6.53 (1H, d, J = 8.4 Hz, H-7), 6.48 (1H, d, J = 15.7 Hz, H-2’), 6.26 (1H, d, J = 8.4 Hz, H-6), 5.21 (1H, m, H-22), 5.16 (1H, m, H-23), 5.14 (1H, m, H-3), 2.22 (1H, s), 2.09 (2H, d, J = 24.8 Hz), 2.03 (2H, d, J = 15.8 Hz), 1.96 (1H, s), 1.85 (1H, d, J = 6.7 Hz), 1.74 (2H, d, J = 13.8 Hz), 1.65 (1H, s), 1.60 (2H, s), 1.53 (2H, s), 1.47 (1H, d, J = 6.3 Hz), 1.41 (1H, s), 1.35 (1H, s), 1.25 (2H, d, J = 7.8 Hz), 1.23 (s, 1H), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 165.4 (C1’), 150.3 (Ar), 149.1 (C3’), 140.6 (Ar), 135.3 (C22), 132.5 (C6), 131.1 (C23), 124.2 (Ar), 121.3 (C2’), 81.9 (C5), 79.6 (C8), 70.2 (C3), 56.3 (C17), 51.7 (C14), 51.2 (C9), 44.7 (C13), 42.9 (C24), 39.9 (C12), 39.4 (C20), 37.1 (C10), 34.5 (C4), 33.4 (C25), 33.2 (C1), 28.8 (C12), 26.5 (C16), 23.5 (C15), 21.0 (C11), 20.8 (C21), 20.1 (C26), 19.8 (C27), 18.3 (C19), 17.8 (C28), 13.0 (C18); HRMS (ESI) m/z, Calcd. for C₃₆H₄₉NO₄ [M + H]⁺: 560.3740, found: 560.3738.

Ergosterol Peroxide-3-(Pyridin-3-yl)Acrylate (3h)

White powder. Yield 95%. ¹H NMR (600 MHz, CDCl₃) δ 7.28 (2H, s, H-3’,H-2’), 7.19 (4H, d, J = 7.7 Hz, H-Ar), 6.50 (1H, d, J = 8.5 Hz, H-7), 6.21 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-22), 5.16 (1H, m, H-23), 4.99 (1H, m, H-3), 2.08 (1H, d, J = 7.8 Hz), 2.01 (2H, s), 1.98 (1H, s), 1.95 (2H, s), 1.86 (1H, s), 1.76 (1H, s), 1.67 (2H, d, J = 10.0 Hz), 1.57 (2H, d, J = 4.5 Hz), 1.51 (1H, s), 1.50 (2H, s), 1.38 (1H, s), 1.25 (2H, d, J = 7.8 Hz), 1.23 (s, 1H), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.91 (3H, d, J = 6.8 Hz, H-28), 0.88 (3H, s, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 172.0 (C1’), 140.6 (Ar), 135.2 (C3’), 135.1 (Ar), 132.3 (C22), 130.9 (C6), 128.5 (C23), 128.3 (Ar), 126.2 (C2’), 81.7 (C5), 79.4 (C8), 69.5 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.1 (C25), 33.1 (C1), 28.6 (C12), 26.2 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.8 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₆H₄₉NO₄ [M + H]⁺: 560.3740, found: 560.3749.

Ergosterol Peroxide-3-(Furan-2- yl)Acrylate (3i)

White powder. Yield 93%. ¹H NMR (600 MHz, CDCl₃) δ 8.53 (2H, d, H-Ar), 7.18 (1H, s, H-Ar), 6.51 (1H, d, J = 8.5 Hz, H-7), 6.21 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-22), 5.16 (1H, m, H-23), 4.99 (1H, m, H-3), 2.95 (1H, s, H-3’), 2.61 (1H, s, H-2’), 2.07 (1H, d, J = 10.1 Hz), 2.01 (2H, d, J = 14.4 Hz), 1.97 (2H, d, J = 12.2 Hz), 1.84 (1H, s), 1.76 (1H, s), 1.68 (2H, d, J = 13.6 Hz), 1.61 (1H, s), 1.57 (2H, d, J = 11.2 Hz), 1.50 (2H, d, J = 9.0 Hz), 1.47 (1H, d, J = 6.7 Hz), 1.42 (1H, s), 1.36 (1H, s), 1.25 (2H, s), 1.23 (1H, s), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.91 (3H, d, J = 6.8 Hz, H-28), 0.88 (3H, s, H-21), 0.83 (9H, m, H-26, H-27, H-29); ¹³C NMR (150 MHz, CDCl₃) δ 171.2 (C1’), 149.4 (Ar), 135.2 (Ar), 135.0 (C22), 132.3 (C6), 131.0 (C23), 124.1 (C2’), 81.7 (C5), 79.4 (C8), 70.0 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 36.9 (C10), 34.6 (C4), 33.1 (C25), 33.1 (C1), 28.6 (C12), 26.2 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₅H₄₈O₅ [M + H]⁺: 549.3580, found: 549.3575.

Ergosterol Peroxide-3-(Furan-3- yl)Acrylate (3j)

White powder. Yield 86%. ¹H NMR (600 MHz, CDCl₃) δ 7.63 (1H, s, H-Ar), 7.55 (1H, d, J = 15.8 Hz, H-3’), 7.42 (1H, s, H-Ar), 6.58 (1H, s, Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.25 (1H, d, J = 8.5 Hz, H-6), 6.12 (1H, d, J = 15.8 Hz, H-2’), 5.22 (1H, m, H-22), 5.15 (1H, m, H-23), 5.11 (1H, m, H-3), 2.21 (1H, d, J = 8.5 Hz), 2.07 (2H, d, J = 13.9 Hz), 2.02 (2H, d, J = 12.3 Hz), 1.96 (1H, d, J = 6.6 Hz), 1.85 (1H, d, J = 6.8 Hz), 1.72 (2H, d, J = 13.8 Hz), 1.63 (1H, s), 1.59 (2H, d, J = 11.0 Hz), 1.52 (2H, s), 1.47 (1H, d, J = 6.5 Hz), 1.42 (1H, s), 1.36 (1H, d, J = 10.6 Hz), 1.25 (2H, s), 1.23 (1H, s) 1.00 (3H, d, J = 6.6 Hz, H-18), 0.92 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.83 (9H, dd, J = 9.9, 6.7 Hz, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.0 (Ar), 144.4 (Ar), 135.2 (C3’), 135.1 (C22), 134.6 (C6), 132.3 (C23), 130.9 (C7), 122.6 (Ar), 118.2 (2’), 107.4 (Ar), 81.8 (C5), 79.4 (C8), 69.5 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.8 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.3 (C25), 33.1 (C1), 28.7 (C12), 26.4 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.7 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₅H₄₈O₅ [M + Na]⁺: 571.3399, found: 571.3409.

Ergosterol Peroxide-3-(Thiophen-2- yl)Acrylate (3k)

White powder. Yield 83%. ¹H NMR (600 MHz, CDCl₃) δ 7.64 (1H, d, J = 15.9 Hz, H-3’), 7.47 (1H, s, H-Ar), 7.32 (1H, s, H-Ar), 7.28 (1H, s, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.24 (1H, d, J = 8.5 Hz, H-6), 6.22 (1H, d, J = 15.9 Hz, H-2’), 5.21 (1H, m, H-22), 5.17 (1H, m, H-23), 5.13 (1H, m, H-3), 2.23-2.20 (1H, m), 2.07 (1H, d, J = 13.2 Hz), 2.03 (2H, d, J = 15.0 Hz), 1.95 (1H, s), 1.85 (1H, d, J = 6.7 Hz), 1.73 (2H, s), 1.64 (1H, s), 1.59 (2H, d, J = 11.2 Hz), 1.52 (2H, s), 1.48 (1H, s), 1.43 (1H, s), 1.37 (1H, s), 1.26 (2H, s), 1.23 (1H, s) 1.00 (3H, d, J = 6.7 Hz, H-18), 0.92 (3H, s, H-28), 0.89 (3H, d, J = 6.9 Hz, H-21), 0.83 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.3 (C1’), 138.1 (Ar), 137.7 (C3’), 135.2 (C22), 135.2 (C6), 132.4 (C23), 131.0 (C7), 127.9 (Ar), 126.9 (Ar), 125.2 (Ar), 118.2 (C2’), 81.8 (C5), 79.4 (C8), 69.6 (C3), 56.3 (C17), 51.7 (C14), 51.1 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.4 (C20), 37.0 (C10), 34.4 (C4), 33.3 (C25), 33.1 (C1), 28.6 (C12), 26.4 (C16), 23.4 (C15), 20.9 (C11), 20.7 (C21), 20.0 (C26), 19.7 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₅H₄₈O₄S [M + Na]⁺: 587.3171, found: 587.3179.

Ergosterol Peroxide-3-(Thiophen-3- yl)Acrylate (3l)

White powder. Yield 94%. ¹H NMR (600 MHz, CDCl₃) δ 7.65 (1H, d, J = 15.9 Hz, H-3’), 7.48 (1H, s, H-Ar), 7.33 (1H, s, H-Ar), 7.28 (1H, s, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.25 (1H, d, J = 8.5 Hz, H-6), 6.22 (1H, d, J = 15.8 Hz, H-2’), 5.22 (1H, m, H-23), 5.17 (1H, m, H-22), 5.11 (1H, m, H-3), 2.21 (1H, d, J = 10.2 Hz), 2.08 (2H, d, J = 13.8 Hz), 2.03 (2H, d, J = 14.4 Hz), 1.96 (1H, d, J = 6.6 Hz), 1.85 (1H, d, J = 6.7 Hz), 1.73 (2H, d, J = 13.6 Hz), 1.63 (1H, s), 1.60-1.56 (2H, m), 1.52 (2H, s), 1.47 (1H, d, J = 6.5 Hz), 1.41 (1H, s), 1.36 (1H, d, J = 10.9 Hz), 1.25 (2H, s), 1.23 (1H, s) 1.00 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.3 (C1’), 138.1 (Ar), 137.6 (C3’), 135.2 (C22), 135.1 (C6), 132.3 (C23), 130.9 (C7), 128.0 (Ar), 126.9 (Ar), 125.1 (Ar), 118.1 (C2’), 81.8 (C5), 79.4 (C8), 69.6 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.3 (C25), 33.1 (C1), 28.6 (C12), 26.4 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₅H₄₈O₄S [M + Na]⁺: 581.3171, found: 581.3179.

Ergosterol Peroxide-3-Phenylpropanoate (3m)

White powder. Yield 85%. ¹H NMR (600 MHz, CDCl₃) δ 7.63 (1H, s, Ar), 7.55 (1H, d, J = 15.9 Hz, H-Ar), 7.42 (1H, s, H-Ar), 6.57 (1H, s, H-Ar), 6.52 (1H, d, J = 8.5 Hz, H-7), 6.24 (1H, d, J = 8.5 Hz, H-6), 6.12 (1H, d, J = 15.8 Hz, H-Ar), 5.21 (1H, m, H-22), 5.16 (1H, m, H-23), 5.12 (1H, m, H-3), 2.20 (1H, d, J = 10.3 Hz), 2.09 (2H, d, J = 11.8 Hz), 2.02 (2H, d, J = 11.7 Hz), 1.95 (1H, s), 1.85 (1H, d, J = 6.7 Hz), 1.73 (2H, s), 1.63 (2H, s), 1.60 (2H, d, J = 6.4 Hz, H-3’), 1.52 (2H, s), 1.47 (2H, d, J = 6.5 Hz), 1.41 (1H, s), 1.34 (1H, s), 1.25 (2H, s), 1.23 (2H, s, H-2’), 1.21 (1H, s), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.92 (3H, s, H-28), 0.91 (3H, d, J = 6.8 Hz, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 166.0 (C1’), 144.4 (Ar), 135.2 (C22), 134.6 (C6), 132.3 (C23), 130.9 (C7), 122.6 (Ar), 118.2 (Ar), 107.4 (Ar), 81.8 (C5), 79.4 (C8), 69.5 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.3 (C25), 33.1 (C1), 29.7 (C3’), 29.3 (C2’), 28.6 (C12), 26.4 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₇H₅₂O₄ [M + H]⁺: 561.3944, found: 561.3943.

Ergosterol Peroxide-3-(Pyridine-4-yl)Propionate (3n)

White powder. Yield 89%. ¹H NMR (600 MHz, CDCl₃) δ 8.67 (2H, s, H-Ar), 7.40 (2H, s, H-Ar), 6.57 (1H, d, J = 8.5 Hz, H-7), 6.53 (1H, d, J = 8.5 Hz, H-6), 5.21 (1H, m, H-22), 5.16 (1H, m, H-23), 5.14 (1H, m, H-3), 2.22 (1H, s), 2.11 (2H, d, J = 11.9 Hz), 2.03 (2H, d, J = 16.5 Hz), 1.96 (1H, s), 1.86 (1H, d, J = 6.7 Hz), 1.74 (2H, d, J = 14.1 Hz), 1.68 (2H, d, J = 9.3 Hz, H-3’), 1.60 (1H, s), 1.58 (1H, d, J = 7.3 Hz), 1.53 (2H, s), 1.47 (2H, d, J = 6.6 Hz), 1.40 (1H, s), 1.35 (1H, s), 1.26 (2H, s), 1.24 (2H, d, J = 9.9 Hz, H-2’), 1.23 (1H, s), 1.00 (3H, d, J = 6.6 Hz, H-18), 0.93 (3H, s, H-28), 0.91 (3H, d, J = 6.9 Hz, H-21), 0.84-0.81 (9H, m, H-26, H-27, H-19); ¹³C NMR (150 MHz, CDCl₃) δ 165.0 (C1’), 149.9 (Ar), 141.4 (Ar), 135.2 (C22), 132.4 (C6), 131.1 (C23), 123.7 (C7), 122.1 (Ar), 81.8 (C5), 79.5 (C8), 70.3 (C3), 56.2 (C17), 51.6 (C14), 51.0 (C9), 44.6 (C13), 42.8 (C24), 39.7 (C12), 39.3 (C20), 37.0 (C10), 34.3 (C4), 33.2 (C25), 33.1 (C1), 29.7 (C3’), 29.3 (C2’), 28.6 (C12), 26.3 (C16), 23.4 (C15), 20.9 (C11), 20.6 (C21), 20.0 (C26), 19.6 (C27), 18.1 (C19), 17.6 (C28), 12.9 (C18); HRMS (ESI) m/z, Calcd. for C₃₆H₅₁NO₄ [M + H]⁺: 562.3896, found: 562.3887.

In Vitro Cytotoxic Activity

Cytotoxic activities of all synthesized compounds against tumor cells were tested by MTT assay. All human cancer cell lines were purchased from the Cell Bank of Chinese Academy of Sciences (Shanghai, China). Cells at logarithmic growth phase were transferred to 96-well plates (1 × 10⁴ cells/well) for 12 h. After incubation, cells were treated with a graded concentration of compound from 1 μM to 60 μM, and incubation was continued for 48 h. Afterward, cells were treated with 10 μL of MTT solution (Sigma Chemical Co., Ltd, USA) for 2 h, and then 100 μL of DMSO was added in place of this solution. The absorbance was measured at 490 nm on a microplate reader. The IC₅₀ values are expressed as averaged ± SD of three independent experiments.

Conclusions

A series of novel ergosterol peroxide derivatives with acrylate or propionate side chain were synthesized and characterized. All compounds were evaluated for their in vitro cytotoxic activities against four human carcinoma cell lines (HepG2, MCF-7, A549, and HCT-116). The MTT results showed that compound 3h displayed remarkable antiproliferative activity against all test tumor cell line, with IC₅₀ values range from 2.70 to 8.05 μM). The structure-activity relationship analysis suggested that the introduction of acrylate or propionate side chain at C-3 position of ergosterol peroxide could led to a significant increase in cytotoxic activity. Compound 3h has potential to become a novel anti-tumor agent through further structural modification.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X221143634 - Supplemental material for Synthesis and Cytotoxic Activity of Novel Ergosterol Peroxide Derivatives with Acrylate or Propionate Side Chain

Supplemental material, sj-docx-1-npx-10.1177_1934578X221143634 for Synthesis and Cytotoxic Activity of Novel Ergosterol Peroxide Derivatives with Acrylate or Propionate Side Chain by Ming Bu, Zhiguo Zhang, Gang Li, Chunhua Xie, Xiaohui Du, Guofang Ma and Hongling Li in Natural Product Communications

Supplemental Material

sj-docx-2-npx-10.1177_1934578X221143634 - Supplemental material for Synthesis and Cytotoxic Activity of Novel Ergosterol Peroxide Derivatives with Acrylate or Propionate Side Chain

Supplemental material, sj-docx-2-npx-10.1177_1934578X221143634 for Synthesis and Cytotoxic Activity of Novel Ergosterol Peroxide Derivatives with Acrylate or Propionate Side Chain by Ming Bu, Zhiguo Zhang, Gang Li, Chunhua Xie, Xiaohui Du, Guofang Ma and Hongling Li in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical Approval is not applicable for this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Qiqihar Science and Technology Bureau under Grant (grant number LHYD-202015) and Optional project of Qiqihar Academy of Medical Sciences (grant number QMSI2022Z-01).

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

ORCID iD

Ming Bu

Supplemental Material

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