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Cytotoxic Activity of from the Fruits of Piper nigrum

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The user has requested enhancement of the downloaded file. Volume 13. Issue 11. Pages 1419-1568. 2018 ISSN 1934-578X (printed); ISSN 1555-9475 (online) www.naturalproduct.us NPC Natural Product Communications

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PROFESSOR MANFRED G. REINECKE Prof. Cristina Gracia-Viguera Dr. Bikram Singh Department of Chemistry, Texas Christian University, Murcia, Spain Palampur, India Forts Worth, TX 76129, USA [email protected] Dr. Christopher Gray Prof. Marina Stefova Saint John, NB, Canada Skopj, Republic of Macodenia PROFESSOR WILLIAM N. SETZER Department of Chemistry, The University of Alabama in Huntsville, Prof. Dominique Guillaume Prof. Leandros A. Skaltsounis Huntsville, AL 35809, USA Reims, France Zografou, Greece [email protected] Prof. John L. Sorensen Prof. Duvvuru Gunasekar PROFESSOR PING-JYUN SUNG Tirupati, India Manitoba, Canada

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No. 11 Cytotoxic Activity of Alkaloids from the Fruits of Piper nigrum 1467 - 1469

Quynh Mai Thi Ngo1, Thao Quyen Cao1, Le Son Hoang, Manh Tuan Ha, Mi Hee Woo and Byung Sun Min*

College of Pharmacy, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea

1These authors contributed equally to this work. [email protected]

Received: July 27th, 2017; Accepted: September 3rd, 2018

Medicinal plants have been shown to have tremendous potential for the development of new drug molecules for various serious diseases. Piper nigrum L. (Piperaceae) is a well-known spice considered to be the “The King of Spices” among various spices. The phytochemicals isolated from P. nigrum L. are potent biological agents with anticancer properties. Our study was designed to evaluate the cytotoxic activities of chemical compounds from the dried fruits of P. nigrum L. Sixteen known compounds (1−16), including fifteen alkaloids, were isolated and identified. Compounds 10, 11, 12, 13, 14, and 15 exhibited cytotoxic activities against a human cervical cancer cell line, Hela, with IC50 values of 49.8, 40.4, 23.1, 22.1, 41.0, and 26.9 µM, respectively. Compounds 10, 12, and 15 exhibited cytotoxicities against a breast cancer cell line, MCF-7, with IC50 values of 36.9, 55.7, and 36.0 µM, respectively. Compounds 6, 12, 13, 14, 15, and 16 exhibited cytotoxic activities against the human promyelocytic leukemia cell line, HL-60, with IC50 values of 26.9, 51.4, 51.6, 54.4, 16.0, and 21.1 µM, respectively.

Keywords: Piper nigrum, Piperaceae, , Anti-cancer, Hela, MCF-7, HL-60.

Many plant-derived products have been found to play important O O O N O N O roles in the treatment of various diseases. The natural course of O O 5 1 O N cancer, a neoplastic disease, is often fatal. Cancer cells exhibit the O O H O 10 properties of invasion and metastasis, and are highly anaplastic [1a]. O N O O O O N 2 6 O Black pepper (P. nigrum L., family Piperaceae) is widely used in n N H O O O folk medicine. P. nigrum can be used not only to relieve digestive 11 n=5 O O N N 12 n=3 system symptoms such as diabetic, diarrhea and indigestion, but O O O 7 3 O N also for the treatment of respiratory system problems such as colds, n O O H O 13 n=7 fevers, and asthma [1b-d]. Anticancer bioactivities of black pepper O O N n N 14 n=5 can be attributed to a wide spectrum bioactivities. Many researchers O O 4 8 n=5 investigated the anticancer bioactivities of pure compounds from P. 9 n=6 nigrum, especially piperine [1e-g]. Piperine, the major chemical O N N constituent of P. nigrum, showed anticancer properties in lung O CHO O cancer, where it suppressed the expression and secretion of matrix O metalloproteinase 9 (MMP 9), decreasing the activation of nuclear 16 O O factor κB (NF-κB) and activator protein 1 (AP-1) transcription O O factors NF-κB and AP-1 leading to inhibition of invasion and 15 metastasis of HT-1080 cell [1h-j]. Pellitorine showed strong Figure 1: Chemical structures of isolated compounds (1−16) from P. nigrum. cytotoxic activities against the human promyelocytic leukemia cell line, HL-60, and the breast cancer cell line, MCF-7, with IC50 values of 13.0 and 1.8 µM, respectively [1k]. Chabamide could In this study, cancer cells (Hela, MCF-7, and HL-60 cell lines) were 5 inhibit proliferation and induce cell death by activating both seeded in 96-well plates at a density of 1 × 10 cells/mL, then apoptosis and autophagy in K562 human leukemia cells [1l]. incubated for 3h, and were treated with sixteen isolated compounds Encouraging results from all these studies prompted us to (1−16) at a concentration of 100µM. The inhibitory process was investigate the cytotoxic activities of isolated compounds from P. assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- nigrum in the Hela, HL-60, and MCF-7 cancer cell lines. tetrazolium bromide (MTT) assay according to Mosmann [3a]. Figure 2 showed the survival rates (%) of treated cancer cells. Chemical investigations of the dried fruits of P. nigrum using Compounds 6, 9, 10, 11, 12, 13, 14, 15, and 16 were shown to efficient separation techniques led to the isolation of sixteen decrease the cell viability of Hela cells by over 50%, while the other compounds (1−16), which were identified as 4,5-dihydropiperine compounds did not affect survival (Figure 2A). Compounds 6, 9, (1), piperine (2), piperolein A (3), pipersintenamide (4), dihydro- 10, 12, 14, 15, and 16 were shown to decrease the cell viability of pipernonaline (5), (2E,4Z,8E)-N-[9-(3,4-methylenedioxy-phenyl)- the MCF-7 cell by over 50%, while the other compounds did not 2,4,8-nonatrienoyl]-piperidine (6), trichostachine (7), piperamide affect survival (Figure 2B). As shown in Figure 2C, only compound C9:1 (8E) (8), isopiperolein B (9), retrofractamide A (10), 1 was not shown to decrease the cell viability from HL-60 cell by guineensine (11), retrofractamide B (12), 4,5-dihydroguineensine over 50%. Therefore, compounds shown to decrease the cell (13), piperchabamide D (14), chabamide (15), and 3,4-methylene- viabilities of cancer cells by over 50% were treated with adriamycin dioxycinnamaldehyde (16) by comparing their spectroscopic data at various concentrations (1, 5, 10, 25, and 50 µM) as the positive with those reported in the literature [2a-2m] (Figure 1). control. Compounds 6 and 16 were inactive against Hela and MCF- 1468 Natural Product Communications Vol. 13 (11) 2018 Ngo et al.

7 cell lines, but displayed cytotoxic activities against the HL-60 cell against HL-60 while (E) geometric isomer 5 showed no inhibitory line, with IC50 values of 26.9 ± 2.2 and 21.1 ± 1.6 µM, respectively. effect on cancer cells. In addition, compounds 10, 11, 12, 13, and 14 Compound 10 revealed cytotoxic activity against Hela and MCF-7 possess an isobutyl group instead of a piperidinyl group. These cell lines, with IC50 values of 49.8 ± 4.1 and 36.9 ± 4.8 µM, results revealed the increasing potential of compounds containing respectively, but was inactive against HL-60 cell line. Compound the isobutyl group as anticancer agents against cancer cell lines. 11 was regarded as inactive against MCF-7 and HL-60 cell lines, Compound 15, named chabamide, a dimeric alkaloid, which but displayed weak cytotoxic activity against the Hela cell line, with probably increase the activity of this compound [1h,3c]. Hence, this an IC50 value of 40.4 ± 1.5 µM. Compounds 13 and 14 were compound could be a useful anticancer agent. Based on these inactive against the MCF-7 cell line, but showed cytotoxic activity results, several alkamides from P. nigrum could be promising against the Hela cell line, with IC50 values of 22.1 ± 2.3 and 41.0 ± candidates to decrease viability of cancer cells. 0.6 µM, respectively. It also displayed weak cytotoxic activity against the HL-60 cell line, with IC values of 51.6 ± 5.0 and 54.4 Table 1: Cytotoxic activity of isolated compounds (1−16) from Piper nigrum. 50 Cytotoxicity (IC , µMa) ± 0.3 µM, respectively. Compound 12 revealed cytotoxic activities Compounds 50 Hela MCF-7 HL-60 against Hela, MCF-7, and HL-60 cell lines, with IC50 values of 23.1 1 >100 >100 >100 ± 4.8, 55.7 ± 5.7, and 51.4 ± 1.2 µM, respectively. Also, compound 2 >100 >100 >100 15 revealed cytotoxic activities against Hela, MCF-7, and HL-60 3 >100 >100 >100 cell lines, with IC values of 26.9 ± 1.4, 36.0 ± 2.0, and 16.0 ± 2.6 4 >100 >100 >100 50 5 >100 >100 >100 µM, respectively, while the other compounds exhibited no cytotoxic 6 >100 >100 26.9 ± 2.2 7 >100 >100 >100 activity (Table 1). In comparison, adriamycin gave IC50 values of 8 >100 >100 >100 1.10 ± 0.09, 0.44 ± 0.08, and 0.03 ± 0.01 µM against Hela, MCF-7, 9 >100 >100 >100 and HL-60 cells, respectively. 10 49.8 ± 4.1 36.9 ± 4.8 >100 11 40.4 ± 1.5 >100 >100 120 A 12 23.1 ± 4.8 55.7 ± 5.7 51.4 ± 1.2 13 22.1 ± 2.3 >100 51.6 ± 5.0 100 14 41.0 ± 0.6 >100 54.4 ± 0.3 80 15 26.9 ± 1.4 36.0 ± 2.0 16.0 ± 2.6 16 >100 >100 21.1 ± 1.6 60 Adriamycinb 1.10 ± 0.09 0.44 ± 0.08 0.03 ± 0.01 a 40 50% inhibition concentrations are expressed as the mean±SD of triple experiments; bPositive control. 20

Cell viability (% of control) of (% viability Cell 0 Experimental

Compounds (100 µM) Plant material: The dried fruits of P. nigrum was purchased from the Kwangmyungdang Medicinal Herbs Co. Ltd (Lot No.: 120 B K4041201406) of Ulsan-si, Korea, and identified by Professor 100 Byung-Sun Min, Catholic University of Daegu, Korea. A voucher 80 specimen (CUD-1007-1) is deposited at the Herbarium of the 60 College of Pharmacy, Catholic University of Daegu, Korea. 40 20 Extraction and isolation: The dried fruits of P. nigrum (1 kg) were 0

Cell viability (% of control) of (% viability Cell extracted with MeOH (3×2 L). After the solvent was evaporated under reduced pressure, the crude MeOH extract (100 g) was Compounds (100 µM) suspended in distilled water (0.5 L) and extracted with CHCl3. The CHCl extract was evaporated in vacuo, yielding 35 g of residue. 120 3 The residue was subjected to column chromatography (CC) over 100 C (n-hexane: acetone, 9: 1 → 0: 1) to yield 9 fractions (PN1 80 ~ PN9). Fraction PN4 (210.4 mg) was further fractionated by silica 60 gel CC (CHCl3: acetone, 8: 1) to yield isopiperolein B (9, 51.2 mg). 40 Fraction PN5 (150.9 mg) was subjected to RP-C18 CC (MeOH: 20 H2O, 1: 1) to yield 3 (5.8mg), 6 (3.9 mg), and 13 (12.3 mg). The

Cell viability (% of control) of (% viability Cell 0 fractions PN6 ~ 8 were re-crystallized from acetone to yield whitish crystalline needles of 2 (13.30 g). After removing piperine from the Compounds (100 µM) combination of fractions PN6 ~ 8 by re-crystallization, the residue Figure 2: Cytotoxic activity of isolated compounds from P. nigrum at concentration (10.55 g) was chromatographed over silica gel CC (n-hexane: 100 µM using Hela (A), MCF-7 (B), and HL-60 cell lines. acetone, 9: 1) to obtain 15 sub-fractions. Sub-fraction PN6.2 (253.4

mg) was subjected to RP-C CC (MeOH: H O, 1: 1) furnishing 1 The above-mentioned data shown the potential of amino-acid ester 18 2 (15.8 mg) and 5 (7.2 mg). Subsequently, fraction PN6.2.16 (58.4 conjugates of piperine as anticancer agents against various cancer mg) was further chromatographed on a RP-C column (MeOH: cell lines (Hela, MCF-7, and HL-60) [3b]. Compound 6 having 18 H O, 1: 1) resulting in the isolation of 4 (3.3 mg), 12 (3.3 mg), 14 eight carbons between 3,4-methylenedioxyphenyl and piperidine 2 (2.9 mg), and 11 (12.0 mg). Fractionation of PN6.3 (1.67 g) by amide showed the potency compared to compounds 1, 2, 3, and 4 silica gel CC (CHCl : EtOAc, 40: 1) produced 16 sub-fractions. having less than eight carbons showed no cytotoxic activity. It 3 Fraction PN6.3.5 (14.1 mg) was purified by preparative layer indicates that the eight-carbon chain between the 3,4- chromatography (n-hexane: acetone, 9: 1) to obtain 16 (3.6 mg). methylenedioxyphenyl and piperidine amide can confer a potent Fraction PN6.3.8 (557.5 mg) was fractionated by silica gel CC (n- inhibitory effect on cancer cells. On the other hand, the (Z) hexane:acetone, 20: 1) to yield 10 sub-fractions. Sub-fraction geometric isomer might exert some influence on decreasing PN6.3.8.6 (132.7 mg) was further purified by RP-C CC (MeOH: viability of cancer cells, as compound 6 displayed cytotoxic activity 18 H2O, 1: 1) resulting in the isolation of 10 (16.8 mg). Fraction 6.3.12 Cytotoxic activity of alkaloids from Piper nigrum Natural Product Communications Vol. 13 (11) 2018 1469

(100.5 mg) was subjected to RP-C18 CC (MeOH: H2O, 1: 1) each well to solubilize the water-insoluble purple formazan crystals. furnishing 15 (21.4 mg) and 8 (5.0 mg). Fractionation of PN6.13 After 1 h, the absorbance was measured at 570 nm with a (211.3 mg) by silica gel CC (n-hexane: EtOAc, 1: 1) yielded 7 (47.1 microplate reader. The 50% reduction in cell number relative to the mg). control was estimated visually. After calculating the cell viability (%), compounds shown to decrease the cell viability from cancer Cytotoxic activity: The cytotoxic activity assay was carried out cells by over 50% were treated at various concentrations (1, 5, 10, using the MTT assay according to Mosmann. Hela, MCF-7, and 25, and 50 µM) with adriamycin as the positive control. Various HL-60 cells were cultured in Dulbecco’s modified Eagle’s medium concentrations of the compounds were prepared with serial (RPMI)/F-12 with 15 mM HEPES buffer, ʟ-glutamine, and dilutions. DMSO (0.1%) was used a control. The experiment was pyridoxine hydrochloride supplemented with 10% fetal bovine also allowed to proceed for 48 h at 37°C in a humidified 5% CO2 serum and 1% penicillin-streptomycin in a 96-well plate at a density atmosphere. Also, later steps for experiment were repeated by the of 1 × 105 cells/mL. After 3h for reaching confluence, the cells were same protocol when treatment at concentration of 100 µM. treated with the compounds. The compounds were dissolved in Adriamycin was used as a commercial standard anticancer agent, dimethylsulfoxide (DMSO) and the final concentration of DMSO too. The 50% reduction in cell number relative to the control or IC50 was 0.1% (v/v). Firstly, sixteen isolated compounds were treated at was estimated visually. concentration of 100 µM. DMSO (0.1%) was used a control. The experiment was allowed to proceed for 48 h at 37°C in a humidified Statistical analysis: Values are expressed as mean ± SD. 5% CO2 atmosphere. To minimize the interference of supernatant residue, the adherent cells were washed twice with Dulbecco’s Acknowledgments - This study was supported by the research phosphate buffered saline (DPBS), and then 20 µL of MTT stock grant from Daegu Catholic University in 2017 (Grant solution (5 mg/mL) was added to each well and the plates were No.20171088) - further incubated for 3 h at 37°C. DMSO (100 µL) was added to

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Xiao-Hua Li, Han-Wen Hu, Lu Tan, Wen-Lin Wu, Zhi-Xing Cao, Yu-Cheng Gu, Yun Deng and Da-le Guo 1419

Kojic Acid Derivatives and Sesquiterpenes from the Aspergillus flavus GZWMJZ-288, A Fungal Endophyte of Garcinia multiflora Yanchao Xu, Liping Wang, Qianyu Gong, Guoliang Zhu, Chunmao Yuan, Mingxing Zuo, Qing Rao, Weiming Zhu and Xiaojiang Hao 1421

A New Taxane Diterpenoid and a New Neolignan from Taxus baccata Xiaoyun Lei, Shuai Huang, Hu Xiao, Feng Gao and Xianli Zhou 1425

Diterpenoid Alkaloids from Delphinium aemulans Nurfida Ablajan, Bo Zhao, Wenjuan Xue, Zukela Ruzi, Jiangyu Zhao and Haji Akber Aisa 1429

Trinulactones A–D, New Dinorsesterterpenoids from Streptomyces sp. S006 Feifei Wei, Wen Li, Rentai Song and Yuemao Shen 1433

Grapefruit Seed Extract Inhibits the Formation of Amyloid-like Fibrils by Trypsin in Aqueous Ethanol Phanindra Babu Kasi, Attila Borics, Mónika Varga, Gábor Endre, Kinga Molnár, Lajos László and Márta Kotormán 1437

Lanostane-type Triterpenoids from Ganoderma lucidum and G. multipileum Fruiting Bodies Pham Thanh Binh, Nguyen Phuong Thao, Nguyen Thi Luyen, Duong Thu Trang, Phung Thi Xuan Binh, Nguyen Phuong Dai Nguyen, Nguyen Tuan Hiep, Nguyen Hai Dang, Tran Manh Tri and Nguyen Tien Dat 1441

Cytotoxic Effects of Cucurbitacin I and Ecballium elaterium on Breast Cancer Cells Kadir Yılmaz, Fuat Karakuş, Ergül Eyol, Emir Tosun, İsmet Yılmaz and Songül Ünüvar 1445

Anti-HIV-1 Activities and Chemical Constituents from Leaves and Twigs of Santisukia pagetii (Bignoniaceae) Suphitcha Limjiasahapong, Patoomratana Tuchinda, Vichai Reutrakul, Manat Pohmakotr, Radeekorn Akkarawongsapat, Jitra Limthongkul, Chanita Napaswad and Narong Nuntasaen 1449

Two New Oleanane-type from Hydrocotyle multifida Mayra Rengifo Carrillo, Anne-Claire Mitaine-Offer, Thomas Paululat, Laurent Pouységu, Stéphane Quideau, Luis Rojas, Carmelo Rosquete Porcar and Marie-Aleth Lacaille-Dubois 1453

Two New Steroidal Alkaloid Saponins from the Whole Plants of Solanum nigrum Bui Huu Tai, Vu Van Doan, Pham Hai Yen, Nguyen Xuan Nhiem, Nguyen Thi Cuc, Do Thi Trang, Dan Thi Thuy Hang, Duong Thi Dung, Duong Thi Hai Yen, Tran Hong Quang, Nguyen Hai Dang, Nguyen Thi Mai, Chau Van Minh and Phan Van Kiem 1457

Competitive Inhibition of Mammalian Hyaluronidase by , Esculeoside A Jian-Rong Zhou, Souta Kimura, Toshihiro Nohara and Kazumi Yokomizo 1461

Application of Racemization Process to Dynamic Resolution of (RS)-Phenylephrine to (R)-Phenylephrine β-D-Glucoside by Nicotiana tabacum Glucosyltransferase Yuya Fujitaka, Daisuke Uesugi, Hatsuyuki Hamada, Hiroki Hamada, Kei Shimoda, Masayoshi Yanagi, Manami Inoue and Shin-ichi Ozaki 1465

Cytotoxic Activity of Alkaloids from the Fruits of Piper nigrum Quynh Mai Thi Ngo, Thao Quyen Cao, Le Son Hoang, Manh Tuan Ha, Mi Hee Woo and Byung Sun Min 1467

A New Oxoaporphine Alkaloid from the Root of Dasymaschalon glaucum Weerachai Silprakob, Nuntaporn Sukhamsri, Chutima Kuhakarn, Sakchai Hongthong, Surawat Jariyawat, Kanoknetr Suksen, Radeekorn Akkarawongsapat, Jitra Limthongkul, Narong Nantasaen and Vichai Reutrakul 1471

Boldine Does Not Modify Gender Specific Wound Healing in Zucker Diabetic Rats Renata Köhlerová, Eva Čermáková and Milena Hajzlerová 1475

Phytochemical Analysis and Antimicrobial Efficacy of Macleaya cordata against Extensively Drug-Resistant Staphylococcus aureus Manead Khin, Alan M. Jones, Nadja B. Cech and Lindsay K. Caesar 1479

Polyphenol Compounds Melanin Prevented Hepatic Inflammation in Rats with Experimental Obesity Natalia Belemets, Nazarii Kobyliak, Tetyana Falalyeyeva, Olena Kuryk, Oksana Sulaieva, Tetyana Vovk, Tetyana Beregova and Liudmila Ostapchenko 1485

Antioxidant and α-Glucosidase Inhibitory Activities of Fisetin Yike Yue, Yongsheng Chen, Sheng Geng, Guizhao Liang and Benguo Liu 1489

Simultaneous Quantification of Two Flavonoids in Morus alba by High Performance Liquid Chromatography Coupled with Photodiode Array Detector Chang-Seob Seo and Hyeun-Kyoo Shin 1493

Chemical Composition and Cytotoxicity of Garcinia rubro-echinata, a Western Ghats Endemic Species Lekshmi N. Menon, Ganapathy Sindhu, Kozhiparambil G. Raghu and Koranappallil B. Rameshkumar 1497

Antioxidant and Anti-inflammatory Activities of Cynaroside from Elsholtiza bodinieri Ying Zou, Min Zhang, Tingrui Zhang, Junwen Wu, Jun Wang, Kehai Liu and Nannan Zhan 1501

Phenolic Constituents from Xyloselinum leonidii Nguyen Phuong Hanh, Nguyen Sinh Khang, Chu Thi Thu Ha, Nguyen Quoc Binh and Nguyen Tien Dat 1505

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