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Koanolide A, antiproliferative germacrane-type sesquiterpene lactone from Koanophyllon gibbosum
Tetrahedron Letters 60 (2019) 1640–1642
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Koanolide A, antiproliferative germacrane-type sesquiterpene lactone from Koanophyllon gibbosum Quírico A. Castillo a,b,⇑, José M. Padrón c, Lukasz Wojtas d, Mehdi Keramane e, Evelyn A. Germosén b a
Escuela de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic Instituto de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic c BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, 38206 La Laguna, Spain d Department of Chemistry, University of South Florida, 4202 East Fowler Ave, Tampa, FL 33612, United States e Biointerfaces Institute, McMaster University, Engineering Technology Building, Room 413, 1280 Main Street West, Hamilton, ON L8S 0A3, Canada b
a r t i c l e
i n f o
Article history: Received 30 March 2019 Revised 16 May 2019 Accepted 18 May 2019 Available online 20 May 2019 Keywords: Koanophyllon gibbosum Koanolide A Germacranolides Sesquiterpene lactones
a b s t r a c t A new germacrane-type sesquiterpene lactone, koanolide A (1), was isolated from the aerial parts of Koanophyllon gibbosum. The new structure was elucidated using spectroscopic and spectrometric data analyses, including 1D and 2D NMR. The absolute configuration of compound 1 was established by Xray crystallography. The antiproliferative activity of 1 was studied in a panel of six representative human solid tumor cell lines and showed GI50 values ranging from 0.34 to 20 lM. Ó 2019 Elsevier Ltd. All rights reserved.
According to the World Health Organization (WHO), cancer is the second leading cause of death globally, being responsible for more than 9 million deaths in 2018 [1]. A large amount of anticancer drugs have a natural origin, especially terrestrial plants [2]. In fact, nearly 70% of anticancer drugs are either natural products or natural product derivatives [3]. Sesquiterpene lactones (SLs) are 15-carbon terpenoids present in more than 100 families of flowering plants, being the Asteraceae family where they have mostly been found [4]. More than 5000 SLs are known to date [5]. Some SLs such as artemisinin and parthenolide and their naturally occurring or synthetic analogues have gained considerable interest as possible chemotherapeutic agents to combat cancer [6] (Fig. 1). A continuous search for bioactive compounds from the flora of the island of Hispaniola, led to the phytochemical study of Koanophyllon gibbosum (Urb.) R. M. King & H. Rob. (syn. Eupatorium gibbosum) (Asteraceae), an endemic species of the island [7], from which the isolation and identification of a new germacrane-type sesquiterpene lactone was possible. The EtOAc fraction (3.2 g) of the acetone extract of K. gibbosum yielded koanolide A (1, 8.1 mg) after different chromatographic
⇑ Corresponding author. https://doi.org/10.1016/j.tetlet.2019.05.036 0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Fig. 1. Structure of koanolide A isolated from Koanophyllon gibbosum.
procedures described in the extraction and isolation section of the supplementary data. Compound 1 [8] was obtained as colorless crystals. Its molecular formula was assigned as C20H24O7, based on its HRESIMS (m/z 399.1419 [M+Na]+, calcd 399.1420) and 13C NMR data, indicating 9 degrees of unsaturation. Its IR spectrum revealed the presence of a conjugated c – lactone (1765 cm1) and a,b-unsaturated ester (1714 cm1) functionalities. The 1H NMR data of 1 are summarized in Table 1 and showed the presence of three methyl groups [dH 1.50 (s, Me-14), 1.94 (s, Me-40 ), 3.82 (s, Me-100 )], five olefinic protons [dH 5.65 (t, J = 1.4 Hz, H-30 a), 5.86 (d, J = 1.8 Hz, H-13a), 6.13 (br s, H-30 b), 6.45 (d, J = 2.1 Hz, H-13b), 6.65 (d, J = 11.1 Hz, H-5)], one methine proton [dH 3.04 (br s, H-7)], and three oxygenated methines [dH 2.70 (m, H-1), 5.23 (t, J = 3.1 Hz, H-8), 5.68 (dd, J = 1.9, 11.1 Hz, H-6)].
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Q.A. Castillo et al. / Tetrahedron Letters 60 (2019) 1640–1642 Table 1 NMR data (1H 700 MHz,
13
C 175 MHz, CDCl3, d in ppm, J in Hz) for 1.
Position
dC, type
dH, mult. (J in Hz)
HMBC
1 2
61.3, CH 26.9, CH2
3
23.4, CH2
4 5 6
132. 9, C 137.4, CH 73.7, CH
2, 3, 1, 1, 1, – 3, 4,
7 8 9
47.9, CH 76.6, CH 43.6, CH2
10 11 12 13
56.6, C 136.1, C 168.6, C 126.0, CH2
14 15 10 20 30
18.2, CH3 166.6, C 165.8, C 135.2, C 127.3, CH2
40 100
18.2, CH3 52.5, CH3
2.70, m 1.53, m 2.34, m 2.58, m 2.83, m – 6.65, d (11.1) 5.68, dd (1.9, 11.1) 3.04, br s 5.23, t (3.1) 1.34, dd (2.5, 15.3) 2.84, m – – – 5.86, d (1.8) 6.45, d (2.1) 1.50, s – – – 5.65, t (1.4) 6.13, br s 1.94, s 3.82, s
9, 4 3, 2, 2,
10 4, 10 4, 5, 15 4, 5, 14, 15
4, 7, 15 7, 8, 12
5, 6, 11, 6, 7, 10, 10, 14 7, 8, 10 – – – 7, 8, 11, 7, 8, 11, 1, 9, 10 – – – 10 , 40 40 10 , 20 , 30 4, 15
12, 13 11, 10
12 12
The 13C NMR data of 1 are summarized in Table 1. The spectrum showed 20 resonances, including three methyl groups, five methylene carbons, five methine carbons (including one olefinic and four oxygenated), and seven quaternary carbons (including three olefinic, one oxygenated and three carbonyl). The fragments CH(1)–CH2(2)–CH2(3), CH(5)–CH(6), CH(8)– CH2(9) deduced after the analysis of the HSQC and 1H–1H COSY spectra of 1 (Fig. 2), together with the HMBC correlations from H-1 to C-10 (dC 56.6); from H2-3 (dH 2.58, 2.83) to C-4 (dC 132.9); from H-5 to C-4; from H-6 to C-7 (dC 47.9); from H-8 to C-7; from H2-9 (dH 1.34, 2.84) to C-10; and from Me-14 to C-1 (dC 61.3), C-9 (dC 43.6), and C-10, supported the structure of a 10 membered ring from C-1 to C-10 with a methyl group at C-10. The presence of a methoxycarbonyl group was deduced due to the observed HMBC correlation from Me-100 to C-15 (dC 166.6). The attachment of the latter group to C-4 was evident after the observed HMBC correlations from both H2-3 and H-5 to C-15, reinforced by the observed HMBC correlation from Me-100 to C-4. The presence of a fused a, b-unsaturated c-lactone ring at C-6 and C-7 was established via the observed HMBC correlations from both H-6 and H-7 to C-12 (dC 168.6); from H-7 to C-11 (dC 136.1) and from both H-13a and H-13b to C-7, C-11 and C-12. The presence of a methacryloyl group was deduced after observing its typical carbon’s chemical shifts, along with the observed HMBC correlations from H-30 a with both C-10 (dC 165.8) and Me-40 , reinforced by the observed HMBC correlation from Me-40 to C-10 , C-20 (dC 135.2), and C-30 (dC 127.3). The observed HMBC correlation from H-8 to C-10 allowed the location of the latter group at C-8. A C-1-C-10 epoxide function was deduced by the observed HMBC correlations from Me-14 to C-1,
C-9, and C-10, further supported by the characteristic resonances of these carbons. The observed NOESY correlations between H-6/Me-14 and between H-1/H-7, and H-7/H-8, suggested that H-6 and Me-14 are cofacial, while H-1, H-7, and H-8 occur on the other side of the 10-membered ring. The absolute configuration of 1 was determined as (1R, 6R, 7R, 8R, 10R) (Fig. 3) based on the anomalous scattering signal in the X-ray diffraction data using the Flack approach [9] and confirmed through Bijvoet-pair analysis and Bayesian statistics [10]. The data was collected using Cu Ka radiation (k = 1.54178 Å) to increase the anomalous dispersion signal as compared to data collected with molybdenum radiation. The Bijvoet-pair analysis and Bayesian statistics were performed using the program Platon [11]. Therefore, the structure of 1 was unambiguously established, for which the name koanolide A is proposed. The antiproliferative activity of compound 1 was studied in a panel of six representative human solid tumor cell lines using our version of the protocol of the National Cancer Institute (NCI) of the USA [12]. The results expressed as GI50 are given in Table 2. The standard anticancer drugs etoposide and cisplatin were used for comparison. The best antiproliferative activity was observed against the line SW1573 (lung) with a GI50 value of 0.34 mM. In summary, a new germacrane-type sesquiterpene lactone, koanolide A (1), was isolated and characterized from the aerial parts of K. gibbosum. The absolute configuration of 1 was defined using single-crystal X-ray diffraction analysis. The antiproliferative activity was studied in human solid tumor cell lines showing a good bioactivity against the tested cell lines. This is the first report
Fig. 3. ORTEP drawing of 1 from X-ray crystallographic data.
Table 2 Antiproliferative activity (GI50) of koanolide A (1) against human solid tumor cells.a Compound Cell line (origin) A549 (lung)
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
T-47D (breast)
WiDr (colon)
1 2.1 (±0.3) 0.54 (±0.19) 1.3 (±0.3) 0.34 (±0.04) 2.6 (±0.2) 3.3 (±0.3) Etoposide 0.7 (±0.2) 2.3 (±0.9) 3.0 (±0.9) 15 (±1.5) 22 (±5.5) 23 (±2.1) Cisplatin 2.1 (±0.6) 1.9 (±0.2) 2.0 (±0.3) 3.0 (±0.4) 15 (±2.3) 26 (±5.3)
Fig 2. Selected 1H – 1H COSY (bold lines) and HMBC (H ? C) correlations of 1.
a Values are given in lM and are means of three to four experiments; standard deviation is given in parentheses.
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of the isolation, identification, and antiproliferative activity of a secondary metabolite from K. gibbosum. Acknowledgments This research was partially supported by the Ministerio de Educación Superior, Ciencia y Tecnología (MESCYT), Dominican Republic, under grant FONDOCYT 2013-1D4-003. Instrumental analyses for this work were conducted at the Biointerfaces Institute, McMaster University, (Hamilton, Ontario, Canada) and the crystallographic analysis at the Department of Chemistry, University of South Florida, Tampa, Florida, USA. Biological activity analyses were performed at BioLab, Universidad de La Laguna, Tenerife, Canary Islands, Spain. QAC thanks Dr. Tracey Campbell (McMaster University) and Mr. Andrew Shilling (University of South Florida) for their help in this research. Appendix A. Supplementary data Supplementary data (general experimental procedures, plant material, extraction and isolation, 1D, 2D NMR, UV, IR, and HRESIMS spectra) to this article can be found online at https://doi. org/10.1016/j.tetlet.2019.05.036. References [1] https://www.who.int/en/news-room/fact-sheets/detail/cancer. [2] A. Modzelewska, S. Sur, S.K. Kumar, S.R. Khan, Curr. Med. Chem. 5 (2005) 477– 499.
[3] A. Ghantous, H. Gali-Muhtasib, H. Vuorela, N.A. Saliba, N. Darwiche, Drug Discov. Today. 15 (2010) 668–678. [4] S. Zhang, Y.K. Won, C.N. Ong, H.M. Shen, Curr. Med. Chem. 5 (2005) 239–249. [5] I. Merfort, Curr. Drug Targets 12 (2011) 1560–1573. [6] Y. Ren, J. Yu, D. Kinghorn, Curr. Med. Chem. 23 (2016) 2397–2420. [7] A.H. Liogier, in: La flora de la Española, Universidad Central del Este, San Pedro de Macorís, 1996, p. 142. [8] Koanolide A (1): colorless crystals; mp 171–174 °C; [a]D20 48.7 (c 0.1, CHCl3); UV kmax (log e) 212 (0.59) nm; IR mmax 1765, 1714, 1318, 1287 cm1; 1 H and 13C NMR data, see Table 1; HRESIMS m/z 399.1419 [M+Na]+, (calcd for C20H24O7Na, 399.1420). X-ray crystal data of koanolide A (1): C20H24O7, fw 376.39, monoclinic, crystal size 0.3 0.16 0.92 mm3, space group P21, a = 10.1848(3) Å, b = 8.2324(2) Å, c = 11.3460(3) Å, V = 951.31(4) Å3, Z = 2, T = 99.99 K, Dcalcd = 1.314 g/cm3, l = 0.829 mm1, F(000) = 400.0, reflections collected 14620 (7.792° 2H 154.230°), independent reflections 3453 (Rint = 0.0387, Rsigma = 0.0335), final R indexes for I 2r(I), R1 = 0.0334, wR2 = 0.0764, final R indexes for all data R1 = 0.0378, wR2 = 0.0789, the goodness-offit on F2 is 1.100, the Flack parameter x was 0.08(11). Crystallographic data for 1 have been deposited in the Cambridge Crystallographic Data Center (CCDC) as deposit no. CCDC 1886776. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ getstructures. The X-ray diffraction data for compound 1 were measured on a Bruker D8 Venture PHOTON 100 CMOS system equipped with a Cu Ka INCOATEC Imus micro-focus source (k = 1.54178 Å). Indexing was performed using APEX3. Data integration and reduction were performed using SaintPlus 6.01. Absorption correction was performed by a multi-scan method implemented in SADABS. Space groups were determined using XPREP implemented in APEX3. The structures were solved using SHELXT and refined using SHELXL-2014 (full-matrix least-squares on F2) through an OLEX2 interface program. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed in geometrically calculated positions and were included in the refinement process using a riding model with isotropic thermal parameters. [9] H.D. Flack, Acta Crystallogr. A39 (1983) 876–881. [10] R.W.W. Hooft, L.H. Straver, A.L. Spek, J. Appl. Crystallogr. 41 (2008) 96–103. [11] A.L. Spek, Acta Crystallogr. D65 (2009) 148–155. [12] G. Silveira-Dorta, I.J. Sousa, M.X. Fernandes, V.S. Martín, J.M. Padrón, Eur. J. Med. Chem. 96 (2015) 308–317.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Koanolide A, antiproliferative germacrane-type sesquiterpene lactone from Koanophyllon gibbosum Quírico A. Castillo a,b,⇑, José M. Padrón c, Lukasz Wojtas d, Mehdi Keramane e, Evelyn A. Germosén b a
Escuela de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic Instituto de Química, Universidad Autónoma de Santo Domingo (UASD), Facultad de Ciencias, Ciudad Universitaria, Santo Domingo, D.N., Dominican Republic c BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, 38206 La Laguna, Spain d Department of Chemistry, University of South Florida, 4202 East Fowler Ave, Tampa, FL 33612, United States e Biointerfaces Institute, McMaster University, Engineering Technology Building, Room 413, 1280 Main Street West, Hamilton, ON L8S 0A3, Canada b
a r t i c l e
i n f o
Article history: Received 30 March 2019 Revised 16 May 2019 Accepted 18 May 2019 Available online 20 May 2019 Keywords: Koanophyllon gibbosum Koanolide A Germacranolides Sesquiterpene lactones
a b s t r a c t A new germacrane-type sesquiterpene lactone, koanolide A (1), was isolated from the aerial parts of Koanophyllon gibbosum. The new structure was elucidated using spectroscopic and spectrometric data analyses, including 1D and 2D NMR. The absolute configuration of compound 1 was established by Xray crystallography. The antiproliferative activity of 1 was studied in a panel of six representative human solid tumor cell lines and showed GI50 values ranging from 0.34 to 20 lM. Ó 2019 Elsevier Ltd. All rights reserved.
According to the World Health Organization (WHO), cancer is the second leading cause of death globally, being responsible for more than 9 million deaths in 2018 [1]. A large amount of anticancer drugs have a natural origin, especially terrestrial plants [2]. In fact, nearly 70% of anticancer drugs are either natural products or natural product derivatives [3]. Sesquiterpene lactones (SLs) are 15-carbon terpenoids present in more than 100 families of flowering plants, being the Asteraceae family where they have mostly been found [4]. More than 5000 SLs are known to date [5]. Some SLs such as artemisinin and parthenolide and their naturally occurring or synthetic analogues have gained considerable interest as possible chemotherapeutic agents to combat cancer [6] (Fig. 1). A continuous search for bioactive compounds from the flora of the island of Hispaniola, led to the phytochemical study of Koanophyllon gibbosum (Urb.) R. M. King & H. Rob. (syn. Eupatorium gibbosum) (Asteraceae), an endemic species of the island [7], from which the isolation and identification of a new germacrane-type sesquiterpene lactone was possible. The EtOAc fraction (3.2 g) of the acetone extract of K. gibbosum yielded koanolide A (1, 8.1 mg) after different chromatographic
⇑ Corresponding author. https://doi.org/10.1016/j.tetlet.2019.05.036 0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Fig. 1. Structure of koanolide A isolated from Koanophyllon gibbosum.
procedures described in the extraction and isolation section of the supplementary data. Compound 1 [8] was obtained as colorless crystals. Its molecular formula was assigned as C20H24O7, based on its HRESIMS (m/z 399.1419 [M+Na]+, calcd 399.1420) and 13C NMR data, indicating 9 degrees of unsaturation. Its IR spectrum revealed the presence of a conjugated c – lactone (1765 cm1) and a,b-unsaturated ester (1714 cm1) functionalities. The 1H NMR data of 1 are summarized in Table 1 and showed the presence of three methyl groups [dH 1.50 (s, Me-14), 1.94 (s, Me-40 ), 3.82 (s, Me-100 )], five olefinic protons [dH 5.65 (t, J = 1.4 Hz, H-30 a), 5.86 (d, J = 1.8 Hz, H-13a), 6.13 (br s, H-30 b), 6.45 (d, J = 2.1 Hz, H-13b), 6.65 (d, J = 11.1 Hz, H-5)], one methine proton [dH 3.04 (br s, H-7)], and three oxygenated methines [dH 2.70 (m, H-1), 5.23 (t, J = 3.1 Hz, H-8), 5.68 (dd, J = 1.9, 11.1 Hz, H-6)].
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Q.A. Castillo et al. / Tetrahedron Letters 60 (2019) 1640–1642 Table 1 NMR data (1H 700 MHz,
13
C 175 MHz, CDCl3, d in ppm, J in Hz) for 1.
Position
dC, type
dH, mult. (J in Hz)
HMBC
1 2
61.3, CH 26.9, CH2
3
23.4, CH2
4 5 6
132. 9, C 137.4, CH 73.7, CH
2, 3, 1, 1, 1, – 3, 4,
7 8 9
47.9, CH 76.6, CH 43.6, CH2
10 11 12 13
56.6, C 136.1, C 168.6, C 126.0, CH2
14 15 10 20 30
18.2, CH3 166.6, C 165.8, C 135.2, C 127.3, CH2
40 100
18.2, CH3 52.5, CH3
2.70, m 1.53, m 2.34, m 2.58, m 2.83, m – 6.65, d (11.1) 5.68, dd (1.9, 11.1) 3.04, br s 5.23, t (3.1) 1.34, dd (2.5, 15.3) 2.84, m – – – 5.86, d (1.8) 6.45, d (2.1) 1.50, s – – – 5.65, t (1.4) 6.13, br s 1.94, s 3.82, s
9, 4 3, 2, 2,
10 4, 10 4, 5, 15 4, 5, 14, 15
4, 7, 15 7, 8, 12
5, 6, 11, 6, 7, 10, 10, 14 7, 8, 10 – – – 7, 8, 11, 7, 8, 11, 1, 9, 10 – – – 10 , 40 40 10 , 20 , 30 4, 15
12, 13 11, 10
12 12
The 13C NMR data of 1 are summarized in Table 1. The spectrum showed 20 resonances, including three methyl groups, five methylene carbons, five methine carbons (including one olefinic and four oxygenated), and seven quaternary carbons (including three olefinic, one oxygenated and three carbonyl). The fragments CH(1)–CH2(2)–CH2(3), CH(5)–CH(6), CH(8)– CH2(9) deduced after the analysis of the HSQC and 1H–1H COSY spectra of 1 (Fig. 2), together with the HMBC correlations from H-1 to C-10 (dC 56.6); from H2-3 (dH 2.58, 2.83) to C-4 (dC 132.9); from H-5 to C-4; from H-6 to C-7 (dC 47.9); from H-8 to C-7; from H2-9 (dH 1.34, 2.84) to C-10; and from Me-14 to C-1 (dC 61.3), C-9 (dC 43.6), and C-10, supported the structure of a 10 membered ring from C-1 to C-10 with a methyl group at C-10. The presence of a methoxycarbonyl group was deduced due to the observed HMBC correlation from Me-100 to C-15 (dC 166.6). The attachment of the latter group to C-4 was evident after the observed HMBC correlations from both H2-3 and H-5 to C-15, reinforced by the observed HMBC correlation from Me-100 to C-4. The presence of a fused a, b-unsaturated c-lactone ring at C-6 and C-7 was established via the observed HMBC correlations from both H-6 and H-7 to C-12 (dC 168.6); from H-7 to C-11 (dC 136.1) and from both H-13a and H-13b to C-7, C-11 and C-12. The presence of a methacryloyl group was deduced after observing its typical carbon’s chemical shifts, along with the observed HMBC correlations from H-30 a with both C-10 (dC 165.8) and Me-40 , reinforced by the observed HMBC correlation from Me-40 to C-10 , C-20 (dC 135.2), and C-30 (dC 127.3). The observed HMBC correlation from H-8 to C-10 allowed the location of the latter group at C-8. A C-1-C-10 epoxide function was deduced by the observed HMBC correlations from Me-14 to C-1,
C-9, and C-10, further supported by the characteristic resonances of these carbons. The observed NOESY correlations between H-6/Me-14 and between H-1/H-7, and H-7/H-8, suggested that H-6 and Me-14 are cofacial, while H-1, H-7, and H-8 occur on the other side of the 10-membered ring. The absolute configuration of 1 was determined as (1R, 6R, 7R, 8R, 10R) (Fig. 3) based on the anomalous scattering signal in the X-ray diffraction data using the Flack approach [9] and confirmed through Bijvoet-pair analysis and Bayesian statistics [10]. The data was collected using Cu Ka radiation (k = 1.54178 Å) to increase the anomalous dispersion signal as compared to data collected with molybdenum radiation. The Bijvoet-pair analysis and Bayesian statistics were performed using the program Platon [11]. Therefore, the structure of 1 was unambiguously established, for which the name koanolide A is proposed. The antiproliferative activity of compound 1 was studied in a panel of six representative human solid tumor cell lines using our version of the protocol of the National Cancer Institute (NCI) of the USA [12]. The results expressed as GI50 are given in Table 2. The standard anticancer drugs etoposide and cisplatin were used for comparison. The best antiproliferative activity was observed against the line SW1573 (lung) with a GI50 value of 0.34 mM. In summary, a new germacrane-type sesquiterpene lactone, koanolide A (1), was isolated and characterized from the aerial parts of K. gibbosum. The absolute configuration of 1 was defined using single-crystal X-ray diffraction analysis. The antiproliferative activity was studied in human solid tumor cell lines showing a good bioactivity against the tested cell lines. This is the first report
Fig. 3. ORTEP drawing of 1 from X-ray crystallographic data.
Table 2 Antiproliferative activity (GI50) of koanolide A (1) against human solid tumor cells.a Compound Cell line (origin) A549 (lung)
HBL-100 (breast)
HeLa (cervix)
SW1573 (lung)
T-47D (breast)
WiDr (colon)
1 2.1 (±0.3) 0.54 (±0.19) 1.3 (±0.3) 0.34 (±0.04) 2.6 (±0.2) 3.3 (±0.3) Etoposide 0.7 (±0.2) 2.3 (±0.9) 3.0 (±0.9) 15 (±1.5) 22 (±5.5) 23 (±2.1) Cisplatin 2.1 (±0.6) 1.9 (±0.2) 2.0 (±0.3) 3.0 (±0.4) 15 (±2.3) 26 (±5.3)
Fig 2. Selected 1H – 1H COSY (bold lines) and HMBC (H ? C) correlations of 1.
a Values are given in lM and are means of three to four experiments; standard deviation is given in parentheses.
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of the isolation, identification, and antiproliferative activity of a secondary metabolite from K. gibbosum. Acknowledgments This research was partially supported by the Ministerio de Educación Superior, Ciencia y Tecnología (MESCYT), Dominican Republic, under grant FONDOCYT 2013-1D4-003. Instrumental analyses for this work were conducted at the Biointerfaces Institute, McMaster University, (Hamilton, Ontario, Canada) and the crystallographic analysis at the Department of Chemistry, University of South Florida, Tampa, Florida, USA. Biological activity analyses were performed at BioLab, Universidad de La Laguna, Tenerife, Canary Islands, Spain. QAC thanks Dr. Tracey Campbell (McMaster University) and Mr. Andrew Shilling (University of South Florida) for their help in this research. Appendix A. Supplementary data Supplementary data (general experimental procedures, plant material, extraction and isolation, 1D, 2D NMR, UV, IR, and HRESIMS spectra) to this article can be found online at https://doi. org/10.1016/j.tetlet.2019.05.036. References [1] https://www.who.int/en/news-room/fact-sheets/detail/cancer. [2] A. Modzelewska, S. Sur, S.K. Kumar, S.R. Khan, Curr. Med. Chem. 5 (2005) 477– 499.
[3] A. Ghantous, H. Gali-Muhtasib, H. Vuorela, N.A. Saliba, N. Darwiche, Drug Discov. Today. 15 (2010) 668–678. [4] S. Zhang, Y.K. Won, C.N. Ong, H.M. Shen, Curr. Med. Chem. 5 (2005) 239–249. [5] I. Merfort, Curr. Drug Targets 12 (2011) 1560–1573. [6] Y. Ren, J. Yu, D. Kinghorn, Curr. Med. Chem. 23 (2016) 2397–2420. [7] A.H. Liogier, in: La flora de la Española, Universidad Central del Este, San Pedro de Macorís, 1996, p. 142. [8] Koanolide A (1): colorless crystals; mp 171–174 °C; [a]D20 48.7 (c 0.1, CHCl3); UV kmax (log e) 212 (0.59) nm; IR mmax 1765, 1714, 1318, 1287 cm1; 1 H and 13C NMR data, see Table 1; HRESIMS m/z 399.1419 [M+Na]+, (calcd for C20H24O7Na, 399.1420). X-ray crystal data of koanolide A (1): C20H24O7, fw 376.39, monoclinic, crystal size 0.3 0.16 0.92 mm3, space group P21, a = 10.1848(3) Å, b = 8.2324(2) Å, c = 11.3460(3) Å, V = 951.31(4) Å3, Z = 2, T = 99.99 K, Dcalcd = 1.314 g/cm3, l = 0.829 mm1, F(000) = 400.0, reflections collected 14620 (7.792° 2H 154.230°), independent reflections 3453 (Rint = 0.0387, Rsigma = 0.0335), final R indexes for I 2r(I), R1 = 0.0334, wR2 = 0.0764, final R indexes for all data R1 = 0.0378, wR2 = 0.0789, the goodness-offit on F2 is 1.100, the Flack parameter x was 0.08(11). Crystallographic data for 1 have been deposited in the Cambridge Crystallographic Data Center (CCDC) as deposit no. CCDC 1886776. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ getstructures. The X-ray diffraction data for compound 1 were measured on a Bruker D8 Venture PHOTON 100 CMOS system equipped with a Cu Ka INCOATEC Imus micro-focus source (k = 1.54178 Å). Indexing was performed using APEX3. Data integration and reduction were performed using SaintPlus 6.01. Absorption correction was performed by a multi-scan method implemented in SADABS. Space groups were determined using XPREP implemented in APEX3. The structures were solved using SHELXT and refined using SHELXL-2014 (full-matrix least-squares on F2) through an OLEX2 interface program. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed in geometrically calculated positions and were included in the refinement process using a riding model with isotropic thermal parameters. [9] H.D. Flack, Acta Crystallogr. A39 (1983) 876–881. [10] R.W.W. Hooft, L.H. Straver, A.L. Spek, J. Appl. Crystallogr. 41 (2008) 96–103. [11] A.L. Spek, Acta Crystallogr. D65 (2009) 148–155. [12] G. Silveira-Dorta, I.J. Sousa, M.X. Fernandes, V.S. Martín, J.M. Padrón, Eur. J. Med. Chem. 96 (2015) 308–317.