Daedophamide, a Cytotoxic Cyclodepsipeptide ... - ACS Publications

Note Cite This: J. Nat. Prod. 2017, 80, 3054-3059

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Daedophamide, a Cytotoxic Cyclodepsipeptide from a Daedalopelta sp. Sponge Collected in Indonesia Carlos Urda,† Rogelio Fernández,† Jaime Rodríguez,‡ Marta Pérez,*,† Carlos Jiménez,*,‡ and Carmen Cuevas† †

Medicinal Chemistry Department, PharmaMar S. A., Pol. Ind. La Mina Norte, Avenida de los Reyes 1, 28770, Colmenar Viejo (Madrid), Spain ‡ Departamento de Química, Facultade de Ciencias e Centro de Investigacións Científicas Avanzadas (CICA), Universidade da Coruña, 15071 A Coruña, Spain S Supporting Information *

ABSTRACT: A new cyclodepsipeptide, daedophamide (1), has been isolated from a Daedalopelta sp. marine sponge collected from Alor Island (Indonesia). The planar structure of 1 was assigned on the basis of extensive 1D and 2D NMR spectroscopy and mass spectrometry. Daedophamide (1) contains 11 amino acid residues and an amide-linked 3-hydroxy2,4,6,8-tetramethylnonanoic acid (Htemna). The amino acid constituents were identified as L-Leu, N-Me-L-Gln, D-Arg, D-Asp, D-allo-Thr, L-Pip, D-Ala, D-Ser, 3,4-dimethyl-Gln, O-MeThr, and 4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (Agdha). The absolute configurations of eight of the amino acid residues in 1 were determined by application of the Marfey’s method after acid-catalyzed hydrolysis, with the relative configurations of the remaining three amino acid residues and the Htemna unit being assigned by comparison of the NMR data with those reported for other similar peptides. Compound 1 displayed strong cytotoxic activity against a panel of four human tumor cell lines with GI50 values in the submicromolar range.

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Aplidin, which is in phase III clinical trials for multiple melanoma tumors.7 Among the cyclic peptides, depsipeptides are characterized by their potent HIV-inhibitory, antifungal, or antitumor properties.6 Some examples are the mirabamides A−H8 from Siliquariaspongia mirabilis and Stelleta clavosa, the papuamides A−F9 from Theonella mirabilis, T. swinhoei, and Melophlus sp., the theopapuamides A−D10 from T. swinhoei and S. mirabilis, the neamphamides A and B11 from Neamphius huxleyi and Neamphius sp., and the stellatolides A−G from Ecionemia acervus.12 A distinguishable feature of these depsipeptides is the presence of one or more unusual amino acids such as 3,4-dimethylglutamine (3,4-diMeGln), β-methoxytyrosine (βOMeTyr), 4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (Agdha), 4-amino-2,3-dihydroxy-1,7-heptandioic acid (Adha), 2-amino3-hydroxy-4,5-dimethylhexanoic acid (Ahdmha), 3-hydroxy2,4,6-trimethylheptanoic acid (Htmha), pipecolic acid, and 3-hydroxy-2,4,6-trimethyloctanoic acid (Htmoa). Additionally, most of the former peptides share a common framework comprising a macrocyclic depsipeptide of seven or eight amino acids that is linked to a side chain consisting of a further three or four other residues.

arine sponges of the family Neopeltidae belonging to the subclass Heteroscleromorpha (known before as the order Lithistida) of the order Tetractinellida comprise four genera, Callipelta, Daedalopelta, Homophymia, and Neopelta.1 Only limited work has been carried out on the natural products chemistry of these sponges and relates to cyclic peptides and depsipeptides. Some examples reported in the literature are the callipeltins A−C2 from Callipelta and the pipecolidepsins A and B3 and homophymines A−E/A1−E14 from Homophymia. There is only one previously reported chemical study of a sponge that closely matches the taxonomic description for the genus Daedalopelta sp., and it describes a nonpeptide macrolide named neopeltolide.5 Peptides isolated from marine species constitute a very important group of bioactive natural products. Some of them display great potential for nutraceutical or medicinal purposes due to their effectiveness in both prevention and treatment of various diseases. Ziconotide (tradename Prialt), isolated from a marine cone snail, was the first marine peptide approved by the FDA in 2004 for analgesic use, and brentuximab vedotin (tradename Adcetris), an antibody−drug conjugate (ADC) derived from a marine peptide isolated from a sea hare, was approved by the FDA for cancer treatment in 2011.6 In this regard, it is noteworthy that our research group at PharmaMar is involved in the development of the cyclic peptide © 2017 American Chemical Society and American Society of Pharmacognosy

Received: August 8, 2017 Published: November 7, 2017 3054

DOI: 10.1021/acs.jnatprod.7b00678 J. Nat. Prod. 2017, 80, 3054−3059

Journal of Natural Products

Note

As part of our ongoing efforts to find novel antitumor agents from marine organisms13 and more specifically from sponges,14 specimens of the genus Daedalopelta were further investigated following initial discovery that the organic extracts displayed cytotoxic activity against human tumor cell lines A-549 (lung), HT-29 (colon), MDA-MB-231 (breast), and PSN-1 (pancreas). Bioassay-guided fractionation of the active organic extract of this sponge resulted in the isolation of a new depsipeptide as the principal bioactive component, which was named daedophamide (1).

Additionally, the NMR data displayed a spin system comprising an oxymethine group at δH 3.54/δC 79.5, two methylene groups at δH 1.12 and 1.31/δC 39.0 and δH 0.92 and 1.20/δC 46.8, four methines at δH 2.61/δC 44.8, δH 1.78/δC 33.6, δH 1.73/δC 26.5, and δH 1.59/δC 29.0, and five methyl groups at δH 1.11, 1.01, 0.93, 0.93, and 0.88/δC 14.9, 17.8, 21.9, 24.6, and 21.4, respectively, which were connected by COSY and confirmed by HMBC correlations. A long-range 1H−13C correlation between the methine at δH 2.61 and the carbon resonance at δC 178.9 indicated the presence of a carbonyl amide group in this residue. Comparison of the NMR data for this fragment in 1 with those of other similar structures reported in the literature (Table 2) showed that it matched with an amidelinked 3-hydroxy-2,4,6,8-tetramethylnonanoic acid (Htemna) group. Although homologues of this fragment are present in several depsipeptides of this kind, homophymine D is the only precedent that bears this residue as the end group.4b The last residue in daedophamide (1) corresponds to a spin system assigned by the COSY and TOCSY correlations to a long chain, CH−CH−CH−CH2−CH2−CH2. The presence of a guanidine functionality was suggested by the nonprotonated carbon at δC 158.6 due to its characteristic chemical shift value. The typical resonances at δC 73.0 for C-2 and at δC 75.3 for C-3 were assigned to carbons binding to hydroxy groups, while the carbon chemical shift at δC 50.8 for C-4 indicated that it was linked directly to a nitrogen atom. The HMBC correlations from oxymethines H-2 at δH 3.88 and H-3 at δH 3.63 to a carbonyl at δC 176.4 allowed the assessment of C-1 as an amide functionality. The chemical shifts for this fragment in 1 were consistent with the proton and carbon chemical shifts assigned to a 4-amino-7-guanidino-2,3-dihydroxyheptanoyl moiety (Agdha) present in neamphamides A and B11 and callipeltin A.2 Assembly of these amino acids was carried out using a combination of HMBC and ROESY data. Long-range correlations from α-protons to carbonyl carbons of adjacent amino acids along with ROESY correlations between α-protons and NH protons of adjacent amino acids (Figure 1) allowed us to establish the sequence as Pip-Asp-OMeThr-N-MeGln-Leu-ArgSer-Thr-3,4-diMeGln-Agdha-Ala-Htemna. The presence of an ester bond between the carbonyl group of pipecolic acid (Pip) and the hydroxy group of the threonine residue (Thr) was deduced by the characteristic chemical shift of the β-hydroxymethine proton (δH 5.80) and corroborated by the HMBC correlation between this proton and the Pip carbonyl carbon at δC 170.8. The relative configurations of O-MeThr and Htemna in 1 were assumed to be identical to those of these moieties reported previously in homophymine D4 (Table 2), as well as through analysis of their 1H and 13C NMR spectra. In a similar manner, the relative configurations of 3,4-dimethyl-glutamine and Agdha in 1 were proposed to be as those reported for the same moiety present in similar peptides (neamphamides11 and callipeltin A2) due to the close resemblance of the 1H and 13C NMR spectra (Table 2). The absolute configurations of D-alanine, D-arginine, D-serine, D-allo-threonine (aThr), L-pipecolic acid (Pip), N-Me-L-glutamine (N-MeGln), D-aspartic acid, and L-leucine residues in daedophamide (1) were determined by comparing the hydrolysis products of 1 (6 N HCl, 110 °C, 18 h), after derivatization with Marfey’s reagent (N-(3-fluoro-4,6-dinitrophenyl)-L-alaninamide, L-FDAA), with appropriate amino acid standards using HPLC-MS chromatography.16

Samples of a Daedalopelta sp. marine sponge, collected by hand off the coast of Alor Island in Indonesia, were extracted several times using CH2Cl2/MeOH (1:1). The organic extract was subsequently fractionated by vacuum flash chromatography (VFC) using a LiChroprep RP-18 column and a gradient mixture of H2O, MeOH, and CH2Cl2 with decreasing polarity. Bioassays against the former human tumor cell lines were used to guide the fractionation, which afforded a very active fraction that eluted with 100% MeOH and was subjected to reversedphase HPLC to yield 1. Daedophamide (1) was obtained as a colorless, amorphous solid. The molecular formula of C71H125N19O22 for 1 was deduced from the protonated molecule [M + H]+ at m/z 1596.9328 by HRESI-TOFMS. The intense doubly protonated molecule [M + 2H]2+ observed at m/z 798.9793 by HRESI-TOFMS was in agreement with this molecular formula. The facile formation of a doubly charged ion suggested the presence of two basic guanidine functionalities in 1.11 The peptidic nature of 1 was evident from the large number of signals for exchangeable amide NH protons (δH 6.45−8.97) and for α-amino acid protons in the deshielded region (δH 4.05−5.51) of its 1H NMR spectrum obtained in CD3OH along with the 17 carbonyl carbons (δC 170.8−180.2) attributable to ester/amide functionalities in its 13C NMR spectrum. Extensive analysis of the 2D NMR experiments of 1, including COSY, TOCSY, HSQC, and HMBC, revealed the presence of six proteinogenic amino acids: alanine, threonine, serine, arginine, leucine, and aspartic acid. The presence of one N-methylated15 and one O-methylated amino acid residue was suggested by the characteristic 1H and 13C NMR chemical shifts of N-methyl and O-methyl groups at δH 3.04/δC 31.6 and δH 3.28/δC 57.2, respectively. HMBC correlations were employed to identify these methylated amino acids as N-methylglutamine (N-MeGln) and O-methylthreonine (O-MeThr). Two further unusual amino acid residues were also elucidated, 3,4-dimethylglutamine (3,4-diMeGln) and pipecolic acid (Pip), which are also present in homophymines A−E and A1−E1.4 3055



Note

Table 1. NMR Data of 1 in CD3OD (500 MHz for 1H and 125 MHz for 13C) residue Htemna

position

δC, type

1 2 2-CH3 3 4 4-CH3 5 6 6-CH3 7 8 9 10

178.9, C 44.8, CH 17.8, CH3 79.5, CH 33.6, CH 21.4, CH3 39.0, CH2 29.0, CH 21.9, CH3 46.8, CH2 26.5, CH 24.6, CH3 14.9, CH3

1 2 3

176.3, C 51.3, CH 17.8, CH3

1 2 3 4 5 6 7 8

176.4, C 73.0, CH 75.3, CH 50.8, CH 26.4, CH2 26.0, CH2 42.2, CH2 158.6, C

1 2 3 3-CH3 4 4-CH3 5-CO

171.3, C 59.4, CH 37.6, CH 14.4, CH3 42.7, CH 14.8, CH3 180.2, C

δH, mult. (J in Hz)

residue Arg

2.61, 1.01, 3.54, 1.78, 0.88, 1.12, 1.59, 0.93, 0.92, 1.73, 0.93, 1.11,

dd (8.8, 6.6) d (6.6) dd (8.8, 3.0) m d (6.4) m; 1.31, m m d (6.4) m; 1.20, m m d (6.5) d (7.1) Leu

Ala

4.32, q (7.3) 1.43, d (7.3)

N-MeGln Agdha

3.88, 3.63, 4.17, 1.63, 1.64, 3.22,

d (8.6) dd (8.6, 1.8) m m m m O-MeThr

3,4-diMeGln

4.19, d (10.4) 2.29, ddt (10.4, 9.0,6.9) 1.11, d (6.9) 2.8, dt (9.0, 5.6) 1.26, d (5.6) Asp

aThr

Ser

1 2 3 4

174.2, C 55.9, CH 71.4, CH 14.8, CH3

5.46, d (3.5) 5.8, dq (6.1, 3.5) 1.26, d (6.1)

1 2 3

173.1, C 60.6, CH 62.0, CH2

4.05, t (3.3) 3.98, m; 4.12, m

Pip

position

δC, type

1 2 3 4 5 6 NH

174.3, C 52.8, CH 28.4, CH2 30.4, CH2 41.9, CH2 158.5, C

1 2 3 4 5 5′ NH

176.5, C 50.9, CH 40.1, CH2 26.0, CH 23.9, CH3 21.6, CH3

1 2 3 4 5 N-CH3

172.7, C 57.9, CH 23.9, CH2 32.4, CH3 177.8, C 31.6, CH3

1 2 3 4 O-CH3 NH

171.1, C 58.9, CH 76.5, CH 16.4, CH3 57.2, CH3

1 2 3 4 NH

171.2, C 47.1, CH 36.5, CH2 174.5, C

1 2 3 4 5 6

170.8, C 53.8, CH2 27.4, CH2 22.0, CH2 26.3, CH2 44.8, CH2

δH, mult. (J in Hz) 4.57, 1.67, 1.60, 3.18,

dd (10.1, 4.1) m; 2.11, m m; 1.72, m m

8.37, d (9.2)

4.67, dd (9.0, 3.2) 1.44,m; 2.20, m 1.97, m 1.05, d (6.6) 1.0, d (6.6) 7.58, d (6.1)

5.51, bs 1.95, m; 2.38, m 2.13, m; 2.23, m 3.04, s

4.41, 4.16, 1.19, 3.28, 6.45,

d (9.3) dq (9.3, 6.3) d (6.3) s d (9.4)

5.34, dd (9.6, 4.1) 2.48, m; 2.93, m 8.27, d (9.7)

5.25, m 2.18,m ; 1.64, m 1.27, m; 1.73, m 1.51, m; 1.64, m 3.08, m, 3.68, m

In summary, a new cyclodepsipeptide, daedophamide (1), was isolated from the organic extract of a Daedalopelta sp. sponge, representing only the second chemical study of an organism belonging to this genus. Its structure was established by spectroscopic methods, Marfey’s method, and comparison with chemical shifts of other cyclodepsipeptides such as neamphamide A and homophymine D. Compound 1 is a new member of a growing class of marine cyclodepsipeptides

Cell proliferation assays against the human tumor cell lines A-549 (lung), HT-29 (colon), MDA-MB-231 (breast), and PSN-1 (pancreas) showed that daedophamide (1) exhibited strong cytotoxicity against the four tumor cell lines with GI50 values in the submicromolar range (Table 3). The antitumor agent doxorubicin was also tested in parallel as a positive standard following an identical procedure, and the results are included in Table 3. 3056



Note

Table 2. Comparison of the NMR Data in CD3OD of Agdha and Htemna Residues in 1 to Those Present in Neamphamide A11a and Homophymine D,4b Respectively Agdha

Htemna

daedophamide (1)

neamphamide A

daedophamide (1)

homophymine D

position

δC

δH

δC

δH

position

δC

δH

δC

δH

2 3 4 5 6 7 8

73.0 75.3 50.8 26.4 26.0 42.2 158.6

3.88 3.63 4.17 1.63 1.64 3.22

72.9 75.3 50.9 26.5 26.3 41.9 158.6

3.88 3.61 4.16 1.74 1.60, 1.70 3.17

1 2 2-CH3 3 4 4-CH3 5 6 6-CH3 7 8 9 10

178.9 44.8 17.8 79.5 33.6 21.4 39.0 29.0 21.9 46.8 26.5 24.6 14.9

2.61 1.01 3.54 1.78 0.88 1.12, 1.31 1.59 0.93 0.92, 1.20 1.73 0.93 1.11

178.7 44.7 17.6 79.1 33.5 21.5 38.0 28.6 21.8 46.4 26.4 24.4 14.5

2.66 1.01 3.59 1.79 0.91 1.18, 1.26 1.60 0.87 0.94, 1.23 1.70 0.91 1.06

Table 3. Cytotoxic Activity Data (μM) of 1a tumor cell lines breast MDAMB-231

compound daedophamide (1)

doxorubicin

GI50 TGI LC50 GI50 TGI LC50

0.3 0.6 0.9 0.2 0.5 2.4

colon lung NSLC HT-29 A-549 0.6 0.8 1.3 0.3 0.9 >17.2

0.4 0.5 0.7 0.2 0.9 >17.2

pancreas PSN-1 0.2 0.3 0.6 0.2 0.5 3.1

a

GI50, compound concentration that produces 50% inhibition on cell growth as compared to control cells; TGI, compound concentration that produces total growth inhibition as compared to control cells; and LC50, compound concentration that produces 50% cell death as compared to control cells.

Figure 1. Fragments deduced by COSY (displayed by bold bonds) in 1 and some key HMBC (plain arrows) and NOE (dashed arrows) correlations.

with ATR sampling. NMR spectra were recorded on a Varian “Unity 500” spectrometer at 500/125 MHz (1H/13C). Chemical shifts were reported in ppm using residual CD3OD (δH 4.87, 3.31 for 1H and δC 49.0 for 13C) as an internal reference. (+)-ESIMS spectra were recorded using an Agilent 1100 Series LC/MSD spectrometer. High-resolution mass spectroscopy (HRMS) was performed on an Agilent 6230 TOF LC/MS system using the ESIMS technique. Animal Material. The Daedadopelta sp. sponge was collected by hand using a rebreather system from Alor Island (Indonesia) (08°19.641′ S/124°19.994′ E) at a depth of 95 m in August 2013 and frozen immediately after collection. A voucher specimen (ORMA123604) is deposited at PharmaMar. Taxonomic description of the organism: massive globular sponge made up of hemispherical tubercles or mamelons with an exhalation zone on the upper part formed of several ducts grouped together, with others in other parts of the sponge; stony consistency with separable ectosome in some areas (inhalants); skeleton formed by pseudophylotrienas of dentate (nontubercular) clades and generally flat; desmas of smooth arms with a high density of terminal zygomas; other larger spicules (megascleres) contributing to the skeletal framework comprise very fine styles and oxeas as well as spiny, small radius anfiasters of differing sizes and quiasters, sanidasters, and spirates. Extraction and Isolation. Samples of Daedadopelta sp. (70 g) were triturated and exhaustively extracted with MeOH/CH2Cl2 (50:50, 3 × 400 mL). The combined extracts were concentrated to yield a mass of 1.7 g, which was subjected to vacuum liquid chromatography (VLC) on a Lichroprep RP-18 column (Merck KGaA) with a stepped gradient from H2O to MeOH and then CH2Cl2. The fraction eluting with MeOH (56 mg) was subjected to semipreparative HPLC

that share the same basic structural skeleton of a seven- or eight-residue macrocyclic ring moiety formed by cyclization through the β-hydroxy group of a Thr residue that is linked through its amino terminus to a 3,4-diMeGln residue of a side chain. That side chain usually contains another two amino acid residues and a hydroxylated polyketide moiety. They are also distinguished by the presence of a high number of D-amino acids and N-methylated amino acids along with several unusual amino acid residues. The macrocyclic ring of daedophamide (1) shares a high degree of structural homology with homophymine D,4b differing in two residues (Arg and alloThr in 1 instead of Orn and 2-amino-3-hydroxy-4,5-dimethylhexanoic acid (Ahdmha), respectively, in homophymine D). The side chain of 1 is similar to that of callipeltin A,2 differing in the polyketide moiety (a 3-hydroxy-2,4,6-trimethylheptanoic acid (Htmha) in callipeltin A instead of Htemna in 1). Finally, daedophamide (1) showed strong cytotoxic activity against a panel of four human tumor cell lines in the submicromolar range. A possible microbial origin for these depsipeptides has been suggested.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were determined using a Jasco P-1020 polarimeter. UV spectra were performed using an Agilent 8453 UV−vis spectrometer. IR spectra were obtained with a PerkinElmer Spectrum 100 FT-IR spectrometer 3057



Note

(Waters Symmetry C18, 7 μm, 7.8 × 150 mm, gradient from 30% to 50% CH3CN in H2O with 0.1% TFA in 20 min, flow: 2.3 mL/min, UV detection) to yield 1 (4 mg, retention time: 12.4 min). Daedophamide (1): amorphous, colorless solid; [α]25D +6.3 (c 0.46, MeOH); UV (MeOH) λmax 200 nm; IR (ATR) νmax 3335, 2958, 1658, 1531, 1455, 1202, 837, 801, 721 cm−1; 1H NMR (500 MHz) and 13C NMR (125 MHz) Table 1; (+)-HRESI-TOFMS m/z 1596.9328 [M + H]+ (calcd for C71H126N19O22, 1596.9319). Absolute Configuration. Daedophamide (1) (0.4 mg) was hydrolyzed in 0.5 mL of 6 N HCl at 110 °C for 18 h. After that time, the excess aqueous HCl was removed under a N2 stream, and 100 μL of H2O, 0.4 mg of 1-fluoro-2,4-dinitrophenyl-5-L-alaninamide (L-FDAA, Marfey’s reagent) in 100 μL of acetone, and 40 μL of 1 M NaHCO3 were added to the dry hydrolysates. The resulting mixture was heated at 40 °C for 1 h. Then, the reaction mixtures were cooled to 23 °C, quenched by addition of 2 N HCl (100 μL), dried, and dissolved in H2O (660 μL). The aliquots were subjected to reversedphase LC/MS [column: Waters Symmetry, 150 × 4.6 mm, 5 μm; mobile phase, CH3CN + 0.04% TFA/H2O + 0.04% TFA; flow rate, 0.8 mL/min] using a linear gradient (20−50% CH3CN over 30 min). The retention times and ESIMS product ions (tR in min, m/z [M + H]+) of the L-FDAA monoderivatized amino acids in the hydrolysate of 1 were established as D-Ala (17.8, 342.2), D-Ser (6.9, 358.0), D-allo-Thr (8.4, 372.0), L-Leu (25.8, 384.2), D-Asp (12.5, 386.1), N-Me-L-Glu (38.6, 414.0), D-Arg (6.7, 427.0), and L-Pip (22.9, 382.0). Retention times for the derivatized amino acid standards are as follows L-Ala 15.2 min, D-Ala 17.8 min, L-Ser 6.7 min, D-Ser 6.9 min, L-Thr 7.4 min, L-allo-Thr 7.6 min, D-Thr 9.5 min, D-allo-Thr 8.4 min, L-Leu 25.7 min, D-Leu 30.0 min, L-Asp 11.8 min, D-Asp 12.5 min, N-Me-L-Glu 38.5 min, N-Me-D-Glu 37.7 min, L-Arg 7.4 min, D-Arg 6.8 min, L-Pip 22.8 min, and D-Pip 21.33 min. Biological Assays. The cytotoxic activity of compound 1 was tested against A-549 human lung carcinoma cells, MDA-MB-231 human breast adenocarcinoma cells, HT-29 human colorectal carcinoma cells, and PSN-1 human pancreas carcinoma cells. The concentration giving 50% inhibition of cell growth (GI50) was calculated according to the procedure described in the literature.17 Cell survival was estimated using the National Cancer Institute (NCI) algorithm.18 Three dose− response parameters were calculated for 1.

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(CEAB-Centro de Estudios Avanzados de Blanes, Spain) for determining the sponge taxonomy. The present research was financed in part by grants from the Ministry of Economy and Competitiveness (MINECO) (Grants AGL2015-63740-C2-2-R and RTC-2016-4611-1), cofunded by the FEDER Programme from the European Union.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00678. 1 H, 13C, HSQC, COSY, HMBC, ROESY, and selective TOCSY 1D NMR spectra, MS, and analysis by Marfey’s method of 1 (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Tel: +34 981 167000. Fax: +34 981 167065. ORCID

Jaime Rodríguez: 0000-0001-5348-6970 Carlos Jiménez: 0000-0003-2628-303X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the help of our PharmaMar colleagues, A. Rodríguez for his excellent technical assistance, C. de Eguilior and S. Bueno for collecting the marine samples, L. F. Garciá for the design of the biological assays, and S. Munt for revision of the manuscript. We also thank Dra. M. J. Uriz 3058



Note

(15) Urda, C.; Pérez, M.; Rodríguez, J.; Jiménez, C.; Cuevas, C.; Fernández, R. Tetrahedron Lett. 2016, 57, 3239−3242. (16) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591−596. (17) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1107−1112. (18) Shoemaker, R. H. Nat. Rev. Cancer 2006, 6, 813−823.

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