Antitubercular and Cytotoxic Chlorinated seco-Cyclohexenes from

Note Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

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Antitubercular and Cytotoxic Chlorinated seco-Cyclohexenes from Uvaria alba Allan Patrick G. Macabeo,*,†,△ Arianne G. Letada,† Simon Budde,‡ Christian Faderl,‡ Hans-Martin Dahse,§ Scott G. Franzblau,⊥ Grecebio Jonathan D. Alejandro,∥ Gregory K. Pierens,# and Mary J. Garson¶ †

Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, 1015 Manila, Philippines ‡ Institut für Organische Chemie, Universität Regensburg, D-93053 Regensburg, Germany § Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute (HKI), D-07745 Jena, Germany ⊥ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States ∥ Plant Sciences Laboratory, Research Center for the Natural and Applied Sciences, University of Santo Tomas, 1015 Manila, Philippines # Centre for Advanced Imaging and ¶School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia S Supporting Information *

ABSTRACT: Two new chlorine-containing polyoxygenated seco-cyclohexenes, albanols A (1) and B (2), along with the oxepinone metabolite grandiuvarone (3) were isolated from the endemic Philippine Annonaceae plant Uvaria alba. Both new compounds exhibited modest antitubercular activity. Compound 1 showed cytostatic activity (ranging from 1−50 μM) against HeLa cells and weak antiproliferative activity against HUVEC and K-562 cells with GI50 values of 106 and 81 μM, respectively.

fforts on the discovery of biologically active compounds from the Annonaceae family have resulted in the identification of secondary metabolites with cytotoxic, antitubercular, antimalarial, insecticidal, immunosuppressive, and antifeedant activities.1,2 Among the members of the Annonaceae, the species-rich genus Uvaria L. is known to be a prolific source of highly oxidized cyclohexenes including their acyclic congeners, the seco-cyclohexenes. Eight Uvaria species have been reported to contain these types of compounds, but these reports provided little information on their biological activities.3 As part of a research interest to explore biologically active natural products from Philippine medicinal plants, especially the discovery of antitubercular and cytotoxic constituents,4 the endemic species Uvaria alba Merr., a small shrub widely distributed in the Bataan and Zambales provinces of Luzon Island, Philippines, and with previously reported anti-infective and cytotoxic activities,5 was explored to identify the active constituents. To date, about 20 species of shrubs to small trees of Uvaria are currently known in the Philippines, and so far three species have been investigated.2,6 Herein, we disclose the identification of two highly oxidized, chlorinated seco-cyclo-

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© XXXX American Chemical Society and American Society of Pharmacognosy

hexenes, albanols A (1) and B (2), along with grandiuvarone (3), using spectroscopic methods. The isolated compounds were tested against Mycobacterium tuberculosis H37Rv and cancer cells to assess their antitubercular and cytotoxic activities, respectively.

Compound 1 was isolated as a colorless oil that gave a protonated molecule at m/z 447.1204 [M + H]+ and a sodium adduct ion at m/z 469.1027 [M + Na]+ in the positive-ion HRESIMS. These data indicated a molecular formula of C23H23ClO7 and implied 12 indices of hydrogen deficiency. Received: August 8, 2017

A

DOI: 10.1021/acs.jnatprod.7b00679 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Note

Table 1. NMR Spectroscopic Data (CDCl3, 600 MHz, 30 °C) for Albanols A (1) and B (2) 1

a

position

1

1a 1b 2 3 4 5 6a 6b 7a 7b 1-OBz 1′ 2′/6′ 3′/5′ 4′ 7′ 6-OBz 1″ 2″/6″ 3″/5″ 4″ 7″ 7-OAc 1‴ 2‴

4.87, s

H (J in Hz)

6.11, d (10.5) 5.10, dd (10.5, 5.1) 4.13, q (5.1) 4.49, dd (11.8, 4.8) 4.45, dd (11.8, 5.7) 4.82, d (12.8) 4.72 d (12.8)

2 13

C, mult.

65.7, CH2

1

2, 7′

4.60, d (11.8) 4.39, d (11.8)

2 2

5.23, 6.04, 5.92, 5.05, 4.91, 3.85, 3.78,

134.2, C 129.6, CH 58.4, CH 72.4, CH 65.4, CH2

7″

59.4, CH2

2, 1‴

8.03, d (6.8) 7.43−7.46, m 7.56, t (7.4)

129.6, 129.6, 128.4, 133.3, 165.9,

C CH CH CH C

8.04, d (7.6) 7.43−7.46, m 7.56, t (7.4)

129.4, 129.7, 128.5, 133.4, 166.4,

C CH CH CH C

1.99, s

HMBCa

170.5, C 20.6, CH3

H (J in Hz)

d (10.4) dd (10.4, 11.0) ddd (11.0, 6.9, 6.9) ddd (13.3, 7.8, 1.3) ddd (13.3, 6.3, 1.5) d (11.9) d (11.9)

13

C, mult.

64.8, CH2

HMBCa 2, 7′

75.3, C 58.7, CH 129.3, CH 128.5, CH 60.2, CH2

7″

63.2, CH2

2

7′ 1′

8.03, d (8.3) 7.42−7.46, m 7.57, t (7.4)

129.7, 129.7, 128.4, 133.2, 166.8,

C CH CH CH C

7″ 1″

8.05, d (8.3) 7.42−7.46, m 7.57, t (7.5)

129.6, 129.8, 128.6, 133.6, 166.5,

C CH CH CH C

2 2

7′ 1′

7″ 1″

1‴

HMBC correlations, optimized for 10 Hz, are from the proton(s) stated to the indicated carbon(s).

The IR spectrum showed bands at 3481, 1771, and 1592 cm−1 characteristic for hydroxy, ester carbonyl, and aromatic moieties, respectively. The 13C NMR spectrum of 1 (Table 1) revealed 19 resonances that were assigned to three sp2 quaternary carbons, three ester carbonyls at δC 170.5, C-1‴, 166.4, C-7′, and 165.9, C-7″, an aromatic/olefinic methine (δC 134.2, C-2, 129.6, C-1′, and 129.4, C-1″), an olefinic methine (δC 129.6, C-3), an oxymethine (δC 72.4, C-5), three oxymethylenes (δC 65.7, C-1, 65.4, C-6, and 59.4, C-7), a chloromethine (δC 58.4, C-4), an acetyl methyl (δC 20.6, C2‴), and six aromatic methines resonating between δC 128.4 and 133.4. The 1H NMR spectrum (Table 1) and multiplicityedited HSQC spectrum provided further evidence to support a seco-cyclohexene skeleton through the presence of aromatic methines for the benzoyl moieties (δH 8.03−7.43, 10H, H-2′ to H-6′; H-2″ to H-6″), an olefinic methine proton at δH 6.11 (d, H-3), an oxymethine proton at δH 4.13 (q, H-5), a chloromethine proton3b,7 at δH 5.10 (dd, H-4), three pairs of oxymethylene protons (δH 4.87, s, H2-1; δH 4.82, d, H-7a; δH 4.72, d, H-7b; δH 4.49, dd, H-6a, 4.45, dd, H-6b), and a singlet at δH 1.99 for an acetyl methyl (H3-2‴). Analysis of the 1H−1H COSY and HSQC spectra revealed connectivities (bold lines) between C-3 → C-4 → C-5 → C-6 (Figure 1). In the HMBC spectrum of 1, the long-range correlations from H2-7, H2-1, H3, and H-4 to the quaternary olefinic carbon at δC 134.2 (C-2) allowed the construction of the seco-cyclohexene motif. Furthermore, HMBC correlations of the H2-1 signals at δH 4.87 and the aromatic protons at δH 8.03 (H-2′,6′) with the ester carbonyl at δC 165.9 (C-7′) and of the H2-6 signals and the aromatic protons at δH 8.04 (H-2″,6″) with the ester carbonyl at δC 166.4 (C-7″) positioned the two benzoyl groups at C-1 and C-6. Finally, HMBC correlations of the acetate

Figure 1. Connectivities deduced from the COSY spectra (bold lines), key HMBC correlations (→, red), and NOESY (↔, blue) observed for compounds 1 and 2.

methyl signal at δH 1.99 and of H2-7 with the ester carbonyl carbon at δC 170.5 (C-1‴) allowed the construction of the 2D structure of 1. NOESY correlations were observed between H-3 and H-1, which gave rise to an E configuration for the Δ2(3) olefinic moiety. The relative configuration of 1 was investigated by NOESY data and by J-based configurational analysis. In the 2D NOESY spectrum, correlations were observed from H-3 to H-4 and H-5 and from H-4 to H-5, H2-6, and H2-7, but not from H-3 to H26. The medium-sized 3J4,5 value of 5.1 Hz (CDCl3) indicated conformational averaging (also in CD3CN or methanol-d4) and could not be used to distinguish the syn (= threo) from the anti B



Note

(1765 and 1718 cm−1), and aromatic (1610 and 1591 cm−1) functionalities. Comparison of the 1H, 13C, and HSQC NMR spectroscopic data (Table 1) with those of albanol A (1) indicated that the two metabolites shared the same carbon skeleton, with the major difference being the absence of a threeproton singlet for an acetyl group in the 1H NMR spectrum of 2. Both sets of spectroscopic data displayed signals due to two benzoyl groups, one oxymethine, three oxymethylenes, one chloromethine, and two olefinic protons. Analysis of the 1 H−1H COSY and HSQC spectra for 2 revealed the partial connectivities (bold line) between C-3 → C-4 → C-5 → C-6 (Figure 1). In the HMBC spectrum, the long-range correlations from the oxymethylene protons at δH 3.78, 3.85 (H2-7) and δH 4.39, 4.60 (H2-1) and chloromethine proton at δH 5.23 to the oxygenated tertiary carbon at δC 75.3 (C-2) gave rise to the seco-cyclohexene substructure. Finally, the C-1 and C-6 locations of the benzoyloxy groups were established by HMBC correlations between H2-1 and C-7′ and between H26 and C-7″, affording the full structure of 2. The Z configuration of the Δ4(5) olefinic bond was assigned on the basis of NOESY correlations between H-3 (δH 5.23)/H2-6 (δH 5.05, 4.91) as well as the observed J value between H-4 and H-5 (11.0 Hz). The NOESY spectrum also featured strong NOE correlations between H-3 and H2-7 and between H-4 and H2-1. Based on biosynthetic considerations, the (2S*,3R*) relative configuration of 2 is similar to that of grandiuvarin B3c (Scheme 1). Thus, the structure of 2 was established as the new natural product (2Z,4S*,5R*)-4-chloro-5-hydroxy-5-(hydroxymethyl)hex-2-ene-1,6-diyl dibenzoate and named albanol B. In this work, two new chlorinated seco-cyclohexene natural products, albanols A (1) and B (2), were obtained from U. alba and possessed structures bearing unusual C-2−C-3 and C-4− C-5 chlorohydrin functionalities. Two chlorinated seco-cyclohexenes from the genus Uvaria were previously reported.3b,i Putative biosynthetic pathways toward the formation of compounds 1 and 2 are shown in Scheme 1. The two metabolites can be considered to derive from a common precursor, grandiuvarin C (5, from U. grandif lora Roxb. ex Hornem.),3c an oxidative cleavage product of epoxidized benzyl benzoate 4.3h First, grandiuvarin C (5) is epoxidized at C-4/C5 to give epoxide 6. Ring-opening of 6 to afford stabilized allylic carbocation 7 followed by concomitant regiospecific attack of chloride ion at C-4 gives albanol A (1), which represents a new C-4/C-5 epoxide-derived chlorohydrin structure. On the other hand, epoxidation of C-2/C-3 affords grandiuvarin A (8, also first reported from U. grandif lora)3c to give the chlorohydrin

(= erythro) diastereomer.8 Selected heteronuclear 2J and 3J values were measured by analysis of J-resolved HMBC data;9 the 3JH‑4/C‑6 and 3JH‑5/C‑3 values were 2.2 and 2.3 Hz, respectively, while the 2JH‑4/C‑3, 2JH‑4/C‑5, and 2JH‑5/C‑6 values were 3.6, 2.5, and, 2.8 Hz, respectively. These small or small to medium J values better matched the anticipated heteronuclear coupling constants for the threo than the erythro diastereomer (Figure 2) and with stereoisomer TI as a significant

Figure 2. 3JHH, 3JHC, and 2JHC values associated with the rotamers of threo-1 (TI-III) and erythro-1 (EI-III).

contributor. The threo diastereomer was also preferred on biosynthetic grounds, as 1 is presumably derived from a (4Z) parent alkene derivative such as grandiuvarin C (5)3c by epoxidation followed by attack of chloride ion at the less hindered and allylic C-4 position (Scheme 1). Furthermore, the alternative anti (= erythro) diastereomer is more likely to convert to an epoxide adduct.7,10 Thus, the structure of 1 was suggested as the new natural product (2E,4*R,5R*)-2(acetoxymethyl)-4-chloro-5-hydroxyhex-2-ene-1,6-diyl dibenzoate and named albanol A. Compound 2 was assigned a molecular formula of C21H21ClO6 by HRESIMS. The IR spectrum showed the presence of hydroxy (3479 and 3474 cm−1), ester carbonyl

Scheme 1. Putative Biosynthetic Pathways toward the Formation of 1 and 2

C



Note

uvamalol D (10),3b via allylic carbocation 9 through attack of chloride ion at C-3. Finally, deacetylation of 10 affords albanol B (2). Conversely, compound 2 may be derived by nucleophilic attack of chloride ion at C-3 of valderrepoxide, a secocyclohexene epoxide isolated recently from U. valderramensis.3i The comparable relative configuration at C-2 and C-3 for 2 and grandiuvarin B3c suggests that they originate from grandiuvarin C (8) with a (2E,4Z) diene motif. seco-Cyclohexenes 1 and 2 and grandiuvarone (3) were evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis H37Rv, by the MABA method,11 and antiproliferative (HUVEC, K-562) and cytotoxic (HeLa) effects against human cell lines by the CellTiter Blue assay.12 All compounds showed modest inhibitory activities against M. tuberculosis H37Rv (MABA MIC = 26 μM for 1; MABA MIC = 38 μM for 2; MABA MIC = 25 μM for 3). Interestingly, 1 showed cytostatic activity against HeLa cells (in the range 1−50 μM), while 2 showed weak antiproliferative as well as weak cytotoxic effects against all tested cell lines (IC50 > 45 μM). Compound 3, bearing an electrophilic enone moiety, had the highest antiproliferative and cytotoxic activities against the three cell lines (Table S14 to S16, Supporting Information). The presence of an acetyl group and a C-2/C-3 olefinic bond may therefore be important for improved biological activity. It is also worth noting that 1 and 2 are new antitubercular natural product prototypes in their class.

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Albanol B (2): colorless, viscous liquid; [α]24 D +116 (c 0.005, MeOH); UV (MeOH) λmax (log ε) 205 (4.12), 229 (3.55) nm; IR (KBr) νmax 3479 (br), 3474 (br), 2924, 1766, 1718, 1611, 1591, 1483, 1438, 1193, 1146, 732, 698 cm−1; 1H and 13C data, see Table 1; HRESIMS m/z 405.1102 [M + H]+ (calcd for C21H22ClO6, 405.1099); 427.0920 [M + Na]+ (calcd for C21H21ClO6Na, 427.0919).

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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.7b00679. NMR spectra of 1 and 2, plant description and image of Uvaria alba, and bioassay results (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +63-2-4061611, ext 4057, or +49-531-6181-4267. Fax: +63-2-7314031 or +49-531-6181-9499. E-mail: allanpatrick. [email protected] or [email protected]. ORCID

Allan Patrick G. Macabeo: 0000-0001-7972-106X Mary J. Garson: 0000-0001-8670-1075 Present Address △

Department of Microbial Drugs, Helmholtz Centre for Infection Research GmbH, Inhoffenstraße 7, 38124 Braunschweig, Germany.

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were obtained using a Jasco P-2000 polarimeter at 589 nm using a 1 mL quartz cell (10 cm path length) for solutions in MeOH. IR data were recorded using a Shimadzu Prestige-21 FTIR spectrophotometer (ATR). NMR spectra were recorded at ambient probe temperature on a Bruker Avance 500 spectrometer using a 5 mm SEI probe, a Bruker 600 MHz Kryo, or a Bruker Avance DRX 700 spectrometer with a 5 mm TXI Zgrad probe. All NMR spectra were acquired in base-filtered CDCl3 and referenced to solvent signals at δH 7.26 and δC 77.16 (CDCl3). The HSQC and HMBC experiments were optimized for 145.0 and 10.0 Hz, respectively. HRESIMS data were acquired using an Agilent Q-TOF 6540 UHD mass spectrometer (sodium formate). Thin-layer chromatography was performed using Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching and staining with vanillin−H2SO4. Column chromatography was performed on Merck 60 silica gel (0.063−0.200 mm) or Merck 60 flash silica gel (0.040−0.063 mm) stationary phases. Plant Material. The leaves of Uvaria alba were collected in the lowlands of Palauig, Zambales, Luzon, Philippines (15°43′ N, 119°91′ E), in October 2013 and were identified and authenticated by one of the authors (G.J.D.A.). Voucher specimens (USTH 01631) have been deposited at the University of Santo Tomas Herbarium and at the Philippine National Herbarium, Manila, Philippines. Extraction and Isolation. A CH2Cl2−MeOH (1:1) extract (300 g) of the ground air-dried leaves of U. alba (2.1 kg) was fractionated into hexanes, CH2 Cl2 , and n-BuOH subextracts. The CH 2Cl2 subextract (90 g) was initially purified by flash silica gel chromatography using EtOAc−hexanes and MeOH−EtOAc gradient systems (20%) to give 14 fractions. Fraction 3 (13 g), eluted with 10:1 hexanes−EtOAc, was separated on a silica gel 60 column to afford 1 as a colorless oil (22.5 mg) and 3 as a brownish, viscous oil (3.1 g). Fraction 4 (3.5 g), eluted with 9:1 hexanes−EtOAc, was purified on a silica gel column and afforded 2 (7.0 mg) as a colorless oil. Albanol A (1): colorless, viscous liquid; [α]24 D −38 (c 0.006, MeOH); UV (MeOH) λmax (log ε) 206 (3.43), 228 (2.8) nm; IR (KBr) νmax 3481 (br), 2933, 1771, 1684, 1615, 1592, 1465, 1405, 1192, 1142, 731, 698 cm−1; 1H, 13C, and HMBC data, see Table 1; HRESIMS m/z 447.1204 [M + H]+ (calcd for C23H24ClO7, 447.1210); 469.1027 [M + Na]+ (calcd for C23H23ClO7Na, 469.1030).

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was funded by the International Foundation for Science (IFS Grant No. F/5376-1). REFERENCES

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Antitubercular and Cytotoxic Chlorinated seco-Cyclohexenes from

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