DOI: 10.1002/chem.

201900591 Communication

1 1
2 2
3 & Natural Products 3
4 4
5 Stachyonic Acid: A Dengue Virus Inhibitor from B. Polystachyon 5
6 6
7 Yuen P. Tan,[a] Sevan D. Houston,[a] Naphak Modhiran,[b] Andrei I. Savchenko,[a] 7
8 Glen M. Boyle,[c] Paul R. Young,[a, b] Daniel Watterson,*[a, b] and Craig M. Williams*[a] 8
9 9
10 10
11 Abstract: Stachyonic acid A, arising from the first in-depth 11
12 phytochemical investigation of the herb Basilicum poly- 12
13 stachyon, was found to display potent inhibitory activity 13
14 against dengue virus, with limited cytotoxicity. Androgra- 14
15 pholide, a known dengue virus inhibitor and closely relat- 15
16 ed labdane-type diterpene, is structurally more complex 16
17 but displayed poor antiviral activity in the PRNT assay, and 17
18 increased cytotoxicity in comparison. Furthermore, a 18
19 Diels–Alder reaction with PTAD identified the active phar- 19
20 macophore of stachyonic acid to be the conjugated 20
21 diene. 21
22 22
23 23
24 24
25 Dengue fever,[1] which is a member of the arbovirus family,[2] is 25
26 estimated to infect 390 million individuals in over 100 coun- 26
27 tries per year, with 96 million subsequently manifesting the dis- 27
28 ease resulting in 25 000 deaths annually.[3] Surprisingly, thera- 28
29 peutics remain unavailable,[1] and although a vaccine has been 29
30 approved recently[4] variability in efficacy has been reported,[5] Figure 1. Top: The dengue virus inhibitors lovastatin (1) and ketotifen (2). 30
Bottom: The biogenetic pathway leading to the labdane skeleton, and
31 all of which reinforces the imperative to escalate discovery and
dengue virus inhibitors andrographolide (3) and stachyonic acid (4).
31
32 development of antiviral treatments in this area. That said, 32
33 there are a handful of small molecules which have been evalu- 33
34 ated in the clinic, with some currently pending a definitive out- the natural products only one diterpene, andrographolide (3) 34
35 come.[6] Interestingly, the majority of these have been natural (Figure 1), has been found to inhibit dengue virus both in vitro 35
36 product derived[7] [for example, lovastatin (1) and ivermectin] and in vivo (i.e., by inducing HO-1 expression).[10, 11] 36
37 as opposed to outright de novo synthetics [for example, keto- In continuation of our program exploring the phytochemis- 37
38 tifen (2) and chloroquine; Figure 1].[6, 8] In terms of dengue try of Australian arid zone plants,[12] we collected Basilicum pol- 38
39 virus inhibitors, there are a wide variety of structure classes en- ystachyon, which is also found in Africa, Asia, and India. Ex- 39
40 gaging various biological targets, that reveal a more even bal- tracts of this plant have been reported to induce a range of 40
41 ance between synthetics and natural products.[9] However, of biological responses, which include antibacterial,[13] antimicro- 41
42 bial,[14, 15] antifungal,[15] antioxidant[15] and cytotoxic activity in 42
43 [a] Y. P. Tan, Dr. S. D. Houston, Dr. A. I. Savchenko, Prof. P. R. Young, biological assays.[15] In the view that only a GCMS analysis of 43
44 Dr. D. Watterson, Prof. C. M. Williams
the essential oil has been detailed previously,[15, 16] we em- 44
School of Chemistry and Molecular Biosciences
45 University of Queensland barked on an 1H NMR-guided fractionation study. Herein, we 45
46 Brisbane, 4072, Queensland (Australia) disclose the stachyonic acids, as new labdane (5) diterpenes 46
47 E-mail: d.watterson@uq.edu.au [biosynthetically derived from geranylgeranyl diphosphate 47
48 c.williams3@uq.edu.au
(6)],[17, 18] in addition to their potent anti-dengue-virus activity 48
[b] Dr. N. Modhiran, Prof. P. R. Young, Dr. D. Watterson
49 Australian Infectious Diseases Research Centre
and low cytotoxicity. 49
50 School of Chemistry and Molecular Biosciences Stachyonic acid A (4) was isolated as a slightly unstable 50
51 University of Queensland pale-yellow oil (i.e., if left on the bench). HR-MS(ESI) contained 51
52 Brisbane, 4072, Queensland (Australia) a molecular ion peak at m/z 325.2138 [M+Na] + in positive 52
53 [c] Dr. G. M. Boyle mode, giving a molecular formula of C20H30O2, which equated 53
QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital
54 Brisbane, 4029, Queensland (Australia)
to the molecule containing six double-bond equivalents 54
55 The ORCID identification number(s) for the author(s) of this article can be
(RDBE). 13C NMR and DEPT supported the occurrence of 20 car- 55
56 found under: bons which comprised four methyl groups, five sp3 methyl- 56
57 https://doi.org/10.1002/chem.201900591. enes, two sp3 methines, six olefinic carbons (one methylene, 57
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 Communication

1 three methines, two quaternary carbons), two sp3 quaternary (dH 5.38) with 6-H (dH 1.97, 1.71) and 5-H. The remaining HMBC 1
2 carbons and one carbonyl at dC 183.81 ppm. The IR spectrum resonances were associated with Me-16 providing cross peaks 2
3 exhibited a broad absorption band at 3281 and 1693 cm 1 with C13 (dC 132.6), C14 (dC 141.6) and C12 (dC 135.4). Interrog- 3
4 which supported the presence of a carboxylic acid residue (see ation of the COSY spectrum suggested a conjugated diene 4
5 Table 1). system from correlations between 14-H to 15-Ha and 15-Hb, 5
6 and that the diene was appended to ring B at C9 via C12 (i.e., 6
7 COSY correlations from 12-H to 11-Ha (dH 2.30), 11-Hb (dH 2.14) 7
Table 1. 1H and 13C NMR spectroscopic data for stachyonic acid (4) and
8 and 9-H (dH 2.01) (Figure 2). 8
compound 7 recorded in CDCl3 (referenced at dH 7.26 and dC 77.0 ppm).
9 Chemical shift values are expressed in ppm.&&ok?&& 9
10 10
11 Stachyonic acid A (4) Compound 7 11
Position dC [a] dH (J in Hz)[b] dC [c] dH (J in Hz)[d]
12 12
13 1a 38.6 1.92, m 39.7 1.85, m 13
1b – 1.13, m – 1.00, ddd (13.4, 3.4, 13.4)
14 2a 18.0 1.56, m 18.9 1.53, m
14
15 2b – 1.56, m – 1.45, m 15
16 3a 37.0 1.78, m 42.3 1.41, m 16
17 3b – 1.66, m – 1.16, ddd (13.1, 3.7, 3.7) 17
4 46.4 – 33.0 –
18 5 44.8 2.01, m 50.2 1.19, dd (12.2, 4.9)
18
19 6a 25.4 1.97, m 23.8 1.97, m 19
20 6b – 1.71, m – 1.87, m 20
21 7 121.8 5.38, m 122.6 5.42, ddd (4.0, 1.5, 1.5) 21
8 135.2 – 135.9 –
22 9 55.1 2.01, m 55.2 1.89, m
22
23 10 36.3 – 36.8 – 23
24 11 a 26.0 2.30, d (17.3) 26.3 2.29, ddd (16.5, 4.0, 1.8) 24
Figure 2. Left: stachyonic acid (4) with selected COSY (bold bonds) and
25 11 b – 2.14, m – 2.11, ddd (16.5, 7.6, 7.6)
HMBC (curved) correlations; Right: Three-dimensional projection of 4 show- 25
12 135.4 5.51, t (6.6) 135.9 5.51, br. t (6.7)
26 13 132.6 – 132.4 –
ing key NOE correlations (optimized with Chem3D, version 15.1). 26
27 14 141.6 6.36, dd (17.3, 10.9) 141.7 6.35, dd (17.4, 10.7) 27
28 15 a 110.0 5.06, d (17.4) 109.8 5.04, d (17.4) 28
29 15 b – 4.90, d (10.7) – 4.89, d (10.7) A literature search unearthed a similar molecule, labda- 29
16 11.9 1.74, s 11.9 1.74, s
30 17 22.4 1.59, s 22.5 1.60, s
7,12(E),14-triene (7) (Figure 3), isolated from Croton oblongifo- 30
31 18 183.8 – 33.3 0.86, s lius,[19] which lacked a carboxylic acid functional group, but 31
32 19 16.8 1.23, s 22.0 0.88, s otherwise the NMR data matched the proposed skeleton for 32
33 20 14.4 0.83, s 14.7 0.79, s stachyonic acid A (Table 1). 33
34 [a] 125 MHz. [b] 500 MHz. [c] 125 MHz [d] 500 MHz. 34
35 35
36 36
37 Review of the HMBC spectrum (hereafter chemical shift 37
38 values will be expressed in ppm)&&ok?&& revealed that 38
39 Me-19 correlated with C3 (dC 37.0), C4 (dC 46.4), C5 (dC 44.8) 39
40 and C18 (dC 183.8), which in turn provided C3 C4 C5 connec- 40
41 tivity, and appended C4 to the carboxylic acid residue. This 41
42 was further reinforced by the carboxylic acid carbonyl (C18) 42
43 having HMBC cross peaks to Me-19, 3-Ha (dH 1.78), and 5-H Figure 3. Labdanes 7–9, which contain either an E or Z diene units. 43
44 (dH 2.01). In addition, COSY resonances for 2-H (dH 1.56, 2 H) 44
45 with 1-Ha (dH 1.92) and 3-Ha (dH 1.78) extended the chain from 45
46 C3 to C1. Together this provided the following uninterrupted The relative stereochemistry of 4 at positions C9 and C10 46
47 bond connection, C1 C2 C3 C4 C5. HMBC correlations were were initially established as b-orientated by comparison of the 47
48 observed for Me-20 to C1 (dC 38.6), C5 (dC 44.8), C9 (dC 55.1) 13
C NMR chemical shift data to that of 7 (Table 1). This was con- 48
49 and C10 (dC 36.3), which formed ring A, along with establishing firmed when 4 was found to display 1D NOE correlations be- 49
50 connections between C10 and C9. Additional HMBC cross tween Me-20 and Me-19. Whereas, irradiation of 1-Hb did not 50
51 peaks arising from 5-H with C4, C6, C10 confirmed the consti- produce a NOE response. Moreover, NOE correlations observed 51
52 tution of the A ring. The methyl group at position 17 revealed for H-12 and H-14 supported the proposed stereochemistry of 52
53 HMBC correlations with C7, C8, C9. Further HMBC correlations the central double bond 12-H/13-H of the diene as E-config- 53
54 were observed for 5-H with C7 (dC 121.8), C8 (dC 135.2), C9 ured (Figure 2). 54
55 (dC 55.1) and C10, which in total afforded the C5 C7 C8 C9 Interestingly, all isolates of 4 contained a minor impurity in 55
56 C10 connectivity (i.e., ring B). Analysis of the COSY spectrum the range of approximately 95:5. This material showed alkene 56
57 confirmed the ring B proposition showing cross peaks for 7-H peaks similar to 4 at dH 6.78 (dd, J = 17.5, 10.9), dH 5.19 (d, J = 57
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 Communication

1 17.1) and dH 5.08 (d, J = 10.9). Unfortunately, the majority of ited amounts of material (Scheme 1). In terms of absolute ste- 1
2 the remaining minor resonances were overlapped and no fur- reochemistry, given the sign of optical rotation for stachyonic 2
3 ther information could be garnered to facilitate full structure acid A (4) (+ 33.5), labdane 7 (+ 3.8)[19] and 9 (+ 19.8)[20] are the 3
4 elucidation. However, 2D NMR signals suggested a stereoiso- same, suggests the configuration of positions 4, 9, and 10 are 4
5 mer of 4 [tentatively assigned as stachyonic acid B (8)] contain- the same for stachyonic acid A. Attempts to generate a crystal- 5
6 ing a Z-configured double bond at C12 (Figure 3). This suspi- line derivate of 4, for example, via the PTAD (13) cycloadduct 6
7 cion was confirmed when the chemical shifts, and coupling 14, failed (Scheme 1). 7
8 constants, of the diene protons for 14-H and 15-H (a and b) Dengue virus activity (anti-DENV activity) was ascertained by 8
9 were compared and found to be a close match with the using a DENV plaque-reduction neutralization (PRNT) assay in 9
10 known labdane, labda-7,12(Z),14-triene (9), which was isolated Vero cells (African green monkey kidney).[24] Evaluation of sta- 10
11 from Abies marocana.[20] chyonic acid A (4), the 95:5 mixture of stachyonic acids A (4) 11
12 However, for optimum biological assay results pure material and B (8), and andrographolide (3) in the PRNT assay revealed 12
13 was required. Fortunately, argentation chromatography [that is, that both the mixture and pure stachyonic acid A was identical 13
14 silver nitrate impregnated upon silica gel (SNIS)][21] resolved (IC50 = 1.4  2/1 mm), whereas that of 3 was much less potent 14
15 this separation difficulty, although derivatization was re- (i.e. IC50 = 51.0  68/29 mm) (Figure 4). Interestingly, cycloadduct 15
16 quired.[22] Firstly, the 95:5 mixture of stachyonic acids A and B 14 displayed no anti-DENV activity, strongly suggesting the 16
17 was converted to the corresponding mixture of methyl esters conjugated diene is the active pharmacophore of the sta- 17
18 (10), followed by SNIS chromatography to give pure methyl chyonic acids. 18
19 esters 11 and 12. Methyl ester cleavage of 11 (and 12) proved 19
20 challenging, but eventually applying conditions reported by 20
21 Waldvogel, involving cyanide as the reagent,[23] afforded pure 21
22 stachyonic acid A (4), but not stachyonic acid B (8) due to lim- 22
23 23
24 24
25 25
26 26
27 27
28 28
29 29
30 30
31 31
Figure 4. Plaque-reduction neutralization (PRNT) assay results for androgra-
32 32
pholide (3, green) and the stachyonic acids [4 and 8 mixture (blue) and 4
33 (red)]. Data are expressed as normalized mean  range from two independ- 33
34 ent experiments. 34
35 35
36 36
37 The mixture (95:5) of stachyonic acids A (4) and B (8), was 37
38 tested for cytotoxicity against human cells, including breast 38
39 (MCF7) and melanoma (SK-MEL-28) cancer cell lines, along 39
40 with primary neonatal foreskin fibroblast cells (NFF), as well as 40
41 the cells used in the PRNT assay. Notably, the mixture of 4 and 41
42 8 showed limited cytotoxicity toward all cell lines investigated 42
43 that is, MCF7 (CC50 = 96  17 mm), SK-MEL-28 (CC50 > 198 mm), 43
44 NFF (CC50 = 66  20 mm) and Vero (CC50 = 93  40/28 mm). In 44
45 comparison, andrographolide (3) was more toxic in Vero cells 45
46 (CC50 = 51  67/29 mm). The selective index against DENV was 46
47 calculated as 62.6 and 0.4, for the mixture of 4 and 8 and an- 47
48 drographolide (3), respectively. 48
49 49
50 50
Conclusions
51 51
52 Phytochemical investigation of Basilicum polystachyon afforded 52
53 stachyonic acid A, which superseded the only known anti- 53
54 DENV labdane (i.e., andrographolide) in terms of potency, 54
55 lower cytotoxicity, and of much less structural complexity. A 55
56 Diels–Alder cycloadduct derived from PTAD identified the 56
57 Scheme 1. Derivatization and purification of stachyonic acids 4 and 8. active pharmacophore of stachyonic acid (4) to be the conju- 57
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1 gated diene opening a new direction in anti-DENV drug dis- [9] Y.-S. Tian, Y. Zhou, T. Takagi, M. Kameoka, N. Kawashita, Chem. Pharm. 1
2 covery. Bull. 2018, 66, 191 – 206. 2
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3 Lee, Sci. Rep. 2016, 6, 32176.
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Acknowledgements
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6 [12] a) Y. P. Tan, A. I. Savchenko, N. Broit, G. M. Boyle, P. G. Parsons, C. M. Wil- 6
The authors thank the University of Queensland (UQ) and the liams, Eur. J. Org. Chem. 2017, 1498 – 1501; b) Y. P. Tan, A. I. Savchenko,
7 N. Broit, G. M. Boyle, P. G. Parsons, C. M. Williams, Fitoterapia 2018, 126,
7
QIMR Berghofer Medical Research Institute for financial sup-
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port. In addition, we gratefully acknowledge Dr. T. Le from UQ
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for assistance with NMR measurements, and Mr. S. Hume from
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19 [19] S. Roengsumran, A. Petsom, D. Sommit, T. Vilaivan, Phytochemistry
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Manuscript received: February 7, 2019 33
van), Springer, Singapore, 2018, Chapter 22.&&ok?&&
34 [7] D. J. Newman, G. M. Cragg, J. Nat. Prod. 2016, 79, 629 – 661. Accepted manuscript online: && &&, 0000 34
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1 COMMUNICATION 1
2 2
3 3
4
Stachyonic acid A, isolated from the & Natural Products 4
herb Basilicum polystachyon, was found
5 to display potent inhibitory activity Y. P. Tan, S. D. Houston, N. Modhiran, 5
6 against dengue virus, and out-perform A. I. Savchenko, G. M. Boyle, P. R. Young, 6
7 the structurally more complex, albeit re- D. Watterson,* C. M. Williams* 7
8 lated labdane, andrographolide. In addi- 8
&& – &&
9 tion, the active pharmacophore was 9
10 identified as the conjugated diene Stachyonic Acid: A Dengue Virus 10
11 opening up a new avenue for anti- Inhibitor from B. Polystachyon 11
12 DENV discovery. 12
13 13
14 14
15 15
16 16
17 Williams, Watterson, and co-workers @UQscience @QIMRBerghofer report a #dengue #virus #inhibitor 17
18 obtained from the herb Basilicum polystachion SPACE RESERVED FOR IMAGE AND LINK 18
19 19
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27 27
28 Please check that the ORCID identifiers listed below are correct. We encourage all authors to provide an ORCID identifier 28
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30 30
agency guidelines for details. Registration is easy and free; for further information, see http://orcid.org/.
31 31
32 Yuen P. Tan
32
33 Dr. Sevan D. Houston 33
34 Dr. Naphak Modhiran 34
35 Dr. Andrei I. Savchenko 35
36 Dr. Glen M. Boyle 36
37 Prof. Paul R. Young 37
38 Dr. Daniel Watterson 38
Prof. Craig M. Williams
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