Isolation, Synthesis And Structure Determination Of Cannabidiol Derivatives And Their Cytotoxic Activities

Article abstract of DOI:10.1080/14786419.2019.1638381

In a continuing effort to explore the structural diversity and pharmacological activities of natural products based scaffolds, herein, we report the isolation, synthesis, and structure determination of cannabidiol and its derivatives along with their cytotoxic activities. Treatment of cannabidiol (1) with acid catalyst POCl₃ afforded a new derivative 6 along with six known molecules 2 ? 5, 7 and, 8. The structure of 6 was elucidated by extensive spectroscopic analyses and DFT calculations of the NMR and ECD data. All the compounds (2–8) were evaluated for their cytotoxic potential against a panel of eight cancer cell lines. Compounds 4, 5, 7, and 8 showed pronounced in vitro cytotoxic activity with IC₅₀ values ranging from 5.6 to 60 μM. Out of the active molecules, compounds 4, and 7 were found to be comparable to that of the parent molecule 1 on the inhibition of almost all the tested cancer cell lines.

Full text of DOI:10.1080/14786419.2019.1638381

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Isolation, Synthesis And Structure Determination
Of Cannabidiol Derivatives And Their Cytotoxic
Activities
Yedukondalu Nalli, Suraya Jan, Gianluigi Lauro, Javeed Ur Rasool, Waseem I.
Lone, Aminur R. Sarkar, Junaid Banday, Giuseppe Bifulco, Hartmut Laatsch,
Sajad H. Syed & Asif Ali
To cite this article: Yedukondalu Nalli, Suraya Jan, Gianluigi Lauro, Javeed Ur Rasool, Waseem I.
Lone, Aminur R. Sarkar, Junaid Banday, Giuseppe Bifulco, Hartmut Laatsch, Sajad H. Syed & Asif
Ali (2019): Isolation, Synthesis And Structure Determination Of Cannabidiol Derivatives And Their
Cytotoxic Activities, Natural Product Research, DOI: 10.1080/14786419.2019.1638381
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1638381
Isolation, Synthesis And Structure Determination Of
Cannabidiol Derivatives And Their Cytotoxic Activities
Yedukondalu Nallia,b, Suraya Janb,c, Gianluigi Laurod, Javeed Ur Rasoola,b
Waseem I. Lonea,b, Aminur R. Sarkara, Junaid Bandaya, Giuseppe Bifulcod,
Hartmut Laatsche, Sajad H. Syedb,c and Asif Alia,b
,
aNatural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road,
b
Jammu-Tawi, J&K, 180001, India; Academy of Scientific and Innovative Research, New Delhi, India;
cPharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu,
d
Sanatnagar Srinagar, 180001, India and 190005; Department of Pharmacy, University of Salerno, Via
e
Giovanni Paolo II 132, Fisciano, 84084, Italy; Institute of Organic and Biomolecular Chemistry,
€
€
University of Gottingen, Tammannstr. 2, Gottingen, D-37077, Germany
ABSTRACT
ARTICLE HISTORY
Received 16 May 2018
Accepted 27 June 2019
In a continuing effort to explore the structural diversity and pharma-
cological activities of natural products based scaffolds, herein, we
report the isolation, synthesis, and structure determination of canna-
bidiol and its derivatives along with their cytotoxic activities.
Treatment of cannabidiol (1) with acid catalyst POCl3 afforded a new
derivative 6 along with six known molecules 2 ꢀ 5, 7 and, 8. The
structure of 6 was elucidated by extensive spectroscopic analyses and
DFT calculations of the NMR and ECD data. All the compounds (2 –8)
were evaluated for their cytotoxic potential against a panel of eight
cancer cell lines. Compounds 4, 5, 7, and 8 showed pronounced in
vitro cytotoxic activity with IC50 values ranging from 5.6 to 60 lM. Out
of the active molecules, compounds 4, and 7 were found to be com-
parable to that of the parent molecule 1 on the inhibition of almost
all the tested cancer cell lines.
KEYWORDS
Cannabis sativa L.;
Cannabinoids; Cannabidiol;
Divergent synthesis;
Cytotoxic activities
CONTACT Asif Ali
asifali@iiim.ac.in
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1638381.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
Y. NALLI ET AL.
1. Introduction
Cannabis sativa L. (CS) has been a part of Indian medicinal and spiritual culture since
as early as 2000 BC (Singh 2016). CS is a prolific producer of structurally diverse phyto-
cannabinoids including cannabigerol (CBG), cannabidiol (CBD), tetrahydrocannabinol
(D9-THC), and cannabichromene (CBC) and their corresponding acidic versions as
major constituents (Radwan et al. 2015). The structural diversity of cannabinoids of CS
has partially attributed to the non-enzymatic transformations of these major constitu-
ents induced by heat, light, pH and atmospheric oxygen (Hanus et al. 2016). In recent
years, cannabinoids and their derivatives have drawn renewed attention due to their
diverse pharmacological activities such as cell growth inhibition, anti-inflammatory
effects, tumour regression (Di Marzo and Piscitelli 2015, Luciano et al. 2011, Nalli et al.
2018). Furthermore, the U.S. Food and Drug Administration (FDA) have approved three
cannabinoid-based drugs (Marinol, Syndros, Cesamet) for the treatment of AIDS wast-
ing syndrome, epilepsy, neuropathic pain, spasticity associated with multiple sclerosis,
and chemotherapy-induced nausea (Seely et al. 2011). In order to explore the struc-
tural diversity and pharmacological activities of cannabinboid based scaffolds, a small
compound library was synthesize based on the non-psychoactive cannabinoid CBD by
using POCl3 as an acid catalyst (Nalli et al. 2016, Nalli et al. 2017). Herein, we report
the isolation, synthesis, structural determination of CBD analogs, and their cytotoxic
potential against a panel of eight human cancer cell lines.
2. Results and discussion
Compound 1 was isolated as a major constituent from the leaves of Cannabis sativa
L., collected from the Botanical garden of the CSIR-Indian Institute of Integrative
Medicine, Jammu (India). The plant was identified by a taxonomist Dr. Sumeet Gairola,
and a voucher specimen (IIIM 23453) was deposited at the Herbarium of the IIIM,
Jammu (India). During our efforts on semi-synthetic modifications of cannabidiol (1),
was reacted with acid catalyst POCl3 at 0 ꢁC for five minutes, the formation of seven
major products were observed. All these products (2 – 8) were isolated by extensive
column chromatography over sephadex LH-20 followed by semi-preparative HPLC
using RP-C8 column affording seven compounds (Figure 1). The structures of com-
pounds 2 – 8 were characterized by HR-ESI-MS, and 1 D- and 2 D-NMR spectroscopic
studies disclosed compound 6 as a new structure. Among known compounds, 2 (D4-
isotetrahydrocannabinol) (Crombie et al. 1988), 3 (D4(8)-isotetrahydrocannabinol)
(Crombie, Crombie, Jamieson and Palmer 1988), 4 (D8-tetrahydrocannabinol) (Cheng
et al. 2013), and 5 (9a-hydroxyhexahydrocannabinol) (Cheng, Xie, Chen, Wang and
Zhou 2013) were known in the literature as secondary metabolites of Cannabis sativa
L.; on the other hand, 7 (9b-hydroxyhexahydrocannabinol) (Cheng, Xie, Chen, Wang
and Zhou 2013), and 8 (8-hydroxy-isohexahydrocannabinol) (Turner et al. 1981) have
been reported as synthetic compounds. The structure of compound 6 was determined
on the basis of detailed analysis of MS and NMR spectral data. Compound 6 was
obtained as brown, viscous oil. The molecular formula, C21H32O3, was established by
the presence of [M þ H]þ ion at m/z 333.2421 in the HR-ESI-MS spectrum, indicating

NATURAL PRODUCT RESEARCH
3
Figure 1. Reagents and conditions: CBD (1 g, 3.01 mmol), POCl3 (3 mL, 31.1 mmol), at 0 ꢁC, 5 min.
1
six indices of hydrogen deficiency. A close inspection of the H-, 13C-, and HSQC-NMR
spectra of 6 revealed the presence of four sp2 quaternary carbons (C-1, C-3, C-5, and
C-10a), two aromatic methines (C-2 and C-4), two sp3 oxygenated quaternary carbons
(C-6 and C-9), two sp3 methines (C-10 and C-12), seven sp3methylenes (C-10, C-20, C-30,
C-40, C-7, C-8, and C-11), and four methyl carbons (C-50, C-13, C-14, and C-15) (Figure
1
S10). The H-1H COSY analysis of 6 led to four partial structural units: H-7 (dH 1.96 – 1.
78) () H-8 (dH 1.51, 1.34); H-13 (dH 1.11) () H-12 (dH 1.69) () H-14 (dH 0.78);
H-10 (dH 3.26) () H-11 (dH 2.42 – 2.36); and H-10 (dH 2.47 – 2.42) () H-20 (dH 1.
31) () H-30 (dH 1.58) () H-40 (dH 1.33) () H-50 (dH 0.89) as shown by bold-
faced lines in Figure S10. Above spin systems were connected to each other on the
basis of HMBC correlations. The HMBC spectrum showed key correlations of H-13 (dH
1.11)/C-9 (dC 76.2), of H-12 (dH 1.69)/C-10 (dC 34.4), of H-8 (dH 1.51, 1.34)/C-12 (dC 32.7),
of H-15 (dH 1.37)/C-6 (dC 74.2), C-7 (dC 35.5) and C-11 (dC 31.7), of H-10 (dH 3.26)/C-1
(dC 157.7), C-5 (dC 153.5), C-6 (dC 74.2), C-9 (dC 76.2) and C-10a (dC 109.2), and of H-10
(dH 2.47 – 2.42)/C-2 (dC 108.4), C-3 (dC 143.0) and C-4 (dC 105.8) (Table S1; Figure S10).
The planar structure of 6 was thus constructed according to the aforementioned spec-
troscopic data analysis. Further, the NOESY spectrum was measured in DMSO-d6 to
determine the relative configuration (Figure S18). The NOESY interactions of –OH (at

4
Y. NALLI ET AL.
Figure 2. The plausible reaction mechanism and isomers formed in the reaction.
C-1) with H3-13, H-12, and H-10 suggested the relative configurations at C-6, and C-10
carbons. However, the configurations of other carbons could not be assigned unam-
biguously because of overlapped signals in the 1H NMR spectrum. To resolve the
stereochemical dilemma, a plausible reaction mechanism of 6 was proposed starting
from 1. In the first step as shown in Figure 2, cannabidiol (1) is assumed to undergo
simultaneous intramolecular cyclisation and double bond migration, thus leading to
3a rather than 3 b as probable intermediate. The high difference of energy (DE3a-3b
¼
-95.2 kcal/mol) computed at the accurate quantum mechanical (QM) level for both 3a
and 3 b also clearly indicated that 3a was the most probable intermediate in the first
step. In the next step, –OH group attached at C-9 of 3a resulting in the formation of

NATURAL PRODUCT RESEARCH
1
5
6a (6 R, 9 R, 10S) and 6 b (6 R, 9S, 10S) as possible isomers. Thereafter, H and 13C NMR
chemical shifts were computed for both 6a (6 R, 9 R, 10S) and 6 b (6 R, 9S, 10S) (Bifulco
et al. 2007, Di Micco et al. 2010). The computed results were then compared to experi-
mental values, allowing us to identify the configurations of 6 as those of 6 b (6 R,9S,
10S). Interestingly, the NOESY correlations were also found to be consistent with the
6 b isomer. Finally, the absolute configurations were established by comparison of the
experimental ECD spectrum of 6 with those predicted for 6 b (6 R, 9S, 10S) and for its
enantiomer 6 benant (6S, 9 R, 10 R) (Cerulli et al. 2017). The results showed that the cal-
culated ECD spectrum of 6 b was in accordance with the experimental spectrum
(Figure S2). Accordingly, the absolute configuration of 6 was confidently assigned as
6 R, 9S, 10S.
Cannabidiol (1) is a known cytotoxic compound against different cancer cell lines,
and its mechanism of action has been thoroughly studied (Ligresti et al. 2006), espe-
cially against the breast cancer cell lines with IC50 values about 6 lM. Therefore, we
evaluated all the compounds (1 – 8) for their cytotoxicity potential against a panel of
eight cancer cell lines including HCT-116 (colon), MCF-7 (breast), K562 (leukemia),
MIAPaCa-2 (pancreas), PANC-1 (pancreas), A549 (lung), PC-3 (prostate) and SW-620
(colon) by tetrazolium based calorimetric cytotoxicity assay (MTT assay). Cell lines were
treated with different concentrations of compounds for 48 h time. Compounds 4, 5, 7,
and 8 showed pronounced in vitro cytotoxic activity against all the cell lines (Table S8)
with IC50 values ranging from 5.6 to 60 lM. The rest of molecules 2, 3, and 6 were not
able to induce cell death even up to 60 mM concentration (IC50 > 60 mM). Out of the
active molecules, compounds 4, and 7 were found to be comparable to that of the
parent molecule 1 (positive control) on the inhibition of most cancer cell lines. Taken
together, our results suggest that analogs of 1 have therapeutic potential and could
be further explored for their potential anticancer activity.
3. Experimental section
3.1. General experimental procedures
High-resolution mass spectra were obtained on Agilent 6540 (Q-TOF) mass spectrom-
eter. Optical rotation was measured on a Perkin Elmer 341 polarimeter in a 1 dm cell
at 25 oC. Reaction was monitored by thin layer chromatograph (TLC) on silica gel
60 F254 (0.25 mm thick, Merck) with spot visualized by UV 254 nm and 365 nm, and ani-
saldehyde reagent was used as developing agent. Column chromatography was per-
formed using sephadex LH-20. Semi preparative HPLC was performed on an Agilent
HPLC with anX Bridge Prep C8 OBD (5 mm, 1.9 ꢂ 250 mm), a photodiode array
detector and auto injector function (Agilent 1260 series). 1H NMR spectra were
recorded (Brucker Avance) at 400 MHz and 13C NMR at 100 MHz in CDCl3 and DMSO-
d6 chemical shifts values were reported in d (ppm) units and coupling constants val-
ues in hertz. Tetramethylsilane (TMS) was used as internal standard. The following
abbreviations were used to explain multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet, br ¼ broad. Cannabidiol (1) was isolated from hexane
extract leaves of Cannabis sativa L. While other regents were purchased commercially
and used without further purification, unless otherwise stated.

6
Y. NALLI ET AL.
3.2. Procedure for preparation & isolation of compounds (2 – 8)
Cannabidiol (1) (1 g, 3.01 mmol) was taken in a 50 mL round bottom flask and placed
in an ice bath at 0 ꢁC containing a stirring bar. Phosphoryl chloride (POCl3) (3 mL,
31.51 mmol) was added drop wise over a period of 5 min, and stirred for 5 minutes.
Finally, cold saturated aqueous NaHCO3 (40 mL) solution was added to quench the
acid. The aqueous layer was extracted with ethyl acetate (3x100 mL), and the com-
bined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to
afford a gummy viscous crude product. TLC (Hex: EtOAc 9: 1 v/v) exhibited multiple
spots, which were fractionated by sephadex LH-20 column chromatography, and col-
umn was eluted with MeOH to afford four fractions (Fr.1–Fr.4), which were separated
using preparative HPLC. The preparative HPLC used was equipped with Agilent 1260
series with PDA detector, X Bridge Prep C8 OBD (5 mm, 1.9 ꢂ 250 mm) column was
o
used at a flow rate of 3.5 mL/min (column temp. 30 C; UV detection at 215, 254 nm),
and the isocratic elution was performed with 75% MeOH in water as mobile phase.
Compounds 2 (135 mg, tR 77.080 min), 3 (115 mg, tR 79.91 min), and 4 (313 mg, tR
82.5 min) from Fr.1 (690 mg) (Figure S20); compounds 5 (11.5 mg, tR 40.04 min), 6 (6.
1 mg, tR 42.9 min), 7 (32 mg, tR 50.89 min) and 8 (17 mg, tR 58.9 min) from Fr.3 (90 mg)
were isolated (Figure S21). Purified compounds were identified and characterized by
HR-ESI-MS, NMR (1 D and 2 D spectroscopy) and were compared with those of the lit-
erature data.
Compound 6: Brown, viscous oil having [a]25 D– 6 (c 1.0, acetonitrile); 1H NMR
(CDCl3, 400 MHz) and 13C NMR data, see Table S1; (þ) HR-ESI-MS m/z 333.2421
[M þ H]þ (calcd for C21H32O3 333.2424).
3.3. Cell culture and growth conditions
A panel of Human cancer cell lines-A549 (lung), PC-3 (prostate), HCT116 (colon), MCF-
7 (breast), K562 (leukemia), MIA PaCa-2 (pancreas), PANC-1 (pancreas) and SW-620
(colon) were procured from U.S. National Cancer Institute (NCI). The human cancer cell
lines including A549, PC-3, T47D, HCT116, MCF-7, K562 and SW were grown in tissue
culture flasks in complete growth medium (RPMI-1640) supplemented with 10% fetal
bovine serum, 100 mg/mL streptomycin and 100 units/mL penicillin. MIA PaCa-2 and
PANC-1 were grown in Dulbecco’s minimal essential medium supplemented with 10%
FBS, 2 mM L-glutamine, 3 mM sodium pyruvate, 100 units/mL penicillin, 100 lg/mL
streptomycin in a carbon dioxide incubator (New Brunswick, Galaxy 170 R, Eppendorf)
at 37 ꢁC, 5% CO2 and 98% RH.
3.4. In vitro cytotoxicity
Cell viability was determined by thiazolyl blue tetrazolium bromide (MTT) and Trypan
blue assays. Briefly, 7 ꢂ 103 cells were seeded into 96-well microtitre plate and differ-
entiated for 48 h. After differentiation and treatments with different concentrations of
compounds MTT dye (2.5 mg/mL) was added and incubated for 4 h at 37 ꢁC; after incu-
bation, the media was aspirated and 150 lL/well DMSO was added and read at
570 nM on Mutliskan GO plate reader (Thermo Fisher Scientific, Waltham, MA, USA).

NATURAL PRODUCT RESEARCH
7
3.5. Computational details
The starting 3 D chemical structures of compounds 3a (6 R, 10 R), 3 b (6S, 10 R), 6a (6 R,
€
9 R, 10S) and 6 b (6 R, 9S, 10S) were built with Maestro11.1 (Schrodinger 2017).
Optimizations of the starting 3 D structures were performed with Macro Model 11.5
€
using the OPLS force field (Jorgensen and Tirado-Rives 1988, Schrodinger 2017) and
the Polak-Ribier conjugate gradient algorithm (PRCG, maximum derivative less than
0.001 kcal/mol). For these compounds, exhaustive conformational searches at the
empirical molecular mechanics (MM) level with Monte Carlo Multiple Minimum
(MCMM) method (50000 steps) and Low Mode Conformational Search (LMCS) method
(50000 steps) were performed, in order to allow a full exploration of the conform-
ational space. Also, molecular dynamics simulations were performed at 450, 600, 700,
and 750 K, with a time step of 2.0 fs, an equilibration time of 0.1 ns, and a simulation
time of 10 ns.
For each diastereoisomer, all the conformers obtained from the conformational
searches were minimized (PRCG, maximum derivative less than 0.001 kcal/mol) and
superimposed. Then, the “Redundant Conformer Elimination” module of Macromodel
€
11.5 (M. J. Frisch 2009, Schrodinger 2017) was used to select non-redundant conform-
ers, excluding those differing more than 21.0 kJ/mol (5.02 kcal/mol) from the most
energetically favoured conformation and setting a 0.5 Å RMSD (root-mean-square devi-
ation) minimum cut-off for saving structures. All the subsequent QM calculations were
€
performed using Gaussian 09 software (M. J. Frisch 2009, Schrodinger 2017). About
compounds 3a and 3 b, the two most energetically favoured conformers identified at
MM level were geometry optimized at the MPW1PW91/6-31G(d) level of theory. Then,
the energy associated at these geometries was computed at the MPW1PW91/6-
31G(d,p) level of theory and accounted for evaluating the relative stability of 3a and
3 b. About compounds 6a and 6 b, all the conformers obtained by MM conformational
search rounds were optimized at the QM level using the MPW1PW91 functional and
the 6-31 G(d) basis set (Cimino et al. 2004). After the optimization of the geometries,
the conformers were visually inspected in order to remove further redundant conform-
1
ers. The computation of the 13C and H NMR chemical shifts was performed on the
selected conformers for the different diastereoisomers of compounds 6a and 6 b,
1
using the MPW1PW91 functional and the 6-31 G(d,p) basis set. Final 13C and H NMR
chemical shift sets of data for each of the diastereoisomers were extracted and com-
puted considering the influence of each conformer on the total Boltzmann distribution
1
taking into account the relative energies. Calibrations of calculated 13C and H chem-
ical shifts were performed following the multi-standard approach (MSTD) (Tables
S2–S3) (Sarotti and Pellegrinet 2009, Sarotti and Pellegrinet 2012). In particular, sp2 13C
1
and H NMR chemical shifts were computed using benzene as reference compound
(Sarotti and Pellegrinet 2009, Sarotti and Pellegrinet 2012), while TMS was used for
computing sp3 13C and 1H chemical shift data. A further set of data was produced
using only TMS as reference compound, and it was subsequently used for the compu-
tation of the DP4þ probabilities (Tables S4–S5).
1
Experimental and calculated 13C and H NMR chemical shifts were compared com-
puting the Dd parameter (Tables S2–S5):

8
Y. NALLI ET AL.
Dd ¼ |dexp - dcalc| where dexp (ppm) and dcalc (ppm) were the 13C/1H experimental
and calculated chemical shifts, respectively.
The mean absolute errors (MAEs) for all the considered diastereoisomers were com-
puted using the following equation:
P
ð
Þ
Dd
MAE ¼
n
defined as the summation (R) of the n computed absolute error values (Dd), nor-
malized to the number of chemical shifts considered (n) (Tables S1–S5). Furthermore,
DP4þ probabilities (Grimblat, Zanardi and Sarotti 2015) related to all the stereoisomers
1
of 6a and 6 b were computed considering both H and 13C NMR chemical shifts, and
comparing them with the related experimental data. In particular, since the available
DP4þ Toolbox (Excel file) for the DP4þ computation allows the setting of sp3/sp2
atoms following the “multi-standard” approach (Sarotti and Pellegrinet 2009, Sarotti
and Pellegrinet 2012), we used the chemical shift data set obtained using TMS as ref-
erence compound (Tables S4 and S5).
Concerning ECD calculations, the conformers obtained by MM experiments, as
above reported, were optimized at quantum mechanical (QM) level by using the
MPW1PW91 functional and the 6-31 G(d) basis set, whereas experimental solvent
effects (acetonitrile) were reproduced using the integral equation formalism version of
the polarizable continuum model (IEFPCM). The selected conformers were accounted
for the subsequent computation of the ECD spectra of 6 b (and of its enantiomer
6 benant) (MPW1PW91//6-31G(d,p), acetonitrile IEFPCM), that were built considering the
influence of each conformer on the total Boltzmann distribution and taking into
account the relative energies. ECD spectrum of 6 b (and of its enantiomer 6 benant
)
were plotted using Spec Dis software, using a Gaussian band-shape function with the
exponential half-width (r/c) of 0.26 eV.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The authors are grateful to Dr. Ram A. Vishwakarma, the Director of CSIR-IIIM Jammu for his
support. We would like to acknowledge the Ministry of AYUSH (New Delhi) for providing finan-
cial support for the work of Y. K. (Z.28015/229/2015-HCP EMR), CSIR (HCP-0008) and SERB-DST
(ECR/2016/000625). G. B. acknowledges the financial support of MIUR Italy PRIN 2017 project
(2017A95NCJ). This manuscript represents IIIM communication number-IIIM/2291/2019. Council
for Scientific and Industrial Research (CSIR), New Delhi, India; Ministry of Ayurveda, Yoga and
Naturopathy, Unani, Siddha and Homoeopathy (AYUSH).
ORCID
Sajad H. Syed
http://orcid.org/0000-0002-0382-4000

NATURAL PRODUCT RESEARCH
9
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