Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity

Article abstract of DOI:10.1016/j.tetlet.2018.06.005

A series of melodorinol analogues were synthesized via a diverted total synthesis approach, leading to structural modifications on several regions of the molecule. Their cytotoxicity was evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6 and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show exceptionally high potency against MCF-7, HT-29 and A549 cell lines.

Full text of DOI:10.1016/j.tetlet.2018.06.005

Accepted Manuscript
Diverted total synthesis of melodorinol analogues and evaluation of their cyto-
toxicity
Tanatorn Khotavivattana, Thitiphong Khamkhenshorngphanuch, Kitiya
Rassamee, Pongpun Siripong, Tirayut Vilaivan
PII:
S0040-4039(18)30734-2
https://doi.org/10.1016/j.tetlet.2018.06.005
TETL 50043
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 April 2018
28 May 2018
1 June 2018
Please cite this article as: Khotavivattana, T., Khamkhenshorngphanuch, T., Rassamee, K., Siripong, P., Vilaivan,
T., Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity, Tetrahedron Letters
(
2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.005
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Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity
a,
b
c
Tanatorn Khotavivattana , Thitiphong Khamkhenshorngphanuch , Kitiya Rassamee , Pongpun
c
d
Siripong and Tirayut Vilaivan
a
Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Bangkok 10330, Thailand
b
BIOTEC, National Science and Technology Development Agency, Pathumthani 12120, Thailand
c
Natural Products Research Section, Research Division, National Cancer Institute, Bangkok 10400,
Thailand
d
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
Abstract
A series of melodorinol analogues were synthesized via a diverted total synthesis approach,
leading to structural modifications on several regions of the molecule. Their cytotoxicity was
evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-
activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the
novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding
non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6
and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit
approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show
exceptionally high potency against MCF-7, HT-29 and A549 cell lines.
Keywords: Melodorinol; Diverted total synthesis; Anticancer; Cytotoxicity

Corresponding author. Tel.: +66-2-218-7621; fax: +66-2-218-7598; e-mail: tanatorn.k@chula.ac.th (T. Khotavivattana)

Melodorinol ((S,Z)-1) (Fig. 1a) is a bioactive heptene isolated from various plants such as
1
2
3
Melodorum fruticosum Lour., Artabotrys madagascariensis, Xylopia pierrei, and Cleistochlamys
4
kirkii. This compound, along with its natural derivatives such as acetylmelodorinol ((S,Z)-2a)
(
Fig. 1a), has been reported to exhibit significant cytotoxic activities against several human tumour
1
-4
4,5
cell lines as well as antimalarial properties; however, the molecular target of these compounds
has not yet been identified. Recently, a range of semi-synthetic melodorinol derivatives ((S,Z)-2b-g)
(
Fig. 1a) were prepared from naturally occurring melodorinol by acylation of the hydroxyl group at
1
d
the C-6 position. The in vitro cytotoxicity studies of these derivatives revealed that short alkyl and
phenyl side-chains significantly enhanced the antiproliferative activity; however, the compound
became inactive when a carboxyl side-chain was introduced. The synthesis of achiral 6-deoxy-
6
melodorinol analogues was also reported; however, the biological activity of these derivatives were
not studied. The dramatic impact of C-6 modification towards cytotoxicity encouraged us to further
investigate the structure-activity relationships at the other positions of the molecule (Fig. 1b). This
includes the effect of the geometry of the double bond across C-4 and C-5 (region 1), the
stereochemistry at C-6 (region 2), and the substituents at C-3 on the furanone ring (region 3) as well
as the hydroxyl groups at the C-6 and C-7 positions (regions 4 and 5, respectively). Due to the
limitation of the semi-synthetic approach to modify the core structure of the molecule, we instead
employed a diverted total synthesis approach in order to achieve such modifications.
Figure 1. (a) Structures of melodorinol ((S,Z)-1a) and its derivatives ((S,Z)-2a-g); (b) The general
structure of the designed melodorinol analogues in this study.
The first total synthesis of melodorinol was reported by Shen and co-workers utilizing the
reaction between (R)-2,3-isopropylidene glyceraldehyde and 5-lithio-2-alkoxyfuran as a key step to
7
construct the seven-carbon skeleton. Pohmakotr and co-workers also utilized a similar approach
starting from lithiated butenolide; however, the alkene which resulted from the subsequent

8
elimination was obtained as a mixture of E- and Z-isomers. This issue was later addressed by
Boukouvalas and co-workers who introduced a bromine atom at the C-3 position as a removable
9
stereocontrolling element. Finally, an alternative route to the heptene core structure was described
1
0
by Lu and co-workers using palladium-catalyzed enyne coupling as the key step.
1
1
Scheme 1. Reagents and conditions: (i) ZnCl
2
, acetone, rt, 12 h, 35%; (ii) NaIO
, Na SO , K CO , CH Cl , reflux, 12 h, 35%; (iv)
, 0 °C, 12 h, 65%; (v) BF ·OEt , CH Cl , •78 °C, 4 h, 30%; (vi) MsCl,
O (1:1), rt, 48 h, (S)-11 58%, (S)-12 7%; (viii)
4
, sat. NaHCO
3
1
2
13
(
aq.), CH
TBSOTf, NEt
pyridine, 0 °C to rt, 2 h, 100%; (vii) AcOH/H
PhCOCl, NEt , CH Cl , 0 °C to rt, 12 h, (S,Z)-1 31%, (S,E)-1 32%, (S,Z)-2f 19%, (S,E)-2f 24%.
2
Cl
2
, rt, 1 h, 99%; (iii) HCOOH, H
2
O
2
2
4
2
3
2
2
1
4
9
3
, CH
2
Cl
2
3
2
2
2
8
9
2
9
3
2
2
According to our proposed structural parameters illustrated in Figure 1b, variations of the
double bond geometry (region 1) can be readily achieved by the synthetic route modified from that
9
previously reported by Boukouvalas and co-workers (Scheme 1). First, (R)-2,3-isopropylidene
1
1
glyceraldehyde ((R)-5) was prepared by selective acetonation of D-mannitol (3) using ZnCl ,
2
1
2
followed by oxidative cleavage with NaIO
4
. Next, silyloxyfuran 8 was prepared by Baeyer-Villiger
1
3
oxidation of furfural to obtain 2(5H)-furanone 7, which was then treated with TBSOTf and NEt
3
to
1
4
give 8. The two components, 8 and (R)-5, were combined via Mukaiyama aldol reaction at -78 °C
9
using BF
3
·Et
2
O as a Lewis acid, followed by dehydration with mesyl chloride in pyridine to give
1
5
(
S)-10 as an inseparable mixture of (Z)- and (E)-isomers in the ratio of 3:1. The hydrolysis of (S)-
1
0 afforded (S)-11 in good yield, along with a by-product (S)-12 obtained via acetylation by acetic
acid. Both (S)-11 and (S)-12 were also obtained as mixtures of (Z)- and (E)-isomers in the ratio of

3
:1. Finally, acylation of (S)-11 using benzoyl chloride afforded a mixture of mono-substituted,
(
S,Z)-1 (melodorinol) and (S,E)-1, and di-substituted products (S,Z)-2f and (S,E)-2f; the four
1
6
products can be easily separated by column chromatography.
1
7
Scheme 2. Reagents and conditions: (i) oxalyl bromide, DMF, CH
2
Cl
2
, 0 °C to rt, 4 h, 84%; (ii)
1
4
TBSOTf, NEt
3
, CH
2
Cl
2
, 0 °C, 2 h, 47%; (iii) BF
3
·OEt
2
, CH
2
Cl
2
, •78 °C, 4 h, (6S)-16 27%, (6R)-16
9
8
3
5%; (iv) MsCl, pyridine, 0 °C to rt, 2 h, (S,Z)-17 90%, (R,Z)-17 68%; (v) AcOH/H
2
O (1:1), rt, 48
, 0 °C to rt, 12 h, (S,Z)-20a
9
1
h, (S,Z)-18 74%, (R,Z)-18 91%, (S,Z)-19 4%; (vi) R COCl, NEt
3
, CH
2
Cl
2
1
8%, (S,Z)-21a 44%, (S,Z)-22a 8%, (R,Z)-20a 17%, (R,Z)-21a 46%, (R,Z)-22a 9%, (S,Z)-20b 12%,
9
(
S,Z)-21b 27%, (S,Z)-22b 5%.
In order to investigate the effect of the substituent at C-3 (region 3), we also synthesized
analogues which contain a bromine atom at the β-position of the furanone ring following the
synthetic route outlined in Scheme 2. First, tetronic acid 13 was treated with oxalyl bromide to
1
7
provide 4-bromofuran-2(5H)-one 14, which was then converted to the corresponding silyloxyfuran
1
1
1
5 using the same protocol as described in Scheme 1. The Mukaiyama aldol reaction of compound
5 with (R)-5, followed by dehydration yielded the corresponding bromine-substituted heptene (S,Z)-
7 as a single diastereomer. Deprotection with AcOH/H O provided diol (S,Z)-18 together with a
2
small amount of the acetylated by-product (S,Z)-19. Benzoylation of (S,Z)-18 afforded novel
brominated melodorinol analogues including dibenzoylated product (S,Z)-20a as well as two
monobenzoylated products (S,Z)-21a and (S,Z)-22a. To observe the effect of the substituent on the
aromatic ring(s), (S,Z)-18 was treated 4-fluorobenzoyl chloride to provide three novel fluorinated
analogues (S,Z)-20b, (S,Z)-21b and (S,Z)-22b. To examine the effect of the stereochemistry at C-6
(
region 2), the synthesis described in Scheme 2 was repeated using (S)-5 instead of (R)-5 in the
Mukaiyama aldol reaction. The corresponding novel enantiomers (R,Z)-20a, (R,Z)-21a and (R,Z)-22a

were obtained in good yields. The previous study revealed that melodorinol analogues containing
1
d
short alkyl side-chains at the C-6 position showed greater cytotoxicities.
In this context, C-6
acylation of (R,Z)-21a and of (S,Z)-21b with propionic anhydride or butyric anhydride was
conducted, leading to three novel melodorinol analogues (R,Z)-23a, (R,Z)-23b and (S,Z)-23c
(
Scheme 3a). Finally, the bromine atom at the C-3 position was replaced by substitution with HNEt
2
1
8
at room temperature. Under these mild reaction conditions, (S,Z)-21a was smoothly converted into
the novel analogue (S,Z)-24 containing a diethylamino group at the C-3 position (Scheme 3b). To the
best of our knowledge, the formation of N-dialkyl tetronamides from 5-alkylidne-4-bromofuranones
is unprecedented; the installation of amino groups via aza-Michael addition/elimination reactions of
1
8b
5
-alkylidne-4-bromofuranones is extremely rare, and the reaction of such compounds with primary
1
8c
amines typically leads to the formation of hydroxylactams instead of tetronamides.
2
Scheme 3. Reagents and conditions: (i) (R CO)
2
O, NEt
3
, cat. DMAP, CH
2
Cl , rt, 2 h, ((R,Z)-23a)
2
1
d
18a
6
8%, ((R,Z)-23b) 96%, ((S,Z)-23c) 48%; (ii) HNEt
2
, THF, rt, 12 h, 78%.
The in vitro cytotoxicity of the synthesized compounds which contain the seven-carbon
1
9
skeleton (1, 2, 9-12 and 16-24) was evaluated by the MTT assay method using five human tumour
2
0
cell lines including KB, HeLa-S3, MCF-7, HT-29 and A549 (Table 1). The synthesized
melodorinol (S,Z)-1 exhibited similar cytotoxicity compared to the naturally isolated compound (see
ESI Section 4 for the comparison). The geometry of the double bond across C-4 and C-5 has little to
no impact on the inhibition activity, as observed by comparing the cytotoxicity between (S,Z)-1 and
(
S,E)-1, and between (S,Z)-2f and (S,E)-2f. The higher activity of the dibenzoylated products 2f is in
1
d
agreement with the previous report. However, no inhibition was observed for the derivatives which
do not contain the benzoyl group ((6R)-9, (S)-10, (S)-11 and (S)-12). This indicates that
hydrophobicity of the side-chains is crucial for good activity, although other types of interaction such
as pi-stacking or charge-transfer interactions cannot be excluded. Strikingly, the corresponding

analogues with a bromine substituent at C-3 showed much higher activity, clearly demonstrated by
comparing (S)-10/(S,Z)-17, (S)-11/(S,Z)-18, (S)-12/(S,Z)-19, and (S,Z)-1/(S,Z)-21a. Many studies
have demonstrated that the α,β-unsaturated lactone scaffold, as a Michael acceptor, is a crucial
2
1
moiety to induce cytotoxicity through various mechanisms, and has been found in various drug
2
2
candidates. In this context, the introduction of a bromine atom as a good leaving group at the β-
position on the furanone ring could enhance the Michael acceptor ability through an efficient
2
3
addition-elimination mechanism, hence leading to greater cytotoxicity. This assumption was
supported as replacement of the bromine atom by the diethylamino group in (S,Z)-24 led to complete
loss of cytotoxic activity; the enamionate compound is expected to be less reactive towards both
addition and addition-elimination reactions due to delocalization of the nitrogen lone pair. The
activity was further improved by the introduction of a fluorine atom at the para-position on the
benzoyl group(s); for example, the IC50 against KB was improved from 4.73 μM for (S,Z)-21a to
1
.43 μM for (S,Z)-21b. This result reveals an opportunity to further optimize the potency of
melodorinol analogues by varying the substituents on the benzoyl moiety to achieve optimal
lipophilicity and/or steric/electronic parameters. The stereochemistry at C-6 also has a slight impact
on the cytotoxicity. In all cases, the (R)-analogues ((R,Z)-17-19 and (R,Z)-20a-22a) exhibit higher
activity compared to the corresponding (S)-analogues. The introduction of acyl substituents at the C-
6
hydroxyl groups, including propionyl ((R,Z)-23a and (S,Z)-23c), butyryl ((R,Z)-23b) and benzoyl
(
(S,Z)-20a-b and (R,Z)-20a) side-chains, led to slight decrease in activity for the series of brominated
furanone analogues. This is in contrast with the trend observed for non-brominated furanone
analogues ((S,Z)-2f and (S,E)-2f) where the introduction of a benzoyl group led to an improvement in
the cytotoxicity. Notably, brominated analogues such as (R,Z)-21a and (S,Z)-21b exhibit
exceptionally high cytotoxicity against MCF-7, HT-29 and A549 cell lines compared to the
non-brominated analogues.
In conclusion, we have conducted the structure-activity relationship of melodorinol, which
can be summarized as follows: (1) The geometry of the double bond across C-4 and C-5 of the
heptene core structure has little to no effect on the cytotoxicity. (2) The substituent on the C-3
position can lead to a dramatic impact on the cytotoxicity; introduction of a good leaving group such
as bromine raised the activity significantly. On the other hand, blocking this position with a
diethylamino group completely inhibits the activity. (3) The (R)-enantiomers, which are less
commonly found in Nature, exhibit higher activity compared to the corresponding (S)-enantiomers.
(
4) The acyl substituents on both hydroxyl groups at C-6 and C-7 also greatly affect the cytotoxicity.
Among all of the synthesized melodorinol analogues, the most potent compounds were the

brominated analogues (R,Z)-21a and (S,Z)-21b with approximately 15-fold higher activity against
human tumour cell lines compared to the parent melodorinol. The knowledge obtained in this SAR
study could provide valuable information for the development of new naturally-derived anticancer
compounds.

Table 1. In vitro cytotoxicity of melodorinol analogues.
a
IC50 (μM)
Compound
KB
HeLa-S3
20.44 ± 0.55
21.26 ± 0.12
5.12 ± 0.26
5.93 ± 0.18
>100
MCF-7
HT-29
A549
b
b
b
(
S,Z)-1
S,E)-1
S,Z)-2f
S,E)-2f
6R)-9
21.47 ± 0.35
21.65 ± 0.28
5.43 ± 0.03
6.86 ± 1.15
>100
-
-
-
b
b
b
(
-
-
-
(
16.19 ± 0.28
18.74 ± 0.95
7.21 ± 0.57
9.84 ± 0.83
53.02 ± 1.02
b
(
-
b
b
b
(
-
-
-
c
b
b
b
(
(
(
S)-10
S)-11
S)-12
>100
>100
-
-
-
c
c
b
b
b
>100
>100
-
-
-
b
b
b
>100
>100
-
-
-
b
b
b
(
6S)-16
6R)-16
S,Z)-17
R,Z)-17
S,Z)-18
R,Z)-18
S,Z)-19
S,Z)-20a
R,Z)-20a
S,Z)-20b
S,Z)-21a
R,Z)-21a
S,Z)-21b
S,Z)-22a
R,Z)-22a
S,Z)-22b
R,Z)-23a
R,Z)-23b
S,Z)-23c
S,Z)-24
Doxorubicin
>100
>100
-
-
-
b
b
b
(
> 100
> 100
-
-
-
b
(
7.79 ± 0.35
3.38 ± 0.07
8.63 ± 0.32
6.54 ± 0.80
5.75 ± 0.44
17.66 ± 0.93
4.79 ± 1.82
13.06 ± 0.88
4.73 ± 0.07
1.40 ± 0.03
1.43 ± 0.04
6.53 ± 1.03
4.65 ± 0.10
1.69 ± 0.08
2.03 ± 0.26
6.37 ± 0.17
2.06 ± 0.05
>100
6.64 ± 0.09
2.49 ± 0.10
6.10 ± 0.38
6.47 ± 0.30
4.38 ± 0.22
11.16 ± 1.34
5.99 ± 0.19
16.35 ± 0.43
2.26 ± 0.07
1.75 ± 0.03
1.69 ± 0.03
4.97 ± 0.08
6.10 ± 0.63
2.26 ± 0.19
4.43 ± 0.79
6.72 ± 0.59
2.53 ± 0.32
>100
7.79 ± 0.59
3.27 ± 0.31
10.35 ± 0.17
7.35 ± 0.43
9.38 ± 0.67
6.41 ± 0.37
2.44 ± 0.09
7.72 ± 0.63
5.93 ± 0.29
6.38 ± 0.17
-
b
(
-
b
(
-
b
(
-
b
(
-
b
b
b
(
-
-
-
b
(
10.55 ± 0.22
9.37 ± 0.59
-
b
b
b
(
-
-
-
b
(
4.93 ± 0.40
1.65 ± 0.09
1.69 ± 0.14
12.81 ± 0.47
5.49 ± 0.10
2.49 ± 0.14
2.83 ± 0.19
5.81 ± 0.15
3.08 ± 0.42
4.44 ± 0.23
1.86 ± 0.10
2.37 ± 0.24
8.50 ± 0.29
6.53 ± 0.08
3.75 ± 0.23
3.71 ± 0.23
6.70 ± 0.22
3.32 ± 0.18
-
(
3.94 ± 0.15
3.46 ± 0.33
(
b
(
-
b
(
-
b
(
-
b
(
-
b
(
-
b
(
-
b
b
b
(
-
-
-
0.21 ± 0.07
0.07 ± 0.02
0.79 ± 0.04
0.33 ± 0.06
0.29 ± 0.02
a
The results are expressed as IC50 values (the concentration of compound that inhibit 50% of the cell multiplication after
4
8 h of treatment) taken as a mean from three experiments in μM ± standard deviation; Doxorubicin was used as a
positive control; Cell lines used are KB (human epidermoid carcinoma), HeLa-S3 (human cervix adenocarcinoma),
b
MCF-7 (human breast adenocarcinoma), HT-29 (human colon adenocarcinoma) and A549 (human lung carcinoma);
c
Not tested; Mixture of (Z):(E) = 3:1.

Acknowledgments
This work was supported by Grants for Development of New Faculty Staff,
Ratchadaphiseksomphot Endowment Fund [DNS60-075-23-011-1], Chulalongkorn University.
Partial supports from Seeding Money for New Faculty Member, Department of Chemistry,
Chulalongkorn University are gratefully acknowledged. Special thanks to Assoc. Prof. Dr. Santi Tip-
pyang, Asst. Prof. Dr. Worawan Bhanthumnavin and Dr. Jirapast Sichaem for proof-reading the
article and for their academic advice throughout this project. We also thank Dr. Nitipol
Srimongkolpithak for obtaining the high resolution mass spectra data.
Conflicts of interest
We declare that we have no conflict of interest.
Supplementary Material
Supplementary data associated with this article can be found, in the online version, at …
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8
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their cytotoxicity against A549.
2
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Graphical Abstract
Diverted total synthesis of melodorinol analogues
and evaluation of their cytotoxicity
Leave this area blank for abstract info.
Tanatorn Khotavivattana, Thitiphong Khamkhenshorngphanuch, Kitiya Rassamee, Pongpun Siripong and
Tirayut Vilaivan

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Structural modification of melodorinol was achieved by diverted total synthesis.
28 derivatives were subjected to antitumor activity test.
SAR studies revealed key parameters that affect the cytotoxicity.