Synthesis of the analogs of plocabulin and their preliminary structure-activity relationship study

Article abstract of DOI:10.1016/j.bmcl.2021.128355

Plocabulin, a marine natural polyketide isolated from the sponge Lithoplocamia lithistoides, is a novel and potent microtubule-destabilizing agent. Guided by the reported binding mode, several new analogs of plocabulin have been designed through removing

Full text of DOI:10.1016/j.bmcl.2021.128355

Journal Pre-proofs
Synthesis of the analogs of plocabulin and their preliminary structure-activity
relationship study
Leiming Wang, Xin Li, Hong Cui, Xinsheng Lei, Hongchun Liu, Quanrui
Wang, Yingxia Li
PII:
S0960-894X(21)00582-5
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2021.128355
BMCL 128355
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Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
26 May 2021
2 September 2021
2 September 2021
Please cite this article as: Wang, L., Li, X., Cui, H., Lei, X., Liu, H., Wang, Q., Li, Y., Synthesis of the analogs of
plocabulin and their preliminary structure-activity relationship study, Bioorganic & Medicinal Chemistry Letters
(2021), doi: https://doi.org/10.1016/j.bmcl.2021.128355
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Synthesis of the analogs of plocabulin and their preliminary
structure-activity relationship study
Leiming Wanga,b,#, Xin Lic,#, Hong Cuib, Xinsheng Leib, Hongchun Liuc,*, Quanrui
Wanga,* and Yingxia Lib,*
a Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China
b Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China
c Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
# These authors contributed equally to this work.
ABSTRACT
Plocabulin, a marine natural polyketide isolated from the sponge Lithoplocamia
lithistoides, is a novel and potent microtubule-destabilizing agent. Guided by the
reported binding mode, several new analogs of plocabulin have been designed through
removing the right aliphatic chain and further modifying on the carbamate group and
the enamide unit. The preliminary results indicate that the right aliphatic chain in
plocabulin is allowed to remove with a little loss of activity, the carbamate group plays
a role in the activity, and particularly, the enamide unit has an important effect on the
activity. This new finding will aid the design of novel potent tubulin-binding agents
based on plocabulin.
Keywords: marine nature products, plocabulin, PM060184, synthesis, antiproliferation
Marine organisms have been viewed as an unignorable source of bioactive natural
products besides terrestrial plants and other nonmarine microorganisms. Harsh marine
conditions drive marine organisms to evolve in distinctive manners from nonmarine
microorganisms, favorably producing structurally unique and diverse secondary
metabolites. These metabolites are prolific sources of products with a wide range of
significant and novel bioactivity.[1-3] This is supported by the fact that eight approved
therapeutic agents have been developed from about 30000 marine natural products
(MNPs) obtained so far, and at least 23 marine-derived compounds are in clinical
trials.[4-6] Therefore, the MNPs are more attractive candidates for drug discovery.
The recent example is plocabulin, a novel and potent microtubule-destabilizing
agent which was isolated from the sponge Lithoplocamia lithistoides collected in
Madagascar (Figure 1)[7] and identified to target a unique site on β-tubulin different
from that of vinca alkaloids, taxanes or eribulin.[8-10] The exact site where plocabulin
binds to tubulin is the maytansine site, and the agents that bind to this site include
maytansine, rhizoxin, disorazole and spongistatin, which are all cyclic molecules
* Corresponding author: For H. L. email: hchliu@simm.ac.cn; For Q. W. email: qrwang@fudan.edu.cn;
For Y. L. email: liyx417@fudan.edu.cn
1

except plocabulin.[9,11] Based on its potent antimitotic activity and distinct biochemical
mechanism, plocabulin is currently undergoing phase II clinical trials for the treatment
of several tumors and has shown superior antitumor efficacy in patients with advanced
solid tumors.[11,12]
As one new member of polyketides, plocabulin possesses some intriguing
structural features, including a chiral α,β-unsaturated δ-lactone, a conjugated triene unit
and L-tert-leucine linked via a (Z)-enamide to a diene moiety containing a carbamate
subunit (Figure 1). This complex structure requires about 18 linear steps (totally 30
steps) for the synthesis of plocabulin.[7,13] Therefore, it is desirable to explore novel and
simplified microtubule-destabilizing agents based on this marine natural product.
Recently, we have explored an efficient copper-catalyzed cross-coupling reaction of
amino acid-derived amides with (Z)-vinyl iodides, and through this reaction we have
developed an improved method for the preparation of plocabulin.[14] As a continuation
of the project, we herein describe a preliminary result on the synthesis of several
simplified analogs of plocabulin and their antiproliferation towards three tested cells.
MeO
O
9
6
O
O
O
21
NH2
O
5
1
O
N
13
H
19
25
HN
17
Plocabulin
MeO
O
MeO
O
O
O
O
O
NH2
O
O
HN
NH2
O
O
O
N
H
N
H
HN
HN
1
2
MeO
O
MeO
O
O
O
O
O
O
NH2
O
O
O
NH2
O
O
N
H
N
H
HN
HN
3
4
MeO
MeO
O
A
O
O
NH2
O
O
O
I
5
O
N
H
HN
Linker
analogs
(A: O, NH)
P
A
P
Bu3Sn
O
P
A
A
O
N
O
H
BocHN
HN
Linker
I
(P: protecting group)
Linker
HN
Linker
Intermediate
Figure 1. The design of the analogs of plocabulin and their retrosynthetic analysis
2

Based on the X-ray crystal complex of plocabulin and the tubulin (PDB: 4TV9),
the binding mode has been disclosed.[9] It indicates that the lactone moiety contributes
to two key hydrogen–bond interactions with the tubulin, and the oxygen atom of the
carbonyl at C13 position, the nitrogen atom at N17 position and the carbamate group at
C21 position also provide three important hydrogen–bond interactions, respectively.
Meanwhile, the conjugated triene moiety provides the rigid scafold and controls those
heteroatoms in the favorable orientations. Notably, the right aliphatic chain from C22
to C25 appears to be unnecessary pharmacophore. Thus, we designed the simplified
analog 1 (Figure 1) by removing the right aliphatic chain, and furthermore, the
carbamate group of 1 is replaced by more rigid aminoformamidoyl group resulted in
compound 2. Considering the potentially unstable (Z)-enamide unit of plocabulin, we
designed the compound 3 by the replacement of the double bond in enamide unit with
a benzene ring. As for compound 4, the purpose of introduction of methyl group at C19
position is to compensate the effect of the right aliphatic chain and to attempt to offer
the favorable orientation of the carbamate group.
As can be seen from Figure 1, the left fragment is commonly shared by all the
designed analog, and therefore the similar strategy was adopted for the synthesis of
those analogs, according to the previous preparation of plocabulin.[7,13] The analogs
could be assembled in the late-stage by the Still coupling reaction between the Z-
iodoalkene 5 and the organostanane intermediates (Figure 1), and the subsequent
functional group transformations produced the targets (1-4). The in-turn intermediates
were formed via amidation between the α,β-unsaturated acid bearing Bu3Sn group and
the corresponding L-tert-leucine amides bearing the different linker fragments. The
amides bearing the linker would be connected via the coupling reaction between L-Boc-
tert-leucine amide with (Z)-vinyl iodides, or via the condensation between L-Boc-tert-
leucine and the corresponding aryl amine. In addition, the iodide compound 5 could be
obtained from commercially 1,3-propanediol in 14 steps according to the known
method.[7,13]
Keep these in mind, we set out to prepare the right fragments for those analogs, as
illustrated in Scheme 1. At first, 1,3-propanediol was selectively protected in the
presence of TBDPSCl, giving the mono-protected 1a in 85% yield. In the presence of
Dess-Martin reagent, 1a was oxidized to the aldehyde 1b with a yield of 67%. Under
the Stork-Zhao olefination condition, 1b could be conveniently transform to the (Z)-
vinyl iodide 1c in 84% yield. Next, starting from but-3-yn-1-ol, 2a was prepared from
phthalimide in 88% yield through the Mitsunobu reaction.[15] Iodination of the terminal
triple bond of 2a was carried out with N-iodosuccinimide (NIS) and AgNO3 in acetone,
giving 2b in 86% yield.[16] After reduction by tosyl hydrazide (TSH) under the basic
condition, 2b was selectively reduced into the (Z)-vinyl iodide 2c in 64% yield.[17] As
for compound 3c, it was easily available from the commercial 2-(2-aminophenyl)ethan-
1-ol through the protection of the hydroxyl group. In addition, treatment of but-3-yn-1-
ol with Me3Al in the presence of Cp2ZrCl2 as a catalyst,[18,19] followed by thermally
isomerization to the (Z)-methylaluminated species (4a) due to the chelation effect of
the terminal hydroxy group, and trapping of 4a by I2 stereoselectively produced (Z)-
3

vinyl iodide 4b in 44% yield. Subsequently the hydroxyl group was protected by TBS,
giving 4c in an almost quantitative yield.
OH
OTBDPS
OTBDPS
OTBDPS
a
b
c
I
HO
O
I
HO
1c
1a
1b
I
d
e
f
OH
Phth
Phth
Phth
2a
2b
2c
O
NH2
NH2
g
OH
OTBS
Phth =
N
O
3c
OH
OTBS
HO
h
i
j
AlMe
O
I
I
4a
4b
4c
Scheme 1. The preparation of the intermediates (1c-4c)
Reagents and conditions: (a) TBDPSCl, Im, DMF, THF, rt, 85%; (b) Dess-Martin Reagent, DCM.
rt., 67%; (c) (Ph3PCH2I)+ I, NaHMDS, THF, 78 oC, 84%; (d) PPh3, phthalimide, DIAD, THF, rt.,
88%; (e) NIS, AgNO3, acetone, rt, 86%; (f) TSH, AcONa,THF, H2O, 65 oC, 64%; (g) TBSCl, Im,
DMF, rt., 91%; (h) ZrCp2Cl2, AlMe3, DCE, 0 oC, reflux; (i) I2, THF, 30 oC, 44%; (j) TBSCl, Im,
DMF, rt., 98%;
With the right fragments in hand, we then carried out the assembly work to prepare
the designed analogs (Scheme 2). Initially, under the standard condition (CuI, K2CO3,
DMEDA, DMF, 90 oC), 1c was coupled with L-Boc-tert-leucine amide to produce 1d,
giving a poor yield (39%). Thus, both 2c and 4c were subjected to our optimized
condition (CuI, Cs2CO3, DMEDA, DME, 55 oC), giving 2d and 4d in much improved
yields (45% and 93%), respectively. On the other hand, 3c and Cbz-L-tert-leucine could
be condensed under the routine amidation condition, providing 3d in 79% yield.
Considering the acidic sensitivity of TBDPS group in the compounds (1d, 3d and
4d), the removal of the Boc group was performed under the pyrolysis conditions (up to
200 oC for about 15 min in ethyleneglycol), leading to the corresponding free amines
in satisfying yields (1e: 53%; 3e: 83%; 4e: 76%;). As for 2e, the Cbz protective group
could be removed in an almost quantitative yield by the routine hydrogenation. Next,
easily available (Z)-3-(tributylstannyl) acrylic acid was condensed with 1-4e under the
routine amidation conditions, resulting in 1-4f in reasonable yields ranged from 63% to
82%. Subsequently, the Stille coupling reaction of the vinyl iodides (1-4f) with the
fragment 5 (the structure shown in Figure 1) was catalyzed by copper (I) thiophene-2-
o
carboxylate (CuTC) in 1-methyl-2-pyrrolidinone (NMP) at 0 C, affording the
corresponding trienes (1-4g) in acceptable yields (50-75%). Removal of TBDPS group
4

in the resultant intermediates (1g, 3g and 4g) with TBAF smoothly furnished the
alcohols (1h: 75%; 3h: 57%; 4h: 55%). The free amine (2h) was fortunately prepared
from 2g by the treatment of N2H4·H2O.[20] Finally, the free alcohols (1, 3-4h) were
reacted with trichloroacetyl isocyanate (TCAI), leading to the trichloroacetyl
carbomates, respectively. Followed by the treatment of Al2O3, those carbomates were
finally transformed into the analogs (1: 69%; 3: 41%; 4: 44%). On the other hand, the
free amine (2h) were treated with KCNO in the presence of diluted HCl aqueous
solution,[21] giving the analog 2 in 3% yield over 2 steps.
R1
R1
R1
O
R1
Bu3Sn
a
b
c
O
O
O
R2HN
H2N
N
I
H
Y
HN
HN
HN
Y
Y
Y
1 = OTBDPS
1 = Phth
R
R
R
R
1 = OTBDPS; R2 = Boc
1 = Phth; R2 = Boc
1 = OTBS; R2 = Cbz
1 = OTBS; R2 = Boc
R
1 = OTBDPS
1 = Phth
R
R
R
R
1 = OTBDPS
1 = Phth
1 = OTBS
1 = OTBS
1c
2c
3c
4c
1d
1e
1f
2f
3f
4f
R
2d
3d
4d
2e
3e
4e
R
R
R
R
R
1 = OTBS
1 = OTBS
1 = OTBS
1
R = OTBS
MeO
MeO
O
O
R1
O
O
R1
d
e
O
O
O
N
O
N
H
H
HN
HN
1g
2g
3g
4g
1h
2h
3h
4h
R
R
R
R
1 = OTBDPS
1 = Phth
1 = OTBS
1 = OTBS
R
R
R
R
1 = OH
1 = NH2
1 = OH
1 = OH
Y
Y
MeO
O
2
4
X = NH; Y =
X = O; Y =
1
3
X = O; Y =
X = O; Y =
O
f
O
O
X
NH2
O
N
H
HN
Y
Scheme 2. The synthesis of the analogs (1-4)
Reagents and conditions: (a) 1d (39%): L-Boc-tert-leucine amide, CuI, K2CO3, DMEDA, DMF, 90
oC; 2d (45%), 4d (93%): L-Boc-tert-leucine amide, CuI, Cs2CO3, DMEDA, DME, 55 oC; 3d (79%):
L-Cbz-tert-leucine, DIPEA, HOAT, HATU, DCM, DMF, 0 oC; (b) 1e (53%), 2e (83%), 4e (76%):
ethylenglycol, 200 oC; 3e (95%): Pd/C, H2, MeOH, rt; (c) 1f (63%), 2f (64%), 3f (82%), 4f (74%),
o
(Z)-3-(tributylstannyl) acrylic acid, DIPEA, HOAT, HATU, DCM, DMF, 0 C; (d) 1g (57%), 2g
(57%), 3g (50%), 4g (75%): 5, CuTC, NMP, 0 oC; (e) 1h (75%), 3h (57%), 4h (55%): TBAF, THF,
o
rt; 2h N2H4·H2O, THF, rt; (f) 1 (69%), 3 (41%), 4 (44%): (1) TCAI, DCM, 0 C; (2) Al2O3, rt; 2
(3%, 2 steps): KCNO, HCl aq., MeOH, H2O, 45 oC.
After analog 1 was obtained, the in vitro antiproliferative activities (A549, HT-29
and HepG2 cells) were at once assessed using the CCK-8 method. The results were
shown in Table 1, and plocabulin previously obtained[14] was used as the positive
compound. As expected, the IC50 (nM) values of plocabulin in this assay were 0.72
(A549), 0.27 (HT-29) and 1.64 (HepG2), respectively, which were similar to the
literature.[11] To our pleasure, the analog 1 also showed potent cytotoxicities towards
the tested cells with IC50 values around nanomolar concentration (A549: 2.4 nM; HT-
29: 1.1 nM; HepG2: 5.8 nM), and its cytotoxicities were generally about one third of
5

those of plocabulin. The comparable activities suggested that the right aliphatic moiety
in plocabulin was permitted to remove, demonstrating our initial design hypothesis.
Table 1. The in vitro antiproliferative activity of plocabulin and its analogs (IC50 ± SEM, nM).
MeO
O
O
R
O
O
N
H
HN
X
IC50 ± SEM (nM)a
HT-29
Compound
R
X
A549
HepG2
1
2
1.1 ± 0.1b
25 ± 5.3c
5.8 ± 1.1b
-OCONH2
-NHCONH2
-Phth
2.4 ± 0.3b
> 100c
> 100c
2g
686 ± 256c
622 ± 125c
5190 ± 1590c
＞10000c
469 ± 76c
> 10000c
2310 ± 13c
3
4
-OCONH2
-OCONH2
-OH
5370 ± 3590c
127 ± 8c
4960 ± 3430c
78 ± 1c
3h
> 10000c
> 10000c
4h
-OH
384 ± 29c
287 ± 45c
taxol
-
-
-
-
4.7 ± 0.2c
0.72 ± 0.07b
(< 0.20)c
3.8 ± 0.3c
0.27 ± 0.02b
(< 0.20)c
10.1 ± 0.7c
1.64 ± 0.12b
(0.36 ± 0.06)c
plocabulin
a Compounds were tested in at least 8-dose IC50 mode in duplicate with 5-fold serial dilution.
b Data was obtained in the first round.
c Data was obtained in the secondary round.
Encouraged by the above results, in the secondary round we evaluated the
activities of the other analogs (2, 2g, 3, 4, 3h and 4h), and their results were compiled
in Table 1. Notably, the IC50 values for plocabulin coming from the same sample were
lower than those values in the first round, while those in two rounds were up to sub-
nanomolar level. Despite that, we believed that both of the data in the two rounds are
relevant and comparable.
6

Based on the results in the secondary round, we found 2 dramatically lost the
cytotoxic activity towards both A549 and HepG2 except HT-29 cell (IC50: 25 nM),
compared with 1. Furthermore, 2g just exhibited marginal cytotoxic activities towards
the tested cells. These results suggested that it seemed to be unbeneficial to replace the
carbamate group with a more rigid bioisostere.
In contrast to 1, 3 also almost lost the cytotoxic activity towards the tested cells
(IC50: > 4960 nM), indicating that the double bond in enamide unit could not be
replaced by the benzene ring with the same rigidity. The reason might be that a limited
space was required for the binding interaction between the enamide unit domain and
tublin, and the benzene ring was larger than the double bond in the enamide. This
statement was also supported to some extent by the results of analog 4, because 4
displayed obviously reduced activities towards the tested cells (IC50: from 78 nM to
469 nM). Compared with 1, 4 was installed with a methyl group on the double bond in
the enamide unit, but the related cytotoxic activities were generally reduced with a
range of 7- to 60-fold. Interestingly, 4h exhibited about 5-fold decreased cytotoxic
activities with IC50 values ranging from 287 nM to 2320 nM, as compared with 4. This
result implied that the carbamate group cannot be simplified to hydroxyl group because
of the obviously decreased activity.
Next, the in vitro assay of the tubulin polymerization was carried out with the
representative compound 4 and plocabulin, using Combretastatin A-4 (CA-4) as a
positive control. The result indicated that the IC50 value of 4 was 16.0+2.6 μM, lower
than those of plocabulin and CA-4 (3.1+0.5 μM and 1.2+0.3 μM, respectively). The
result confirmed the interaction mechanism of the analogs with tubulin.
Figure 2. The best docking poses for Compound 1-4 with tubulin (PDB: 4TV9). A: the overlap of
compound 1 (Gyan) and plocabulin (Green); B: the overlap of compound 2 (Magenta) and
plocabulin (Green); C: the overlap of compound 3 (Yellow) and plocabulin (Green); D: the overlap
of compound 4 (Pink) and plocabulin (Green).
7

Then, the above results were further analyzed by the molecular modelling study
according to the reported X-ray crystal complex structure.[9] The result suggested that
compound 1-4 could interact with tubulin in a similar manner to plocabulin,
respectively (Figure 2). Notably, the carbamate moiety in 1 adopted a different
orientation from that in plocabulin due to loss of the side aliphatic chain, which resulted
in partially decreased activity (Figure 2A). Upon the replacement of the carbamate
group with the aminoformamidoyl group, 2 adopted a more similar molecular pose to
plocabulin, but the L-tert-leucine amide moiety was in an obviously different
orientation, leading to an evident loss of activity (Figure 2B). In addition, when the
double bond in the enamide moiety of 1 was replaced with the benzene ring, 3 appeared
to overlap well with plocabulin, but its carbamate moiety was forced to stretch in a
different direction, making a dramatical loss of activity (Figure 2C). In contrast to 1,
the installment of methyl group at the double bond made the linker of 4 adopt a twisted
posture, having an adverse effect (Figure 2D).
In summary, guided by the disclosed binding mode, a set of analogs of plocabulin
were designed through removing the right aliphatic chain and further modifying on the
carbamate group and the enamide unit in plocabulin. All the designed analogs were
synthesized and evaluated for their cytotoxic activity. Most of them showed
significantly reduced cytotoxic activity towards A549, HT-29 and HepG2 cells,
however, the analog (1) without the right aliphatic chain remained potent cytotoxicities
towards the tested cells with IC50 values around nanomolar level, and furthermore, the
replacement of the carbamate group with hydroxyl group (4 vs 4h) could result in a
decrease of the activity to an evident extent. This new finding will assist the design of
novel potent tubulin-binding agents based on plocabulin.
Acknowledgements
We would like to thank National Natural Science Foundation of China (No. 81773576)
and National Key R&D Program of China (2018YFC0310905) for the financial support.
Supplementary data
Supplementary data is available on the publishers’ web site along with the published
article.
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MeO
O
O
9
6
O
O
O
21
NH2
5
1
O
N
13
H
19
25
HN
17
Plocabulin
MeO
O
MeO
O
O
O
O
O
NH2
O
O
HN
NH2
O
O
O
N
N
H
H
HN
HN
1
2
MeO
O
MeO
O
O
O
O
O
O
NH2
O
O
O
NH2
O
O
N
H
N
H
HN
HN
3
4
11