Insights into the structure–activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A critical role played by the conjugated trienyl lactone moiety

Article abstract of DOI:10.1016/j.bmcl.2016.06.057

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure–activity relationship study, two new analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated trienyl lactone moiety of the molecule by replacing the C2–C3 double bond in ZJ-101 with a single bond and switching the geometry of the C4–C5 double bond in ZJ-101 from Z to E, respectively. Biological evaluation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of the molecule is critical for its anticancer activity.

Full text of DOI:10.1016/j.bmcl.2016.06.057

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Insights into the structure–activity relationship of the anticancer
compound ZJ-101, a derivative of marine natural product
superstolide A: A critical role played by the conjugated trienyl
lactone moiety
Shan Qian a, Aashay K. Shah a, Sarah A. Head b, Jun O. Liu b,c, Zhendong Jin a,
⇑
a Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
b Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA
c Department of Onocology, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was pre-
viously developed in our laboratory. In the subsequent structure–activity relationship study, two new
analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated
trienyl lactone moiety of the molecule by replacing the C2–C3 double bond in ZJ-101 with a single bond
and switching the geometry of the C4–C5 double bond in ZJ-101 from Z to E, respectively. Biological eval-
uation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less
active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of
the molecule is critical for its anticancer activity.
Received 26 April 2016
Revised 20 June 2016
Accepted 21 June 2016
Available online xxxx
Keywords:
Superstolide A analog
Anticancer agent
Structure–activity relationship
Drug design
Ó 2016 Elsevier Ltd. All rights reserved.
Asymmetric synthesis
Natural products have been a major source of drugs for cen-
turies.1 Since ziconotide, the first drug from the sea, was approved
in the United States in 2004 for the treatment of chronic pain in
spinal cord injury, biologically active marine natural products have
been playing an increasingly important role in drug discovery and
development.2 In fact, we are likely experiencing a 21st century
renaissance of drug discovery based on marine natural products.3
In addition, potent anticancer natural products play very important
roles in both antibody-drug conjugates (ADCs) and small molecule-
drug conjugates (SMDCs) therapies because natural products can
be used as cytotoxic payloads.4
Superstolide A (1) (Fig. 1), isolated in minute amounts from the
deep-water marine sponge Neosiphonia superstes, exhibits potent
antiproliferative activity against several tumor cell lines with IC50
values ranging from 4.8 to 64 nM.5 Its potent anticancer activity
suggests a potential use of superstolide A as a payload for an anti-
body-drug conjugate (ADC) or a small molecule-drug conjugate
(SMDC). However, the lack of adequate compound supply from
natural resources coupled with the overwhelming difficulty in
the development of a practical total synthesis approach6 severely
impeded the preclinical evaluation of this group of structurally dis-
tinct and mechanistically unique marine natural products.
We recently designed and synthesized a truncated superstolide
A (named as ZJ-101) that maintains the potent anticancer activity
of the original natural product (Fig. 1).7 Because our synthetic
approach is very efficient and the synthesis can be scaled up, we
have for the first time successfully developed a synthetic strategy
that enabled sufficient amounts of material for additional biologi-
cal and mechanistic evaluation. A possible novel mechanism of
action8 plus the potential use as a payload for an antibody-drug
conjugate (ADC) or a small molecule-drug conjugate (SMDC)
demands careful understanding the structure–activity relation-
ships of ZJ-101.9
While the potent anticancer activity of ZJ-101 partially con-
firmed our original hypothesis that the 16-membered macrolac-
tone is likely the pharmacophore responsible for interacting with
its putative target,7 it is imperative to precisely characterize the
role of the conjugated trienyl lactone moiety in its anticancer activ-
ity. Therefore, we designed two analogs ZJ-105 and ZJ-106 (Fig. 2)
where the C2–C3 double bond is replaced with a single bond and
the geometry of the C4–C5 double bond is switched from Z to E,
respectively. These two analogs would not only enable us to gain
insights into the structure–activity relationship of ZJ-101 but also
⇑
Corresponding author. Tel.: +1 319 353 5359.
E-mail address: zhendong-jin@uiowa.edu (Z. Jin).
http://dx.doi.org/10.1016/j.bmcl.2016.06.057
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Qian, S.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.057

2
S. Qian et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Figure 1. Superstolide A and truncated superstolide A (ZJ-101).
reveal the significance of the conjugated trienyl lactone moiety on
the anticancer activity. Herein, we report our synthesis and biolog-
ical evaluation of compounds ZJ-105 and ZJ-106.
The retrosynthetic analyses of ZJ-105 and ZJ-106 are analogous
to that of ZJ-101 and are outlined in Scheme 1. These synthetic
routes are advantageous as they are flexible and convergent.
The commercially available butane-1,4-diol 8 was converted to
compound 9 using reported procedures (Scheme 2).10 Compound 9
reacted with TBAF to give alcohol 10 in 57% yield. Swern oxidation
of the primary alcohol 10 to aldehyde 11 followed by Pinnick oxi-
dation provided the carboxylic acid 6 in excellent yield. Compound
6 was then converted to anhydride 12 in 91% yield.
Scheme 1. Retrosynthetic analysis of ZJ-105 and ZJ-106.
Regioselective esterification reaction of diol 57 and anhydride
12 gave ester 13 in 80% yield (Scheme 3). Compound 13 was trea-
ted with Ti(O-i-Pr)4 to obtain the desired ester 14, which under-
went intramolecular Stille coupling to provide compound ZJ-105
(3) in 53% yield.7
But-2-yn-1-ol 15 was converted to vinyl stannane 16 using
published literature procedures (Scheme 4).11 Vinyl stannane 16
reacted with iodine gave vinyl iodide 17 in 91% yield. MnO2-medi-
ated allylic oxidation of compound 17 followed by Horner–Wads-
worth–Emmons olefination provided ester 18 in 73% yield with
complete E-stereoselectivity. Ester 18 was hydrolyzed to car-
boxylic acid 7, which was converted to anhydride 19 in excellent
yield.
Regioselective esterification reaction of diol 5 and anhydride 19
gave ester 20 in 91% yield (Scheme 5). Compound 20 was treated
with Ti(O-i-Pr)4 to obtain the desired ester 21, which underwent
intramolecular Stille coupling to provide compound ZJ-106 (4) in
65% yield.7
Scheme 2. Synthesis of compound 12.
Figure 2. Designed analogs ZJ-105 and ZJ-106.
Scheme 3. Synthesis of ZJ-105.
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S. Qian et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
Antiproliferative effect of ZJ-105 and ZJ-106 on four malignant tumor cells (Alamar
Blue assay)
Entry
Cell Line
ZJ-105 IC50
(nM)
ZJ-106 IC50
(nM)
ZJ-101 IC50
(nM)
1
2
3
4
MDA-MB-231
SF-295
MCF-7
>5000
>5000
>5000
>5000
384.3
610.6
376.0
1068
63.0
63.5
36.5
RKO
213.8
has confirmed our original hypothesis that the trienyl conjugated
lactone moiety of the molecule is indeed the pharmacophore and
future structural optimization should keep the chemical structure
of this region intact. Research in this direction is currently under-
way and will be reported in due course.
Scheme 4. Synthesis of compound 19.
Conflict of interest statement
Dr. Zhendong Jin is the founder and a shareholder of InnoBio-
Pharma, LLC that sponsored the project, ‘Development of novel
anticancer agents based on natural products’ at the University of
Iowa.
Acknowledgments
This work was made possible by the generous support of the
GAP funding from the Office of the Vice President for Research
and Economic Development (OVPRED) at the University of Iowa
and funding from InnoBioPharma, LLC (D2015070002). Aashay K.
Shah was supported by a fellowship from the University of Iowa
Center for Biocatalysis and Bioprocessing, and by activities of the
Predoctoral Training program in Biotechnology, NIH grant
2T32GM008365. Special thanks are due to the Graduate College
and College of Pharmacy at the University of Iowa for providing a
dissertation fellowship to Aashay K. Shah.
References and notes
1. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311. and references cited
therein.
Scheme 5. Synthesis of ZJ-106.
2. Chen, J.-W.; Wu, Q.-H.; Rowley, D. C.; Al-Kareef, A. M. Q.; Wang, H. J. Asian Nat.
Prod. Res. 2015, 17, 199. and references cited therein.
3. Montaser, R.; Luesch, H. Future Med. Chem. 2011, 3, 1475.
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references cited therein.
5. (a) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A. J. Am. Chem.
Soc. 1994, 116, 6658; (b) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.;
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8. Jin, Z. Unpublished results.
9. Shah, A. K.; Qian, S.; Zhang, D.; Head, S. A.; Liu, J. O.; Jin, Z. Bioorg. Med. Chem.
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The antiproliferative effects of ZJ-105 and ZJ-106 were deter-
mined in MDA-MB-231 (human breast cancer), SF-295 (human
glioblastoma), MCF-7 (human breast cancer) and RKO (human
colon cancer) cell lines using the Alamar Blue viability assay, along
with ZJ-101 as the positive control.12 The IC50 values are shown in
Table 1. ZJ-105 completely lost its antiproliferative activity in these
four cell lines, suggesting that the C2–C3 double bond is absolutely
essential for its biological activity. In addition, the activity of ZJ-
106 dropped by up to 10 folds, suggesting the Z-geometry of the
C4–C5 double bond is also important.
10. Taillier, C.; Gille, B.; Bellosta, V.; Cossy, J. J. Org. Chem. 2005, 70, 2097.
11. Lipshutz, B. H.; Clososki, G. C.; Chrisman, W.; Chung, D. W.; Ball, D. B.; Howell, J.
Org. Lett. 2005, 7, 4561.
In conclusion, we have designed and synthesized compounds
ZJ-105 and ZJ-106 by replacing the C2–C3 double bond in ZJ-101
with a single bond and switching the geometry of the C4–C5 dou-
ble bond in ZJ-101 from Z to E, respectively. The biological testing
12. Ahmed, S. A.; Gogal, R. M.; Walsh, J. E. J. Immunol. Methods 1994, 170, 211.
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