Bioorganic & Medicinal Chemistry Letters
New phenstatin–fatty acid conjugates: Synthesis and evaluation
b
b
Jinhui Chen a, David P. Brown a, , Yi-Jun Wang , Zhe-Sheng Chen
⇑
a Department of Chemistry, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
b Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New phenstatin–fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7
and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar
level paralleling an increase in un-saturation in the fatty acid component.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 May 2013
Revised 10 July 2013
Accepted 16 July 2013
Available online 24 July 2013
Keywords:
Conjugates
Fatty acids
Microtubule-binding drugs
Cancer chemotherapy
Drug resistance reversal
The quest for more potent and less toxic candidates in the treat-
ment of various elusive forms of cancer remains unrelenting; and
especially so, in light of the emergence of new multidrug resistance
(MDR) mechanisms. It has been reported that this persistent MDR
barrier is the most significant reason for treatment failures in ex-
cess of 90% of subjects with metastatic cancers.1 Among the group
of promising antineoplastic agents are new chemical entities
which are hybrids of naturally occurring bioactive substances.
These hybrids are often comprised of either the whole or partial
structures of the natural product of interest. Indeed, reports indi-
cate several cases of improved activity of the hybrids relative to
the parent natural product.2 Of direct relevance are the hybrids
of recognized anti-cancer compounds and various unsaturated
fatty acids, ranging from the monounsaturated systems (MUFAs)
to different polyunsaturated systems (PUFAs).
This study focuses on the effects of conjugating various fatty
acids on the antiproliferative activity of the reported tubulin-bind-
ing compound phenstatin7 1. Presently, intense efforts have been
devoted to the development of novel analogues of phenstatin
and its derivatives, largely based on the fact that being a benzophe-
none derivative, its structure is not prone to the (Z)/(E) isomeriza-
tion associated with combretastatin A-4 (CA-4), the cause of
decreased efficacy. We have also examined hybrids of the new
compound isophenstatin 2 (Fig. 1).
Phenstatin, like CA-4, binds to the colchicine site of endothelial
tubulin, thus interfering with the equilibrium dynamics associated
with the cell division process.8 Mitotic arrest typically follows
leading to apoptosis and cell death.9
Herein we report the synthesis of some novel MUFA and PUFA-
conjugates of phenstatin and isophenstatin.
The incorporation of unsaturated fatty acids provides a very
promising alternative in addressing tumor-targeting delivery of
drugs in an effort to improve the overall efficacy of these chemo-
therapeutic agents.3 PUFAs such as linoleic acid (LA) and docosa-
hexaenoic acid (DHA) fulfill significant roles in cell growth and
development.4
Furthermore, studies have shown that PUFAs are readily taken
up by tumor cells, and that certain PUFA-drug conjugates exhibit
tumor specific accumulation through in vitro and in vivo studies.5
For instance, Ojima et al. have synthesized conjugates of DHA or
LNA (linolenic acid) with next generation taxoids that have demon-
strated greatly improved efficacy.6
O
O
MeO
MeO
OH
MeO
MeO
OMe
OH
OMe
1
2
OMe
MeO
MeO
OMe
MeO
MeO
NHAc
OMe
OMe
OH
O
3
Colchicine
OMe
OMe
⇑
Corresponding author. Tel.: +1 718 990 5219; fax: +1 718 990 1876.
Figure 1. Structures of phenstatin, isophenstatin, CA-4 and cholchicine.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Chen, Jinhui
