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Antiangiogenic Agents : Studies on Fumagillin and Curcumin Analogs

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Cancer is a general term used to describe many disease states, each of which are characterized by abnormal cell proliferation. The causes which bring about this abnormal cellular behavior are specific to each type of cancer. The success of tumor-targeted therapy is limited by this diversity. One common denominator for all types of cancer is the requirement of a suitable blood supply. Therefore, tumor vasculature has emerged as a potential target for therapeutic intervention. New blood vessel growth from preexisting vasculature stimulated by biochemical signals is termed angiogenesis. Tumor masses require a constant supply of oxygen and nutrients, and a means of efficient waste removal to ensure sustained development. Diffusion from nearby capillaries can supply adequate nutrition for tumors less than 2 mm in size, but for continued growth the tumors must develop their own blood supply. Alteration of the delicate balance of angiogenic stimulating factors and angiogenic inhibitors results in the phenotypic change from quiescence to active endothelial proliferation. To date, this angiogenic switch is not completely understood. The goal of antiangiogenic therapy is to interfere with these mechanisms and prevent tumor cells from developing a viable blood supply. Fumagillin is a naturally occurring antifungal agent. Curcumin is a natural product isolated from the spice turmeric. Both compounds have been shown to have antiangiogenic properties in vitro and in vivo. This paper describes efforts to design and prepare fumagillin and curcumin analogs and evaluate their corresponding antiangiogenic activities.
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Content Preview
Current Pharmaceutical Design, 2005, 11, 357-373
357
Antiangiogenic Agents: Studies on Fumagillin and Curcumin Analogs
M.S. Furnessb, T.P. Robinsonb, T. Ehlersb, R.B. Hubbard, IVb, J.L. Arbiserc, D.J. Goldsmithd and
J.P. Bowena,*
aDepartment of Chemistry and Biochemistry, 435 New Science Building, PO Box 26170, University of North Carolina at
Greensboro, Greensboro, NC 27402, bCenter for Biomolecular Structure and Dynamics, Department of Chemistry,
University of Georgia, Athens, GA 30602-2556, cDepartment of Dermatology, Emory University School of Medicine,
5007 Woodruff Memorial, Building, Atlanta, GA 30322 and dDepartment of Chemistry, Emory University, Atlanta, GA
30322

Abstract: Cancer is a general term used to describe many disease states, each of which are characterized by abnormal cell
proliferation. The causes which bring about this abnormal cellular behavior are specific to each type of cancer. The
success of tumor-targeted therapy is limited by this diversity. One common denominator for all types of cancer is the
requirement of a suitable blood supply. Therefore, tumor vasculature has emerged as a potential target for therapeutic
intervention. New blood vessel growth from preexisting vasculature stimulated by biochemical signals is termed
angiogenesis. Tumor masses require a constant supply of oxygen and nutrients, and a means of efficient waste removal to
ensure sustained development. Diffusion from nearby capillaries can supply adequate nutrition for tumors less than 2 mm
in size, but for continued growth the tumors must develop their own blood supply. Alteration of the delicate balance of
angiogenic stimulating factors and angiogenic inhibitors results in the phenotypic change from quiescence to active
endothelial proliferation. To date, this angiogenic switch is not completely understood. The goal of antiangiogenic therapy
is to interfere with these mechanisms and prevent tumor cells from developing a viable blood supply. Fumagillin is a
naturally occurring antifungal agent. Curcumin is a natural product isolated from the spice turmeric. Both compounds
have been shown to have antiangiogenic properties in vitro and in vivo. This paper describes efforts to design and prepare
fumagillin and curcumin analogs and evaluate their corresponding antiangiogenic activities.
Key Words: Angiogenesis inhibitors, curcumin analogs, fumagillin analogs, SVR assay.
INTRODUCTION
today is at risk of developing some form of cancer, and, for
those individuals who do, a staggering 65% will not survive
From the beginning of recorded civilization various
at the present mortality rates.
diseases and epidemics have posed a constant threat to
humankind. Each period of human history has had specific
Since cancer is not a single disease and each person has a
diseases that were especially feared. Some diseases seem-
unique genetic makeup, there are many different treatment
ingly have even threatened society itself. While there have
options available. Choosing the most effective medical
been significant strides in preventing and curing many ill-
approach to use in a given situation is a function of the
nesses in the late 20th and early 21st centuries, many serious
patient, the particular type of cancer, and its degree of
and life threatening diseases still exist. While all of the life-
progression at the time of its detection. Surgery is the oldest
threatening diseases that strike an individual are tragic,
and most widely used method for the successful treatment of
cancer continues to invoke a particular fear in our society.
cancer [2]. This approach involves surgical removal of the
tumor, which is usually quick and effective if diagnosed
In reality, cancer is not one disease but a group of closely
early. Over the years, the improvements in surgical
related diseases, each of which is characterized by abnormal
techniques, anesthesiology, and the control of infection have
cell growth. The causes of this abnormal cell growth are
benefited cancer patients. Surgery, however, has several
specific to each type of cancer, and the success of tumor-
important disadvantages. First, it is an invasive procedure.
targeted drug therapies are limited because of this diversity.
Second, the removal of a visible tumor does not guarantee
Despite the significant and impressive advances in the medi-
elimination of small microscopic tumor extensions [2].
cal sciences, current statistics indicate that approximately
Third, as a result of these extensions, surgeons usually have
one out of every six deaths in the United States is caused by
to excise a substantial amount of surrounding healthy tissue.
cancer [1]. Cancer mortality rates are second only to cardio-
Such radical surgeries may severely impair the patient’s day-
vascular disease. Nearly one in every four Americans living
to-day functioning or appearance. Fourth, surgery may not
even be a viable option if a tumor encloses a vital organ [3].
Fifth, perhaps one of the biggest shortcoming of the surgical
*Address correspondence to this author at the Department of Chemistry and
removal of a tumor relates to potential metastasis, where the
Biochemistry, 435 New Science Building, PO Box 26170, University of
cancer cells have already spread (metastasized) throughout
North Carolina at Greensboro, Greensboro, NC 27402, USA;
E-mail: jpbowen@uncg.edu
the body.
1381-6128/05 $50.00+.00
© 2005 Bentham Science Publishers Ltd.

358 Current Pharmaceutical Design, 2005, Vol. 11, No. 3
Furness et al.
Radiation treatment, a noninvasive therapy, is preferable
as much as by the total mass of the tumor [6]. There are
to surgery in many situations because it can destroy a tumor
several different classes of antineoplastic drugs (chemo-
effectively while inflicting minimal damage to the surround-
therapeutic agents). Each of them utilizing a distinct
ing healthy tissue [4]. In addition, normal tissue can recover
mechanism of action.
from radiation exposure more quickly than tumor cells. X-
The alkylating agents were the first class of antineo-
rays or gamma rays are used to irradiate the region of the
plastic drugs developed [7]. In the 1940s scientists noticed
body where the cancerous tumor exists. Most commonly,
that mustard gas (used in World War I) interfered with the
irradiation methods result in genetic damage sufficient to
growth of cancer cells [8]. The reactivity of mustard gases is
either kill cells directly or indirectly by inducing cellular
a function of the heteroatom and the availability of the lone
suicide (apoptosis) [5]. Radiation treatments have an
pair of electrons to undergo an internal nucleophilic attack
advantage over surgery in that the small microscopic
on the beta carbon, which is bonded to a halogen. Nitrogen
extensions of cancerous tissue surrounding a tumor that
mustards, as opposed to the sulfur mustards used as chemical
might have been missed otherwise are destroyed. Hospital-
warfare agents, are less reactive. As a result of this observa-
ization is normally unnecessary, so radiation is a much more
tion, mechlorethamine (1) was developed as a chemothera-
attractive option for older patients who might experience age
peutic agent as outlined in Fig. ( 1). The mechanism of action
related difficulties in recovering from surgery.
of these compounds is the covalent attachment of the alkyl
Several crucial shortcomings regarding radiation therapy
groups to DNA strands, which in turn produce defects in the
must not be overlooked. One potential concern is that
normal double helical structure of the molecule [9].
radiation can fail to completely eradicate all the cancer cells
The disruption of the DNA strands may take the form of
of a tumor, which is also a concern regarding the surgical
breaks and inappropriate links between strands. Unless DNA
removal of tumors [4]. Radiation therapy is essentially a
repair mechanisms correct the damage, cellular suicide is a
localized event. Consequently, the procedure cannot treat
likely outcome. Mechlorethamine has significant biological
widespread metastases that will eventually develop into
activity, but it is also a highly reactive electrophile and an
tumors at distant sites. Finally, repeated or prolonged expo-
indiscriminate DNA alkylating agent. Second generation
sure to all forms of ionizing radiation has been demonstrated
nitrogen mustards are less reactive, and, as a result, are safer
to cause cancer under the “right” conditions. Therefore, the
and easier to use (relatively speaking). The most widely used
inherent limitations of this method of treatment need to be
alkylating agents are cyclophosphamide (2) and chlor-
carefully considered.
ambucil (3), shown in Fig. (2).
Clearly, as noted above, the choice of the specific clinical
The development of less reactive nitrogen mustards can
approach for treating the patient is a function of the specific
be argued as an early example of rational drug design. As
type of cancer, the condition of the patient, and stage of the
discussed above, the reactivity of the nitrogen mustards is a
disease. In many cases, a combination of surgery and
function of the availability of the lone pair of electrons. The
radiation therapy is desirable and complements each other
less available the electron pair, the slower the reaction
quite effectively. Given that surgery and radiation do not
becomes. Transforming the tertiary nitrogen from an
provide effective treatments for cancer that has already
apliphatic amine into a compound wherein the electrons are
spread to distant parts of the body, the administration of
delocalized via resonance and/or inductive effects, reduces
systemic anticancer agents (chemotherapy) may be used. In
the availability of the lone pair of electrons and consequently
general, the history of drug therapy has had spectacular
the reactivity. Consequently, new drugs were designed based
successes and heartbreaking tragedies. Compared to surgery
on this reasoning.
and radiotherapy, chemotherapy is not limited by metastasis
Cl
H3 C N
H
N
3 C
Nucleophilic attack
on unstable aziridine
Cl
by DNA bases
Cl
mechlorethamine (1)
Fig. (1).
Cl
Cl
HO
N
N
Cl
2C(H2C)3
O
P
O
Cl
NH
cyclophosphamide (2)
chlorambucil (3)
Fig. (2).

Antiangiogenic Agents
Current Pharmaceutical Design, 2005, Vol. 11, No. 3 359
One successful stratagem in the physician’s armamen-
marrow and gastrointestinal toxicity. Hair loss and skin
tarium of anticancer agents has been the idea of introducing
rashes are also common while taking these medications.
compounds that interfere with and arrest the proper
Another class of drugs that react with DNA directly is the
functioning of the cellular machinery of cancer cells. One
DNA-intercalating agents [7]. These compounds are flat
class of chemotherapeutic agents serves as false substances
aromatic or heteroaromatic substances. They initiate their
in the biochemical reactions of living cells, and are therefore
biological activity by inserting themselves in-between the
known as anti-metabolites. These medicinal agents have a
stacked base pairs of DNA. A combination of hydrophobic
much narrower spectrum of activity than other antineoplastic
effects, hydrogen bonding, electrostatics, charge transfer,
agents. Perhaps the most well-known example in this class of
and London dispersion forces are responsible for their
agents is methotrexate (4), which is a close chemical analog
binding affinity. Ethidium bromide (8) and proflavine (9),
of the nutrient dihydrofolic acid (5), which is critical in the
Fig (5), have the requisite structural features and are
complex, but well understood, steps of the biosynthetic
effective intercalating agents. Once intercalated, the structure
pathway. See Fig. (3). Consequently, methotrexate prevents
of the surrounding DNA is perturbed. It is now believed that
cells from dividing by inhibiting their ability to biosyn-
intercalation is only the first step in the overall mechanism of
thesize new DNA. During the 1980s, significant effort by
action and that subsequent interactions with topoisomerase I,
computer-assisted drug design (CADD) scientists was
for example, as well as other enzymes, are responsible for
focused on structure-based design applications of DHF
the observed anti-tumor activity.
inhibitors [10].
O
CO
NH
2H
2
NH2
N
CO
H
2H
N
Br
N
N
N
H2N
CH2CH3
CH3
H
N
N
2N
H
H
N
NH
2N
2
methotrexate (4)
ethidium bromide (8)
O
CO
proflavine (9)
2H
Fig. (5)
OH
N
CO
H
2H
N
A fourth group of compounds, closely associated with
N
N
intercalating agents, is the topoisomerase inhibitors. Replica-
H
tion of cellular genetic material requires a way of dividing
H
N
N
2N
H
the DNA double helix into two separate strands. This separa-
dihydrofolic acid (5)
tion is accomplished most typically with the topoisomerase
enzyme that cleaves one strand, passes the other strand
Fig. (3).
through the break, and reattaches the severed ends [13].
Another interesting antimetabolite useful in cancer
Drugs that inhibit the ability of topoisomerase enzymes to
chemotherapy is 5-fluorouracil, 5-FU, (6), which is a pyrimi-
reattach the broken ends cause pervasive DNA strand breaks.
dine analog of uracil (7), that inhibits thymidylate synthase,
When this happens in cells that are dividing quickly, the
Fig. ( 4). The substitution of a fluorine for a hydrogen atom
consequence is cellular death. Of this class, doxorubicin
in the 5-position of uracil yields an analog that is unable to
(10), Fig (6), is possibly the most important anticancer drug
have a positively charged fluorine, F+, abstracted in a critical
available because of its broad spectrum of activity [14].
step in the biosynthetic mechanism. Hence, 5-FU is an
Unfortunately, its use may result in serious side effects in the
irreversible inhibitor that takes advantage of a crucial step in
heart, lung, and gastrointestinal tract.
the methylation of uracil.
Several promising analogs of doxorubicin have been
shown to have impressive clinical activity and less cardio-
H
H
toxicity [15]. One of these analogs, the anthracenedione
N
O
N
O
mitoxantrone (11) shown also in Fig. (6), has been approved
for use in the treatment of nonlymphocytic leukemia.
NH
NH
F
Mitoxantrone also causes less nausea, vomiting, and hair loss
than does doxorubicin [16]. Furthermore, it is only slightly
O
O
less active than doxorubicin when used as a single agent for
metastatic breast cancer [7].
5-fluorouracil (6)
uracil (7)
The last family of antineoplastic agents discussed here is
Fig. (4).
comprised of the antimitotic agents. Some examples of this
Every drug has toxic side effects and even unexpected
particular class of compounds are the complex bis-indole
adverse events. Unfortunately, 5-fluorouracil [11], like
alkaloids derived from Vinca rosea Linn., which have well
methotrexate [12], has been shown to have devastating bone
established roles in the contemporary treatment of cancer.

360 Current Pharmaceutical Design, 2005, Vol. 11, No. 3
Furness et al.
O
OH
O
HO
H
OH
N
OH
O
HN
OH
CH
O
3O
OH
O
OH
O
HN
OH
H3 C
O
N
H
NH2
doxorubicin (10)
mitoxantrone (11)
OH
Fig. (6).
These include vincristine (12) and vinblastine (13), Fig (7).
ANGIOGENESIS AND ANTIANGIOGENIC COM-
These compounds prevent cell division as a result in binding
POUNDS
to the protein tubulin [4]. This protein forms fibers that help
It is readily apparent that the majority of antineoplastic
to coordinate cell division. These fibers pull duplicated DNA
drugs now available for internal tumors often give rise to
chromosomes to either side of the cell, which ensures that
side effects so harmful that they compromise the benefits of
each new cell has a full set of DNA. These drugs interfere
treatment. As a result, these side effects impose a limit on
with the assembly of tubulin fibers, which prevents cells
the doses that physicians can administer. Although strategies
from dividing successfully [17]. Like all of the agents listed
for eliminating these side effects are being developed,
so far, these bis-indole alkaloids have deleterious side
classical chemotherapy has another inherent weakness. Just
effects, most notably neurotoxicity. Certain types of
like bacteria can become resistant to antibiotics, tumors are
vincristine administration have produced devastating results,
becoming increasingly able to survive the anticancer drugs
including seizures, coma, and even death [18].
used to treat them [9]. Certain tumors have been resistant
from the outset, whereas others develop resistance upon
CH
repeated treatments. This is a major clinical problem, as
2CH3
some tumors can develop resistance to multiple drugs after
N
OH
only one drug has been administered to the patient. Although
R = CHO Vincristine (12)
improving existing drugs keeps the medical community one
step ahead of resistance emergence, drug rejuvenation is
R = CH3 Vinblastine (13)
unfortunately threatened in the long term by the same
N
CO2CH3
resistance emergence factors that plagued its predeccesors
H
[23]. The most promising long term solution to the problem
is the introduction of new antineoplastics into clinical use
N
with novel structures that would be much more difficult for
tumors to impede via resistance.
H3CO
H
CH3
R
O
N
2O
OCOCH
OH
H
3
R
OH
O
O
OCOCH
H
3
R
O
Fig. (7).
1
N
H
O
OH
H
Another class of antimitotic agents is the taxels, which
OH
O
OCH3
are plant alkaloids such as paclitaxel, Taxol, (14) and doce-
taxel, Taxotere (15), displayed in Fig. (8). These compounds
O
were isolated from the bark of the Western yew tree in 1971
by Wani and Wall [19]. The taxels differ from the vinca
alkaloids in that they promote rather than inhibit microtubule
R
formation. Pictures taken of paclitaxel treated cells shows
1 = Ph, R2 = Ac Taxol (14)
R
the presence of polymerized, irregular tubulin, which
1 = O-t -Bu, R2 = H Docetaxel (15)
prevents cell division [20]. After its introduction into clinical
Fig. (8).
trials, Taxol was approved for treatment of ovarian cancer in
1992 [21]. The only serious side effect of paclitaxel is its
One of the most promising new approaches to cancer
bone marrow toxicity, although this rapidly reverses itself
chemotherapy is the use of angiogenesis inhibitors. In 1971,
within 15-21 days [22]. Mild muscle pain may be experi-
Judah Folkman proposed that tumors require a blood supply
enced occasionally several days after administration.
to grow from a small, clinically apparent nodule to an

Antiangiogenic Agents
Current Pharmaceutical Design, 2005, Vol. 11, No. 3 361
invasive tumor capable of metastasis [24]. A corollary of this
stimulate angiogenesis through G-protein-coupled receptors
hypothesis is that tumors generate factors that stimulate
(Edg1, 3, 5), and G-protein activation may synergize with
ingrowth of host blood vessels (proangiogenic factors). A
tyrosine kinase activation (bFGF, VEGF) to promote
second corollary of this hypothesis is that cells undergoing
angiogenesis.
malignant transformation gradually acquire the ability to
The isolation of angiogenic stimulators also enabled in
produce proangiogenic factors. A final corollary of this
vitro analysis of potential angiogenesis inhibitors. The first
hypothesis is that compounds that inhibit angiogenesis may
inhibitor to be discovered was interferon alpha. It was
be useful, especially in combination with chemotherapy,
discovered that interferon alpha was able to inhibit endo-
radiation, and surgery, to treat cancer. Since 1971, all of
thelial migration, a potential rate limiting step in angioge-
these have proven true in both animals and humans, and
nesis. This led to the first clinical trials of interferon for
angiogenesis inhibition is proving to be a rich source of
hemangiomas of infancy, a benign neoplasm that can be life
potential therapeutics.
threatening when it compromises vital organs or causes high
Proving the first hypothesis required the isolation of
output cardiac failure.
microvascular endothelial cells. Prior to the development of
Several observations led to the development of the
the ability to culture endothelial cells from small vessels, the
angiogenic switch concept. First, in a transgenic model of
primary source of endothelium was from human umbilical
cancer, mice engineered to develop tumors in the islet cells
veins (HUVECS). It was soon realized that HUVECS are
of the pancreas were noted to have high levels of the
biologically different than small vessel (microvascular) endo-
angiogenic stimulator VEGF prior to the development of
thelium in that angiogenesis occurs in major part through
malignant tumors. Despite this, the density of vessels only
stimulation of small vessel endothelium rather than large
increased with increasing tumor growth, leading to the
vessel endothelium. More recently, it has been recognized
development of the concept of a balance between endo-
that endothelium from different organs have characteristics
genous angiogenesis stimulators and inhibitors. Second,
that persist long after they have been removed from the
Arbiser et al. [28] demonstrated that introduction of onco-
body. For example, brain endothelium is critical to the blood
genic ras, which is mutated in up to 40% of human cancers,
brain barrier (BBB), and expresses high levels of P glyco-
causes upregulation of proangiogenic factors such as VEGF
protein, that excludes lipophilic molecules (and chemothera-
and matrix metalloproteinases, and downregulation of the
peutic agents) from entering the brain. Endothelium derived
endogenous tissue inhibitor of matrix metalloproteinases.
from endocrine organs (adrenals, pancreatic islets) are
Finally, loss of tumor suppressor genes such as p53 was
fenestrated, and they have enhanced responses to endocrine
noted to cause upregulation of VEGF, and conversely, rein-
derived angiogenic factors. Arterial and venous endothelium
troduction of tumor suppressor genes result in downregu-
have transcription factors and receptors that can be used to
lation of VEGF. Thus, while early tumors may upregulate
differentiate them. Finally, endothelium can be derived from
angiogenic factors such as VEGF, rapid tumor growth does
bone marrow stem cells, and can be recruited to the site of
not occur until the relative proportion of angiogenesis stimu-
injury or tumors by a variety of factors. Tumors may rely on
lators exceeds the production of angiogenesis inhibitors.
local angiogenesis or recruitment of bone marrow precursors
to varying extents, and this may account for differing
Based upon the clinical observation that excision of a
responses to various therapeutic agents.
large primary tumor in patients sometimes results in the
rapid development of metastases, Folkman proposed that
The isolation of microvascular endothelium made it
large tumors may produce endogenous inhibitors. These
possible to assay for factors that stimulate endothelial survi-
endogenous inhibitors may suppress distant metastases.
val and growth. The first factor isolated was basic fibroblast
Removal of the large tumor resulted in the activation of
growth factor (bFGF) [25], which is a potent mitogen for
metastases through the removal of angiogenesis inhibitors.
endothelium. The second factor to be isolated was vascular
O’Reilly et al . [29] found a mouse tumor that exhibited the
endothelial growth factor (VEGF) [26], a polypeptide
same behavior, which led to the isolation of two angio-
generated by alternate splicing to form peptides of 121, 165,
genesis inhibitors, angiostatin and endostatin. Angiostatin is
and 189 amino acids. While bFGF is a potent mitogen,
a proteolytic fragment of plasminogen, a serum protein, and
VEGF is perhaps the most potent endothelial chemoattrac-
endostatin is a fragment of collagen XVIII. These proteins
tant, stimulating endothelial cells to migrate in a directional
are generated through proteolytic cleavage of native proteins
manner. VEGF was initially discovered as a potent vascular
by tumor or stroma derived enzymes. Remarkably, these
permeability factor (VPF), which stimulates blood vessels to
proteins exhibit activity specifically against endothelium
leak, a common finding in tumors.
cells, and not against other normal or tumor cells. Thus these
Subsequently, a number of other ligands have been shown
angiogenesis inhibitors are called direct inhibitors, as they
to stimulate angiogenesis, and these ligands, consisting of
act directly on endothelial cells and not on tumor cells.
both small molecules and peptides, interact with either
In addition to direct angiogenesis inhibitors, pharmaco-
tyrosine kinase receptors or G-protein-coupled receptors to
logic interventions can decrease production of angiogenesis
stimulate angiogenesis [27]. Corticotropin releasing hormone
stimulators such as VEGF, bFGF, CRH, matrix metallopro-
(CRH) is a 41 amino acid peptide that acts with G-protein-
teinases, or increase (the) production of angiogenesis inhibi-
coupled receptors to stimulate endothelial chemotaxis, and is
tors such as interferons and tissue inhibitors of matrix
generated by inflammatory disorders and tumors. Overex-
metalloproteinases. Since these inhibitors may act on tumor
pression of CRH stimulates tumorigenesis in animal models.
cells rather than endothelial cells (but inhibit angiogenesis),
Other factors such as sphingosine-1 phosphate (S1P) also
they are known as indirect angiogenesis inhibitors. Many of

362 Current Pharmaceutical Design, 2005, Vol. 11, No. 3
Furness et al.
these pharmacologic interventions inhibit signaling mechan-
include proliferation, migration towards sources of growth
isms that are constitutively activated in tumors. These
factors, increased survival promoted by growth factors,
signaling pathways include phosphoinositol 3-kinase, mito-
remodeling of basement membranes, and investment by
gen activated protein kinase (MAP kinase), reactive oxygen
smooth muscle. There are various in vivo assays of angio-
signaling, and nuclear factor kappa beta (NFkB). Other
genesis currently in use, including the chicken chorioallan-
pharmacologic interventions include inhibiting the function
toic membrane, zebrafish embryonic development, corneal
of receptors that stimulate the above pathways. Among the
micropocket assay, and inhibition of tumor growth in mice
drugs that inhibit these signaling pathways are glucocor-
remain the most common. The SVR endothelial cell
ticoids, which inhibit NFkB, PS-341, a specific inhibitor of
proliferation assay has been used as a broad spectrum assay
NFkB, antioxidants such as N-acetylcysteine.
for angiogenesis inhibitors, including the compounds listed
below. The SVR assay can detect multiple events such as
Inhibitors of receptors include gleevec (16), Fig. (9),
inhibition of endothelial cell proliferation and survival, as
which was initially developed to inhibit the nonreceptor
well as inhibiting indirect angiogenesis by blocking
tyrosine kinase bcr-abl, but also inhibits receptor tyrosine
production of VEGF in the transformed endothelial cells.
kinases (e.g., platelet derived growth factor receptor beta and
the c-kit receptor. Other inhibitors include iressa (17), Fig.
(9), which inhibits epidermal growth factor receptor (EGFR).
ANGIOGENESIS INHIBITORS
Several angiogenesis inhibitors [31-33] have been repor-
ted, but all of these agents have shown problems with regard
CH3
to efficacy and toxicity. Ingber et al. [34], however, showed
N
CH
that fumagillin (18), shown in Fig. (10), a commercially
3
H
available compound with antibiotic properties, demonstrated
N
N
N
potent anti-angiogenic activity. The only important side
effect that limited prolonged administration was a 10 to 15%
N
reduction in the body weight of the host. With this small
molecule lead, efforts have been undertaken to modify the
HN
structure. Several chemical modification schemes [35-37]
were pursued to obtain analogs retaining the potent anti-
N
O
angiogenic properties of fumagillin while minimizing the
side effects. The most notable of these analogs was TNP-
Gleevec (imatinib mesylate) (16)
470, AGM-1410, (19). Fumagillin is similar in structure to
another natural product, ovacilin (20).
F
The other analogs that were prepared in these modifica-
tion studies replaced the polyene carboxylic side chain [35],
O
HN
Cl
the methoxy side chain [36], and the spiro-epoxide [37] of
N
O
fumagillin. There have been no modifications of the unsubs-
N
tituted positions on the cyclohexane ring or the epoxyene
side of fumagillin. Therefore, we began a synthesis of bicy-
H
N
3CO
clic fumagillin analogs in an effort to obtain leads retaining
potent antiangiogenic activity and minimizing any toxic side
Iressa (gefitinib) (17)
effects. Once it was decided that bicyclic analogs were the
initial goal of this project, the next important steps were the
Fig. (9).
synthetic preparation of the desired target compounds and
the biological testing. Before the synthetic and biological
ASSESSMENT OF ANGIOGENESIS INHIBITORS
assays are discussed, it is necessary to review the thinking
Angiogenesis is a multistep process that can be inhibited
behind the design of the target molecules.
at multiple points [30]. Steps involved in angiogenesis
O
O
O OH
O
O
OCH
OCH
3
O
3
H
O
CO
OCH3
2H
O
N
Cl
O
O
O
O
Fumagillin (18)
TNP-470 (19)
Ovalicin (20)
Fig. (10).

Antiangiogenic Agents
Current Pharmaceutical Design, 2005, Vol. 11, No. 3 363
DESIGN OF BICYCLIC FUMAGILLIN ANALOGS
active site. Thus, fumagillin forms a covalently bound
complex. The opening of the spiro-epoxide confirmed our
When the project described herein was undertaken in the
initial suspicions that this functional group was critical for
mid 1990s, there were no x-ray data available for classic
binding. Fig. (13) is a close-up view of fumagillin bound to
structure-based drug design. Subsequent x-ray crystallagra-
the active site, where the active site functional groups are
phic studies by Clardy at Cornell [38] of fumagillin bound to
displayed with a solid surface.
the target protein, methionine aminopeptidase-2 (MetAP-2),
have justified the ligand-based approach initially undertaken.
Through standard molecular graphics methods, using the
Sybyl molecular modeling program, fumagillin was removed
Previous efforts by other research groups had been
from the binding cavity and 23, as well as related analogs,
limited to side chain and functional group modifications of
was docked into the active site and adjusted to maximize the
fumagillin. In examining the structure of fumagillin, the
fit. See Fig. (14). Gratifyingly, it turned out that our second
spiro-epoxide ring was presumed to play a critical role in the
assumption was also valid: the additional ring did not
binding process. As a necessary part of any pharmacophore,
interfere with any of the MetAP-2 residues. In fact, a very
it was determined to keep this or an equivalent electropilic
nice fit between the active site and the proposed small
functional group in any small molecule targets designed.
molecule targets was predicted. Fig. (15) shows the spiro-
Thus, the working hypothesis adopted was that (1) the spiro-
epoxide bicyclic ketal and fumagillin molecular structures
epoxide or similar functional group was essential for
superimposed.
biological activity and (2) the binding site would be able to
tolerate extra steric bulk. Without any additional experimen-
PREPARATION OF BICYCLIC FUMAGILLIN
tal data, assumptions (1) and (2) were used as a simple
ANALOGS
working pharmacophore model. Given there were no reports
of ring-altered fumagillin analogs, it seemed reasonable to
Fig. (16) outlines the retrosynthetic analysis envisioned
investigate multiple ring analogs of fumagillin. It should be
for the preparation of analogs of 22 and 23. The synthetic
noted that everyone involved in the conception of this
approach undertaken begins with a Diels Alder reaction,
project was aware that a new ring system could interfere
whereby the bicyclic ring system can be rapidly assembled.
with the receptor. That is to say, the new hydrocarbon
In order to test our retrosynthetic strategy to prepare
portion of the analogs could compete with the residues of
these functionalized bicyclic systems, it was necessary to
MetAP-2 for common space and render the proposed analogs
prepare the appropriate reagents for the key Diels Alder
less effective. Instead of having a single cyclohexane ring, it
transformation. As shown in Fig. (17), the commercially
was determined to explore bicyclic (all carbon rings)
available o-vanillin (25) is converted into the desired
fumagllin analogs initially, Fig. (11). The ultimate target was
dienophile in two steps following a modified literature
a compound that replaced the six-membered ring with a
procedure by Dawson and Ng [39]. The first step was an acid
decalin ring system (21). Structure 21 incorporated the
catalyzed hydrogenation of 25 to yield 26. Oxidation with
necessary structural features present in fumagillin but with a
potassium nitrosodisulfonate (Fremy’s salt) [40] afforded the
decalin ring system core. Another similar analog that could
desired benzoquinone (27) in 80% yield.
be prepared more readily was the spiro-epoxide decalin ketal
(22) and a more simplified ketal analog (23) that did not
Similarly, the desired diene can be prepared in three steps
have the epoxide side chain.
using procedures reported by Oida and Ohki [41], as outlined
in Fig. ( 18). Knoevenagel condensation of malonic acid (29)
During the course of the synthetic preparation of
and acrolein (28) gave vinyl acrylic acid (30), which was a
compound 23 and related analogs, as discussed above, an x-
bright yellow solid [42]. Without purification, the crude acid
ray crystal structure of fumagillin bound to MetAP-2 was
30 was immediately converted into the corresponding methyl
determined [38]. Prior to the publication of this work, we
ester (31) using classical Fisher esterification conditions.
were kindly provided the data. Fig. (12) shows fumagillin
Reduction of methyl 2, 4-pentadienoate (31) with lithium
bound to MetAP-2. The x-ray, 1.8 Å resolution, of both the
aluminum hydride easily produced the desired 2, 4-
free and inhibited MetAP-2 convincingly demonstrated that
pentadienol (32). It should be noted that these dienes and
the spiro-epoxide had undergone a ring-opening reaction via
their acetate derivatives can cause an allergic reaction in
a nucleophilic attack by a histidine residue (His-231) in the
some individuals resulting in blistering.
O
O
O
O
O
OCH3
OCH
OCH
O
CO
3
3
2H
OCH
O
3
OCH3
O
O
Bicyclic Fumagillin Analog (21)
Bicyclic Fumagillin Ketal (22)
Simplified Bicyclic Fumagillin Ketal (23)
Fig. (11).

364 Current Pharmaceutical Design, 2005, Vol. 11, No. 3
Furness et al.
Fig. (12).
Fig. (13).

Antiangiogenic Agents
Current Pharmaceutical Design, 2005, Vol. 11, No. 3 365
Fig. (14).
Fig. (15).

366 Current Pharmaceutical Design, 2005, Vol. 11, No. 3
Furness et al.
O
O
R
R
OCH3
OCH
OCH
3
3
O
OCH3
O
24
37
O
OCH3
OCH3
O
34
O
O
+
OCH3
H3 C
OCH3
O
O
HO
OH
33
32
27
Fig. 16. Retrosynthetic analysis of the bicyclic fumagillin analog (24).
OCH
OCH
OCH
3
3
3
OH
a
OH
b
O
CHO
CH3
O
CH3
25
26
27
Fig. 17. Synthesis of 2-methoxy-6-methyl-[1,4]-benzoquinone (27).
(a) H2, Pd/C, EtOAc, H2SO4 (cat.) (b) Fremy’s Salt / H2O, NaOEt, CHCl3
O
CO2H
a
b
c
+
H
CO2H
CO2H
CO2CH3
CH2OH
28
29
30
31
32
Fig. 18. Synthesis of 2,4-pentadienol (32).
(a) Pyridine, 80°C (b) CH3OH, H+ (c) LAH, ether, 0°C

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