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Punganuru et al., Med chem (Los Angeles) 2016, 6:3
http://dx.doi.org/10.4172/2161-0444.1000341
Medicinal chemistry
Research Article
Open Access
Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor
Heterogeneity
Surendra R Punganuru, Hanumantha Rao Madala and Kalkunte S Srivenugopal*
Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
Abstract
The axiomatic tumor heterogeneity of human cancers reflecting a differential genetic, phenotypic and functional
makeup of cells within a single tumor and between tumors of its kind poses a great challenge to chemotherapy. The
combination chemotherapy regimens, despite having several drugs with dissimilar cytotoxic mechanisms have not
been successful in eliminating the drug resistance. Therefore, innovative strategies of designing more effective cancer
drugs that can impact two or more targets and trigger synergistic cytocidal events are gaining attention. Recently,
there has been a lot of interest in developing colchicine derivatives with higher efficacy and lower toxicity. Here, we
summarize the hybrid drug development incorporating the colchicine pharmacophore with drugs such as the vorinostat
(SAHA), cobalamin, adamantine, pironectin, triazoles and the established vinca and taxols as well. Cathepsin-cleavable
colchicine composite drugs and conjugates with algal metabolites have also been developed. The cytotoxic activity
mechanisms of these drugs and their interactions with tubulin are described. Since colchicine is also useful in treating
many other disorders, the composite drugs also bear a repurposing potential.
Keywords: Colchicine; Cancer chemotherapy; Hybrid drugs;
Microtubule inhibitors; Drug resistance
Introduction
Most human cancers are characterized by a high level of
heterogeneity in their genetic make-up due to random and multiple
molecular alterations in many cellular pathways governing their
genetic stability, cell cycle progression, apoptosis and angiogenesis
[1,2]. The molecular pathways of tumorigenesis, DNA damage and
alterations of target genes can vary greatly within a defined tumor and
among the specimens of the same tumor type [3]. Tumor heterogeneity
results in mixed populations of malignant cells, some of which are
drug-sensitive while others are drug-resistant. Chemotherapy kills
drug-sensitive cells, but leaves behind a higher proportion of drugresistant cells. Therefore, the chemotherapy regimens almost always
involve anticancer drugs belonging to different classes and mechanisms
of actions to allow for additive or synergistic effects on the tumor.
However, many of these treatments still lead to the emergence of drug
resistant cells and marginal response rates in a large number of cancers
[3,4]. A pharmaceutical combination of several drug molecules also
raises challenges such as the extent of bioavailability, pharmacokinetics,
metabolism and drug interactions [5,6]. Therefore, a new strategy on
the development of hybrid agents, which comprise the incorporation
of two or more pharmacophores into a single molecule, has gained
much attention [7]. The aim of this approach is to target multiple
pathological processes involved in human malignancies simultaneously
by integrating the structural requirements from selective ligands into
a single molecule that can span multiple targets [8]. As stated in the
Abstract, simultaneous or near simultaneous hits on more than one
target is likely to be beneficial in providing superior anticancer efficacies.
Microtubules are cytoskeletal filaments consisting of α,β- tubulin
heterodimers and are involved in a wide range of cellular processes
such as organization of cell shape, transportation of vesicles,
mitochondria, and other cellular organs, cell signaling, cell division
and mitosis [9,10]. Microtubules play a key role in mitosis separating
the daughter chromosomes and constitute a strategic target in cancer
treatment [11]. The search for selective inhibitors of tubulin assembly
or disassembly has led to the development of some of the most useful
antitumor drugs currently in clinical use. These tubulin targeting
drugs are broadly classified as microtubule-stabilizing drugs (taxanes
1 and 2) and microtubule-destabilizing drugs (vinca alkaloids 3 and
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4) (Figure 1) [12]. There are three ligand binding sites in the tubulin
α/β-heterodimer: paclitaxel binding site [13] vinblastine binding site
[14,15] and colchicine binding site [15].
Colchicine (5), a well-known bioactive alkaloid and a prototype
microtubule disrupting drug is not clinically used to treat cancer [16],
because of its overbearing systemic toxicity that produces unacceptable
side effects when administered intravenously [17]. However, the
antiproliferative effects of colchicine through the inhibition of
microtubule formation, leading to mitotic arrest, antivascular
disruption, and cell death by apoptosis, together with its inherent water
solubility, commercial availability and low cost have renewed interest in
modifying this molecule and developing less toxic hybrid compounds
incorporating the colchicine nucleus.
Colchicine-Vinca Alkaloid Hybrids
Polyvalent interactions are characterized by the simultaneous
binding of multiple ligands on one biological entity (a molecule, a
surface) to multiple receptors on another [18]. These interactions
can be cooperatively much stronger than corresponding monovalent
interactions. Combination into a single molecule of two identical or
different structural entities or fragments of well-known biologically
active natural products or synthetic drugs with the aim of either
increasing the potency of the parent compounds or combining
complementary actions has remained a viable strategy [19].
Consequently, a series of novel hybrid compounds (9-11) were
prepared by attaching the thiocolchicine with anhydrovinblastine (7),
vinorelbine (8), and vindolines (6) using two types of diacyl spacers
(Figure 2) [20]. Influence on the tubulin polymerization was studied
with these hybrid drugs and found to be more active when compared
*Corresponding author: Kalkunte Srivenugopal, Department of Biomedical
Sciences, TTUHSC School of Pharmacy, Amarillo, TX 79106, USA, Tel: +1(806)
414-9212; Fax: +18063564770; E-mail: [email protected]
Received March 11, 2016; Accepted March 26, 2016; Published March 29, 2016
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based
Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem (Los
Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
Copyright: © 2016 Punganuru SR, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Volume 6(3): 165-173 (2016) - 165
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
R1
OH
= Ph,
OH
OH
N
NH O
O
R1
O
R 2O
O
R2 =
H
N
H
O
O
OHO O
O
O
O
CH3CO : Paclitaxel 1
N
H3CO
H H
N
O
R
OH
O
O
O
O
H3CO
NH
OCH3
O
Colchicine 5
R = CHO: Vincristine 3
R = CH3: Vinblastine 4
R1 = tert-C4H9O, R2 = H : Docetaxel 2
Stabilizing agents
O
OCH3
Destabilizing agents
+
-
Figure 1: Structures of tubulin stabilizing and destabilizing agents.
N
NH
O R
H3CO
N
H
MeOOC
N H OHCOOMe
R = COCH3 6
O
n
OCH3
N
H
OCH3
O
H3CS
n=29
n = 8 10
N
H
MeOOC
N H OHCOOMe
O
N H OHCOOMe
H
R
OCH3
O
N
O
R = COCH3 7
R=H8
NH
H3CO
NH
H
OCH3
NH
O
O
N H OHCOOMe
11
O
OCH3
2 N
H
OCH3
O
H3CS
Figure 2: Structures of colchicine-vinca alkaloid hybrid compounds.
to the parent compounds. The results of this study indicated that the
length of the spacer is crucial and compounds 9 and 11 with succinic
acids displayed potent activity.
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Colchicine-HDAC Inhibitor Hybrids
Histone deacetylases (HDAC) play crucial roles in a number of
biological processes through their repressive influence on transcription
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Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
[21]. Histone deacetylase inhibitors are a diverse group of smallmolecule drugs that induce a broad range of effects on cancer cells,
including cell cycle arrest, apoptosis, cell differentiation, autophagy and
anti-angiogenic effects [22-25]. There are 11 members in the classical
HDAC family, and different subtypes play distinct roles. A typical
HDAC inhibitor consists of a capping group, a metal-binding moiety
and an appropriate linker. Over twelve HDAC inhibitors are currently
in clinical trials for different cancers. Among them, vorinostat (SAHA)
(12) and romidepsin (FK228) (13) have been approved by the FDA for
the treatment of cutaneous T-cell lymphoma [26]. Dual inhibitors of
HDACs and other targets remain intensively studied areas to overcome
tumor recurrence, metastasis and drug resistance. Reports of synergistic
antitumor effects of HDAC and antimitotic agents [27] led to design
colchicine-SAHA hybrids by the incorporation of a zinc binding
hydroxamic acid moiety to the colchicine [28]. Such dual inhibitors of
tubulin and histone deacetylases were evaluated for HDAC inhibition as
well as cytotoxicity in five different cancer cell lines. Length of the linker
was systematically varied to determine the most suitable molecule.
All the hybrids (15a-e) displayed potent HDAC inhibition activity,
suggesting that colchicine moiety is an appropriate capping group
for the HDAC inhibition (Figure 3). Appropriate linker length might
contribute to the binding of the hydroxamic acid segment with a zinc
ion at the bottom of the active site. SAHA-like segment introduction
to the colchicine did not hamper tubulin inhibition activity. Among
the conjugates prepared, compound 15a showed the strongest HDAC
inhibitory activity as well as powerful antiproliferative activity on five
cancer cell lines tested. The same research group further designed
and synthesized a new series of colchicine-HDAC dual inhibitors
by attaching a benzamide moiety to the colchicine as an HDAC zinc
binding group [29]; the resulting compounds were evaluated for their
inhibitory activity against HDAC, tubulin polymerization as well as
their effects on cell cycle and cell viability. Results indicated that most of
these hybrids with colchicine moiety as HDAC capping group exhibited
potent HDAC inhibitory activity. Compared with molecules equipped
with unsubstituted benzamide ZBG, hybrids with bis(aryl)-type
ZBG showed good HDAC inhibitory activities. Among the different
compounds prepared, 16 displayed the potent anti-HDAC activity
which was comparable with mocetinost (14). Further, the introduction
of HDAC pharmacophore into the colchicine core did not affect its
anti-tubulin activity. Compounds 16, 20 and 23 displayed similar antitubulin activity similar to colchicine. Compound 23 with powerful
tubulin inhibitory activity and moderate anti-HDAC activity showed
superior cytotoxicity compared with the positive control compound
Linker
N
H
O
H3CO
Recently, Malysheva et al. synthesized new colchicine-tubulizine
antimitotic bivalent ligands connected by flexible spacers [30]. The
colchicine binding site includes 239Cysb of b-tubulin [31], while
tubulizine interacts with 12Cysb of the same protein molecule and
12Cysb is known to be a part of the exchangeable GTP-binding site
[32]. These heterodimers were prepared by linking of azide-containing
deacetylcolchicine and acetylene-substituted tubulizine entities using
copper-mediated 1,3-dipolar cycloaddition (Figure 4). The cytotoxic
activity of the synthesized heterodimers with several different linker
lengths was investigated toward HBL100 human mammary cell line,
and all the prepared compounds exhibited substantial cell killing
(IC50 = 0.599 - 2.93 mM). Than deacetylcolchicine, but more active
when compared to tubulizine. Analysis of the structure-activity
relationship for synthesized hybrids (27 a-j) showed that their ability
for microtubule destabilization decreases based on the linker length
and cytotoxic activity depends on hydrophobicity of the molecule. The
highest activity among the heterodimers was achieved for ligand 27e
(IC50 = 0.687 ± 0.013 mM). The reported modular synthesis and simple
‘click’ chemistry methodology make it useful to expand the bivalent
hybrid library by generating a variety of new members.
Tubulin binding molecules (TBMs) bind on either b-tubulin or
b-tubulin modules to disrupt the microtubule dynamics and block
mitosis. TBMs that bind to β-tubulin are by far more abundant, and
interestingly, function to both disrupt and stabilize the microtubules.
The TBMs include colchicine, vinca alkaloids and taxol derivatives,
which all bind to β-tubulin, albeit at different sites within the protein
moiety [33]. Nevertheless, a few compounds are known to bind
to a-tubulin and the first reported compound were the naturally
occurring 5,6-dihydro-α-pyrone (pironetin) [34]. Pironetin (29) is
a potent inhibitor of tubulin assembly and was found to arrest cell
cycle progression in the G2/M phase [35]. Vilanova et al. in 2014 have
prepared a set of hybrid molecules containing a colchicine moiety and
a fragment structurally related to the natural product pironetin (30, 31)
[36]. Two such structural moieties were connected through a spacer
of variable lengths containing an ester and an amide group. Cytotoxic
activities of all these compounds (32-42) and the interactions of some
of them with tubulins were examined. Almost all the compounds
displayed potent cytotoxicity against the cancer cells tested (HT29 and
MCF7), however, were less toxic when compared to parent molecules
O
OH
N
N
H
H
N
NH2
N
N
O
ZBG
12
NH2
H
N
O
ZBG
13
N
H
14
ZBG
X
O
HN
O
n
H3CO
H3CO
Colchicine-Tubulizine Hybrids
O
O
H
N
Capping group
(IC50 2-105 nM).
OCH3
H3CO
O
HN OH
15a n = 1
15b n = 2
15c n = 3
15d n = 4
15e n = 5
O
HN Y
H3CO
H3CO
OCH3
O
N
H
NH2
Y: CH2
16 para-, X=H
17 para-, X=thienyl
18 meta-, X=H
19 meta-, X=thienyl
Y: C=O
20 para-, X=H
21 para-, X=thienyl
23 meta-, X=H
24 meta-, X=thienyl
Figure 3: Structures of colchicine-HDAC inhibitor hybrids.
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Volume 6(3): 165-173 (2016) - 167
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
R
O
H3CO
O
HN
N
N
H
H3CO
H3CO
H3CO
5
O
H3CO
N
Click-chemistry
Z
N
N
H
N
O
HN
N
OCH3
nNH
N
H3CO
O
OCH3
Tubulizine site
ligand
O
O
HN
N
N N
N
Colchicine site
ligand
26 Tubulizine B, R = cyclo-C6H11
N
N
Tubulizine site
ligand
+
N
H
25 Tubulizine A, R = i-Pr
N
H
H3CO
N
N3
OCH3
OCH3
H3CO
Colchicine site
ligand
NH
N
H
N
N
O
O
O
z
OCH3
NH
OCH3
N
H
OCH3
OCH3
OCH3
OCH3
27 a - j Z = CH2 or (CH2)mC(O)O(CH2)2
28 Z = 10
m = 2, 3, 4, 8, 15
Figure 4: Structures of colchicine-tubulizine hybrids and the strategy of hybridization.
colchicine and pironetin. Further, it was found that the binding of
these compounds to tubulin was strongly influenced by the length of
the connecting spacer and explained the reasons for the less potency
when compared to parent molecules. If the distance between the
pironetin and the colchicine ends is small (short spacer), the sterically
bulky colchicine moiety hinders the hybrid molecules from arriving
at the pironetin binding site. Consequently, the reversible binding
at the colchicine site still takes place, though with a reduced affinity.
For longer spacers, the steric hindrance to enter the pironetin site is
lower, and the molecules may be able to bind covalently at that site.
Subsequently, the same research group in another study investigated the
effect of these hybrid molecules on the expression of VEGF, hTERT and
c-myc genes [37]. Tumor angiogenesis is a complex process involving
a tight interplay of the vascular endothelial growth factor (VEGF) with
many other factors [38]. VEGF promotes endothelial cell survival,
proliferation and migration while increasing vascular permeability.
VEGF Overexpression occurs in various cancer [39]. Similarly, the
hTERT and c-myc are also overexpressed and relate to the activation
of telomerase in human cancers [40]. The authors considered that all
three genes are of vital importance in the carcinogenesis and malignant
progression, and analyzed their downregulation after treatment with
pironetin-colchicine hybrid molecules.
It was found that the hybrid molecule (34), which has a ten-carbon
spacer, was best in inhibiting the expression of the VEGF, hTERT and
c-Myc genes. Compound 42, with the same spacer length but with a
different pironetin analogue fragment, had a similar VEGF inhibitory
activity but was less active in inhibiting the expression of the hTERT
and c-Myc genes. Compounds 33 and 36, which have a short spacer,
were similarly to 32 and 42 in inhibiting VEGF secretion but were much
less active in curtailing the expression of the telomerase-related gene
(Figure 5).
Caulerpenyne–colchicine Hybrids
In another effort, Bourdron et al. synthesized Caulerpenyne–
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colchicine hybrids and evaluated their effects on tubulin polymerization
and angiogenesis [41]. Caulerpales, marine algae produce
sesquiterpenoids and diterpenoids such as caulerpenyne (43), flexiline
(45), dihydrorhipocephaline (46), and crispatenine (45) with a common
functional group of 1,4-diacetoxybutadiene for its chemical defense
[42]. The 1,4-Diacetoxybutadiene moiety represents an acetylated bisenol form of the 1,4-dialdehyde constellation, to which a high degree
of biological activity was attributed [43]. It was reported that these
compounds share the antiproleferative activity along with inhibition
if tubulin polymerization. Two hybrids A and B (47 and 48) were
synthesized and the strategy for the design of hybrid A was justified by
its perfect superimposition with colchicine in which all heteroatoms
or basic functions overlap. Replacement of bis-allylic acetate functions
by a thio- or amino-moiety during binding with the amino acids
of the tubulin led to the design of hybrid B (Figure 6). These hybrid
compounds, however, inhibited the tubulin polymerization weakly
despite showing potent cytotoxicity against the HaCaT keratinocyte
cells.
Glycorandomized Colchicine Analogs
Sugars appended to pharmaceutically important natural products
are known to influence drug solubility, pharmacology, target recognition,
toxicity, and mechanism of action [44]. However, studies designed
to systematically understand and exploit the role of carbohydrates
in drug discovery are often limited by the availability of practical
synthetic tools (Figure 7a). To address these problems, Ahmed et al.
have reported two complementary strategies namely chemoenzymatic
glycorandomization and neoglycorandomization that allow for the
rapid glycosylation of natural product scaffolds [45]. Utilizing these
methods, they have successfully prepared glycorandomized colchicine
analogs (49). Interestingly, some of these modified colchicines, while
not significantly cytotoxic by themselves, they increased the cell
killing effects of either colchicine or paclitaxel through unknown
mechanisms [45].
Volume 6(3): 165-173 (2016) - 168
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
O
OMe OH
O
O
O
OMe
OMe OH
O
C5H11
C5H11
30
pironetin 29
H3CO
O
O
H3CO
N
H
H3CO
31
H3CO
n O
H3CO
O
OCH3
34 n = 10 35 n = 14
36 n = 3
37 n
=6
39 n
= 14
38 n = 10
H3CO
H3CO
O
O
33 n = 6
H3CO
n O
N
H
O
32 n = 3
O
O
H3CO
O
O
OCH3
O
O
OMe OH
O
41 n = 6
40 n = 3
O
O
O
n O
N
H
42 n = 10 42 n = 14
OCH3
Figure 5: Structures of pironetin, its fragments and colchicine- pironetin hybrids.
AcO
AcO
OAc
OAc
OAc
Caulerpenyne 43
OAc
R
Crispatenine 44
R = H; Flexiline
46
R = OAc; Dihydrorhipocephaline
O
OCH3
O
Hybrid A 47
OAc
H3CO
O
O
O
OAc
45
O
H3CO
H3CO
AcO
H3CO
OAc
AcO
OCH3
Hybrid B 48
Figure 6: Structures of Caulerpenyne-colchicine hybrids.
Colchicine and Adamantine Hybrids
The well-established structure activity relationship studies of taxol
revealed that the most important contribution for its tubulin binding
is provided by the N-benzoyl or N-tertiarybutoxycarconyl-(2R,3S)-
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phenylisoseryl side chain [46]. The main function of the taxane skeleton
is to provide proper orientation of the substituent important for tubulin
binding [47]. Based on this hypothesis, Zefirova et al. synthesized a
series of analogues by combining an adamantane-based paclitaxel
mimetic with colchicine and tested for cytotoxicity in a cell-based
Volume 6(3): 165-173 (2016) - 169
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
assay with the human lung carcinoma cell line A549 (Figure 7a) [48].
Compound 50 was found to be highly cytotoxic with an IC50 of 2 nM and
it interfered with the microtubule dynamics in an interesting fashion.
Cell treatments with these hybrid compounds promoted disassembly
of microtubules followed by the formation of stable tubulin clusters.
Structure–activity relationships revealed the presence of adamantine
(or another bulky hydrophobic and non-aromatic moiety) was found to
play a role in clustering the protein. Structural requirements for optimal
activity were partially explained with the aid of molecular modeling in
this study.
The structure-activity relationship of combretastatins (53) [50]
and colchicine (5) such as bis-aryl system with two aromatic rings or
an aromatic ring and a tropolone ring linked via two carbon bridge
(Figure 8) [51] are well defined. Based on these observations, Andres
et al. synthesized combretatropones comprising of 1,2-diaryl ethane
nucleus of combretastatin and the tropone moiety of colchicine.
Combretatropone (54) exhibited potent activity in the in vitro inhibition
of tubulin polymerization.
Colchicine Dipeptide Conjugated Prodrugs
Interestingly, the microtubule inhibitor combinations such as the
colchicine and paclitaxel given together have been shown to yield
results unlike those obtained with either inhibitor alone [52]; The
cooperative interaction of the microtubule inhibitors in this context is
not well understood (Figure 9).
Practical anticancer medicines derived from colchicines have not
been developed so far because of their toxicity to normal cells. To address
this problem, many groups have tried to develop colchicine derivatives
with improved potency and reduced toxicity. Recently, Yasobu et al.
prepared novel colchicine derivatives having various substituents at
the C4 position and found that 4-halo derivative (51) exhibited higher
activity against cancer cell lines (A549, HT29, HCT116) as well as in
mice transplanted with the HCT116 human colorectal carcinoma cell
line than colchicine (Figure 7b) [49]. Further, utilizing the 4-substituted
colchicines, they have prepared pro-drugs (52) with a dipeptide side
chain and demonstrated that these prodrugs were activated by cathepsin
B, a lysosomal protease enzyme overexpressed in tumor cells, which
exhibited selective toxicity against the tumor cells.
Colchicine-combretastatin Hybrids: Combretatropones
O
N OCH
3
O
H3CO
Click chemistry is an efficient approach for the synthesis of diverse
compounds based on a handful of “near-perfect” (very selective,
modular, high-yielding, wide in scope) carbon–heteroatom bond
O
HO
NH
O
H3CO
F
H3CO
Ph
H3CO
O
O
NH
N
H
O
O
OCH3
Prodrug
Boc
50
Cbz
NH
Fragmentation
F
NH2
H3CO
OCH3
NH2
52
OH
N
H
O
H3CO
OCH3
Ph
Figure 7b: Structure of a colchicine - adamantine hybrid.
Cleavage by cathepsin B
O
O
O
OCH3
Figure 7a: Structure of a glycorandomized colchicine analog.
O
O
O
H3CO
OCH3
49
H
N
H3CO
H3CO
H3CO
These observations encouraged Bombuwala et al. to synthesize
colchitaxel containing both colchicine and paclitaxel structures
with the combination of depolymerizing and stabilizing agents [53].
Previous studies suggested that the acetamide linkage on ring B could
be replaced by other alkyl amides with little change in potency [54].
Moreover, colchicine with an altered B ring still bound to the tubulin
[55]. Alteration of the C-7 site on paclitaxel similarly had little or no
inhibitory effect on its biological activity. Colchitaxel was prepared by
attaching B ring amine of the colchicine C-7 hydroxyl group of taxol
using glutamate linker. Colchitaxel (55) had some of the same effects on
microtubules as the combination of starting compounds. It also caused
shortening and fragmentation of the + end protein cap. More studies
are required to characterize the microtubule dynamics and consequent
changes in cell shape and growth in cells treated with colchitaxel.
Triazole Functionalized Colchicine Derivatives
OH
O
The Development of Colchitaxel
O
OCH3
51
Figure 7c: Structure of a colchicine and dipeptide hybrid which undergoes fragmentation in the presence of cathepsin B.
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Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
H3CO
OH
H3CO
H3CO
NHAc
H3CO
H3CO
H3CO
O
OH
OCH3
OCH3
OCH3
5
H3CO
OCH3
O
OCH3
53
54
Figure 8: Structure of combretatropone synthesized from colchicine and combretastatin.
OCH3
O
O
O
O
O
O
O
Ph
O
O
OH
H
N
O
O
OCH3
O
O
H3CO
O
HO
OCH3
O
O
55
Figure 9: Structure of colchitaxel.
forming reactions [56]. In the few years since its discovery, the Cucatalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) has been
established as one of the most reliable means of click chemistry for the
covalent assembly of complex molecules. It has enabled a number of
applications in synthesis, medicinal chemistry, molecular biology, and
materials science [57]. Thomopoulou et al. synthesized a series of novel
colchicinoids (55-69) with a variable triazole unit in the place of amide
through Cu(I)-catalyzed 1,3-dipolar cycloaddition (click-chemistry) of
a colchicine-derived azide with various alkynes (Figure 10) [58]. These
compounds were evaluated for their cytotoxicity against THP-1 and
Jurkat cancer cell lines. Three particularly active compounds (64-66)
(IC50 ≤ 5 nM) were further investigated in terms of their efficacy against
relevant solid tumor cell lines (HeLa, A549, and SKMES 1). Besides
distorting the microtubule morphology by tubulin depolymerization,
69 also exhibited a pronounced centrosome declustering effect in the
triple negative breast cancer cells (MDA-MB-231) and non-small cell
lung cancer cells (H1975).
It should be noted that we did not include the combretastatin A4and vinca-based microtubule disruptors in this review. CA4 binds to
the colchicine site on tubulin to inhibit polymerization and exert potent
cytotoxicity against a variety of human cancer cell lines and also is
noted for its tumor-disrupting properties [59]. The activity of CA4 is
hampered by isomerization of the active cis-stibene configuration into
the corresponding inactive trans analog; a huge effort has gone into the
development of stabilized CA4 –like compounds locked in its cis-form.
Recently, we designed and developed C-7 arlylated piperlongumine
derivatives, which conferred a combretastatin A4 like structure while
Med chem (Los Angeles)
ISSN: 2161-0444 Med chem (Los Angeles), an open access journal
retaining the piperlongumine configuration [60]. Novel agents such as
the spiroketal pyrans (SPIKET), targeting the spongistatin binding site
of beta-tubulin, and COBRA compounds, targeting a unique binding
cavity on alpha-tubulin continues to be discovered [61].
Conclusion
The Hybrid drugs composed of rationally incorporated two
or more drug pharmacophores in to single molecules are basically
designed to interact with multiple targets and amplify the cytotoxic
actions through action on another bio target or counterbalance the
known adverse effects associated with one of the hybrid partners. The
present review summarized the designs and strategies employed for
the synthesis of colchicine-based composite anticancer agents. Tubulin
dynamics remains a highly promising target for new chemotherapeutic
agents. The colchicine binding site is one of the most important pockets
for potential tubulin polymerization destabilizers. A large number of
molecules with significant structural diversity that interact with the
colchicine binding site have been synthesized, and the continuing efforts
in this area reflect the promise and interest in this research area. Many of
the colchicine-hybrid structures described here including the HDACinhibitor composites, and the cathepsin-targeted antimicrotubule
prodrugs appear very potent and their effects on microtubule dynamics
and anticancer activities need to be tested and validated in tumor
xenograft models. Furthermore, since colchicine is also used in the
treatment of gout, arthritis and relief for hypersensitivity reactions, the
hybrid drugs noted here, at least some of them, may have non-cancer
Volume 6(3): 165-173 (2016) - 171
Citation: Punganuru SR, Madala HR, Srivenugopal KS (2016) Colchicine-Based Hybrid Anticancer Drugs to Combat Tumor Heterogeneity. Med chem
(Los Angeles) 6: 165-173. doi:10.4172/2161-0444.1000341
N N
N
H3CO
H3CO
RHN
O
O
56
57
58
59
O
OCH3
OCH3
R = Boc
R = Ac
R = Cbz
R=H
NH
S
60 R = Boc 61 R = Boc
OCH3
O
64 R = Boc
63 R = Boc
N N
N
H3CO
H3CO
62 R = Boc
N N
N
H3CO
O
n
O
H3CO
O
OCH3
OCH3
O
O
OCH3
R
65 n = 0
68 F = ortho
66 n = 1
69 F = meta
70 F = para
67 n = 2
Figure 10: Structures of triazole functionalized colchicine derivatives.
applications as well.
Acknowledgements
This work was supported by grants from the Cancer Prevention Research
Institute of Texas (RP130266), the Carson-Leslie Foundation and the Association
for Research of Childhood Cancer, all to K.S.S.
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