Bio-inspired synthesis and biological evaluation of a colchicine-related compound library

Article abstract of DOI:10.1016/j.bmcl.2012.04.007

A bio-inspired investigation of the reactions of substrates of type 1 with VOF₃ and PIFA [phenyliodine(III) bis(trifluoroacetate)] led to a collection of colchicine-like compounds 2-5 and related systems. Biological evaluation revealed that som

Full text of DOI:10.1016/j.bmcl.2012.04.007

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3776–3780
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Bio-inspired synthesis and biological evaluation of a colchicine-related
compound library
K.C. Nicolaou a,b,c, , Roman A. Valiulin a, Jonathan K. Pokorski a, Vicki Chang a, Jason S. Chen a
⇑
a Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
b Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
c Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A bio-inspired investigation of the reactions of substrates of type 1 with VOF3 and PIFA [phenyliodine(III)
bis(trifluoroacetate)] led to a collection of colchicine-like compounds 2–5 and related systems. Biological
evaluation revealed that some of the synthesized products had significant cytotoxic properties against
the colon cancer cell line HT-29.
Received 8 March 2012
Accepted 2 April 2012
Available online 7 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Bio-inspired synthesis
Colchicine-like compounds
Natural products
Oxidative coupling
Anti-cancer agents
The continuous unraveling of nature’s molecular diversity has
led to an impressive number of medications for the treatment of
disease.1,2 Natural products have served directly as therapeutics
or lead compounds for the discovery of clinically used drugs3 as
well as myriad of biological tools.4,5 Important pharmaceuticals
originating from natural sources are used in various capacities,
including as pain killers, anti-infectives, immuno-suppressants,
and anti-cancer drugs.
and an oxidative phenol–phenol coupling, respectively.8 However,
the conversion of isoandrocymbine to demecolcine and thence col-
chicine (IV to V and VI) is more complex and rather speculative
(see Scheme 1).8 These complexities are reflected in the fact that
a biomimetic total synthesis of colchicine still has not been
Colchicine, a natural product used for the treatment of acute
gout disease, has been the focus of numerous investigations as a
potential anti-cancer drug.6 Its potent cytotoxicity (IC50 = 0.008
l
M against HT-29, human colon adenocarcinoma)7 makes colchi-
cine an intriguing chemotherapeutic candidate. However, a lack
of selectivity has prevented it, thus far, from being an approved
medication for cancer patients. As part of our program of creating
molecular diversity as inspired by natural products and their bio-
syntheses, we investigated a number of synthetic pathways to col-
chicine-like and related compounds. Herein we report the
synthesis of a library of bio-inspired compounds, and their biolog-
ical evaluation as cytotoxic agents.
Scheme 1 summarizes the postulated biosynthetic pathway
leading from dopamine (I) and phenol aldehyde (II) to demecolcine
(V) and thence colchicine (VI) via (S)-autumnaline (III) and (S)-iso-
androcymbine (IV). The first two enzymatic transformations of
(I + II to III) and (III to IV) are well understood as a Pictet-Spengler
Scheme 1. Postulated biosynthesis of demecolcine (V) and colchicine (VI) from
dopamine (I) and phenol aldehyde (II). Colors indicate atoms joining to form the
corresponding C–C bond. The complex skeletal rearrangement from IV to V or VI
can be found in Ref. 8.
⇑
Corresponding author. Tel.: +1 858 284 2400; fax: +1 858 284 2469.
E-mail address: kcn@scripps.edu (K.C. Nicolaou).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.007

K. C. Nicolaou et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3776–3780
3777
Figure 1. Possible oxidative pathways depicted in retrosynthetic format to
compounds 2–5 from substrates 1.
Scheme 3. Reaction of compound 1e with vanadyl trifluoride (VOF3). Synthesis of
compounds 2e, 10a,b, 11a–j,j0. Reagents and conditions: (a) VOF3, TFA–TFAA–CH2Cl2
(10:1:100), 0–25 °C, 3 h, 1e ? 10a (9%) plus 11a (17%); (b) VOF3, TFA–TFAA–CH2Cl2
(75:1:0), 0–25 °C, 6 h, 1e ? 2e (46%) plus 11a (27%); (c) VOF3, TFA–TFAA–
CH2Cl2 (10:1:150), 0–25 °C, 16 h, 1e ? 11a (49%); (d) AcCl, Et3N, CH2Cl2, 0 °C,
0.5 h, 11b (64%); (e) CyC(O)Cl, Et3N, CH2Cl2, 0 °C, 0.5 h, 11c (88%); (f) PhC(O)Cl, Et3N,
CH2Cl2, 0 °C, 0.5 h, 11d (94%); (g) MeOC(O)Cl, Et3N, CH2Cl2, 0 °C, 0.5 h, 11e (54%); (h)
2,2,2-trichloroethyl chloroformate, Et3N, CH2Cl2, 0 °C, 0.5 h, 11f (77%); (i) PhOC(O)Cl,
Et3N, CH2Cl2, 0 °C, 0.5 h, 11g (56%); (j) 1,10-thiocarbonyldiimidazole, Et3N, CH2Cl2,
25 °C, 1 h, 11h (39%); (k) MsCl, Et3N, CH2Cl2, 0 °C, 0.5 h, 11i (74%); (l) Tf2O, Et3N,
CH2Cl2, ꢀ78 °C, 0.5 h, 11j (37%) plus 11j0 (51%). TFA, 2,2,2-trifluoroacetic acid; TFAA,
trifluoroacetic anhydride; Cy, cyclohexyl; Bz, benzoyl; Troc, 2,2,2-trichloroethoxy-
carbonyl; C(S)imid, thionoimidazolide.
reported.6 Thus, while the non-enzymatic conversion of (I + II to
III) has been demonstrated in the laboratory, not all the subse-
quent steps have been reported as yet by chemical means.9 Our
studies were, therefore, focused on finding conditions to realize
useful pathways for the formation of colchicine-like structures
and related scaffolds starting from substrates 1 (Fig. 1), which
are derivatives of autumnaline (III). The four possible tetracyclic
structural motifs 2–5 were expected to be formed oxidatively from
1, as shown in Figure 1 (see color code).
Scheme 2 summarizes the results of our investigations of the
reaction of the readily available substrates 1a–f (synthesized by
standard methods; see Supplementary data)8,10 with VOF3–TFA–
TFAA, an approach previously reported by Kupchan and co-work-
ers.10d,11 At the outset of our work, the potential of this reaction
to produce novel molecular diversity was still considered to be
high because of the limited number of products and biological data
reported by Kupchan et al.10d,11 Indeed, under two different sets of
conditions [(a) or (b)] a variety of additional products were ob-
tained as shown in Scheme 2. Thus, under conditions (a) [VOF3,
TFA–TFAA, CH2Cl2, 0–25 °C] several new compounds were isolated:
2a (22% yield from 1a); 8c (7% yield) plus 9c (6% yield) from 1c; 2d
(17% yield) plus 7d0 (5% yield) plus 9d (7% yield) from 1d; 2e (46%
yield)10d,11 plus 11a (27% yield) from 1e; and 2f (<2% yield) plus 7f
(23% yield)10d,12 plus 8f (<2% yield) from 1f. At lower temperatures,
Scheme 2. Reactions of compounds 1a–f with vanadyl trifluoride (VOF3). Synthesis
of compounds 2a,b,d–f, 7a,b,d0,e,f, 8c,f,f0,f00 and 9a,c,d. Reagents and conditions: (a)
VOF3, TFA–TFAA (10:1), CH2Cl2, 0–25 °C, 0.5–3 h, 1a ? 2a (22%); 1c ? 8c (7%) plus
9c (6%); 1d ? 2d (17%) plus 7d0 (5%) plus 9d (7%); 1e ? 2e (46%) plus 11a (27%);
1f ? 2f (<2%) plus 7f (23%) plus 8f (<2%); (b) VOF3, TFA–TFAA (10:1), CH2Cl2, ꢀ20 to
0 °C, 0.5–1 h, 1a ? 2a (22%) plus 9a (7%) plus 7a (<2%); 1b ? 2b (34%) plus 7b (7%);
1e ? 7e (11%); (c) AcCl, Et3N, CH2Cl2, 0 °C, 0.5 h, 8f0 (50%); (d) PhOC(O)Cl, Et3N,
CH2Cl2, 0 °C, 0.5 h, 8f00 (58%); (e) 1a ? 7a (17%), ꢀ10 °C, 0.3 h; (f) 1b ? 7b (19%),
ꢀ30 to ꢀ10 °C, 0.8 h; (g) 7d ? 7d0 through C-ring expansion (see Supplementary
data); (h) 8f can be formed from 1f with PIFA in refluxing benzene or via a skeletal
rearrangement from 3f (Scheme 4) in the presence of a Lewis acid (BF3ꢁEt2O in
CH2Cl2) or a protic acid (p-TsOH in AcOH) (see Supplementary data). TFA, 2,2,2-
trifluoroacetic acid; TFAA, trifluoroacetic anhydride.

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K. C. Nicolaou et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3776–3780
Scheme 5. Synthesis of compounds 5a–e. Reagents and conditions: (a) BnBr or MeI,
K2CO3, acetone, reflux, 2 h; (b) LiAlH4, DME, 0 °C, 1 h; (c) HCOOH–H3PO4 (2:1),
100 °C, 7–20 h, 13 ? 5a (19%); 13 ? 5c (38%) plus 5d (14%); (d) AcCl, Et3N, CH2Cl2,
0 °C, 0.5 h, 5b (80%); 5e (70%). Bn, benzyl; DME, 1,2-dimethoxyethane.
Scheme 4. Reaction of compounds 1a–f with phenyliodine(III) bis(trifluoroacetate)
(PIFA). Synthesis of compounds 3a–f,e0 and 4a–e,c0,e0. Reagents and conditions: (a)
PIFA, CH2Cl2, 0–25 °C, 0.5–2 h, 1a ? 3a (13%); 1b ? 3b (35%); 1c ? 3c (14%) plus
4c0 (9%); 1d ? 3d (5%) plus 4d (7%); 1e ? 3e (8%) plus 3e0 (6%) plus 4e (<2%);
1f ? 3f (25%); (b) PIFA, benzene, 80 °C, 0.5–1 h, 1a ? 4a (12%), 2.4 h; 1b ? 4b
(<2%); 1c ? 4c (22%), 0.5 h; 1d ? 4d (<2%); 1e ? 4e (10%) plus 3e (<2%) plus 3e0
(<2%); (c) AcCl, Et3N, CH2Cl2, 0 °C, 0.5 h, 4e0 (83%). TFA, 2,2,2-trifluoroacetic acid.
conditions (b) [ꢀ20 ? 0 °C], the VOF3 reaction yielded compounds
2a (22% yield) plus 9a (7% yield) plus 7a (<2% yield, this compound
was obtained in 17% yield under different conditions, see Scheme
2) from 1a; 2b (34% yield) plus 7b (7% yield, this compound was
obtained in 19% yield under different conditions, see Scheme 2)
from 1b; and 7e (11% yield) from 1e.10d Since we were primarily
interested in generating molecular diversity rather than any partic-
ular compound, no further attempts were made to improve the
selectivity of this reaction.
Scheme 6. Reaction of isoquinoline 13 with PIFA. Preparation of compound 17 and
proposed mechanism of its formation from 13 via 11a. Reagents and conditions: (a)
PIFA, CH2Cl2, 0–25 °C, 1 h, 11a (11%) plus 17 (7%). TFA, 2,2,2-trifluoroacetic acid.
VOF3 [TFA–TFAA–CH2Cl2, 10:1:100, conditions (a)] at 0–25 °C for
3 h furnished scaffolds 10a (9% yield) and 11a (17% yield). Carrying
out the same reaction in neat TFA–TFAA [75:1, conditions (b)] led to
the isolation of 2e in 46% yield and 11a in 27% yield. Modifying
Hoping to synthesize additional novel products from substrate
1e, we explored its reaction with VOF3 under three additional sets
of conditions [(a), (b) and (c), Scheme 3]. Thus, treatment of 1e with

K. C. Nicolaou et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3776–3780
3779
Figure 2. Cytotoxicity of synthesized compounds against HT-29 cancer cells. HT-29 cells were grown in RPMI-1640 media supplemented with 10% newborn calf serum (NCS),
and maintained at 37 °C with 5% CO2 and 95% air. Cells were plated in a 96-well plate (5 ꢂ 103 cells/well) 24 h prior to incubation with the indicated compound. The media
was then replaced with fresh media containing varying concentrations of the indicated compound. Following a 96-h incubation, MTT (5 mg/mL, 25
lL/well) was added and
incubation was continued at 37 °C for 1–2 h (or until formazan crystals were visible in control wells). Media was carefully aspirated and DMSO was added (200
lL/well) to
dissolve the purple MTT-formazan crystals. The absorbance of the dissolved formazan was quantified at 570 nm using UV–vis plate reader and cell viability was determined
as a fraction of absorbance relative to untreated control wells. Each experiment was performed in triplicate and individual data points are presented as averages standard
deviation. This figure shows examples of compounds with high (IC50 <1 lM; red), medium (IC50 <10 lM; blue), low (IC50 <50 lM; black) and negligible (IC50 more than 50 lM
or n.d., not determined) anti-HT-29 activity. Bn, benzyl; Bz, benzoyl; Cy, cyclohexyl; Troc, 2,2,2-trichloroethoxycarbonyl; C(S)imid, thionoimidazolide; MTT, 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.
these conditions further [TFA–TFAA–CH2Cl2, 10:1:150 for 16 h,
conditions (c)] afforded 11a in 49% yield. Derivatives 11b–j were
prepared from 11a by standard procedures as summarized in
Scheme 3. Compounds 10b and 11j0 were also formed as shown
in Scheme 3, the latter as a major byproduct of the reaction of
11a with trifluoromethanesulfonic anhydride (Tf2O).
We then examined the reaction of substrates 1a–f with pheny-
liodine(III) bis(trifluoroacetate) (PIFA)13 from which a number of
new molecular scaffolds were isolated as shown in Scheme 4. Thus,
exposure of tetrahydroisoquinolines 1a–f to PIFA in CH2Cl2 at
0 ? 25 °C led to products 3a (13% yield) from 1a; 3b (35% yield)
from 1b; 3c (14% yield) plus o-quinone 4c0 (9% yield) from 1c; 3d

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K. C. Nicolaou et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3776–3780
(5% yield)9 plus 4d (7% yield) from 1d; 3e (8% yield)10d,11 plus 3e0
(6% yield) plus 4e (<2% yield) from 1e; and 3f (25% yield) from
1f.8,9,12,14 Changing the solvent from CH2Cl2 to benzene and heating
at 80 °C, the PIFA reaction with 1a–f mostly favors the formation of
motif 4, producing 4a (12% yield) from 1a; 4b (<2% yield) from 1b,
among a complex mixture of other products; 4c (22% yield) from
1c; 4d (<2% yield) from 1d; and 4e (10% yield) plus 3e (<2% yield)
plus 3e0 (<2% yield) from 1e. Derivative 4e0 (83% yield) was pre-
pared from 4e as indicated in Scheme 4. The formation of products
3a–f is presumed to proceed via either the addition–elimination
pathway13d,e (intermediate 12a), or the phenoxenium ion path-
way13d,e (phenoxenium ion 12b and its resonance counterpart—
carbenium ion 12c) as demonstrated in Scheme 4. The generation
of compounds 4a–e is assumed to proceed through fleeting inter-
mediates 12b, 12c and 12d (1,4-quinomethine) (Scheme 4).
Supplementary data
Supplementary data contains experimental procedures, cell via-
bility studies and NMR spectra. Supplementary data associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2012.04.007.
References and notes
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Compounds 5a–e were prepared from isoquinoline 1315 as
summarized in Scheme 5. Thus, benzylation or methylation of 13
(K2CO3, BnBr or MeI) and subsequent reduction with lithium
aluminum hydride (LAH) gave rather labile derivative 14a or
14b. Heating the latter compounds in the presence of HCOOH–
15
H3PO4 led, through presumed iminium species 15, to 5a (19%
overall yield) from 13, 5c (38% overall yield) plus 5d (14% overall
yield) from 13. Acetylation of 5a and 5d led to derivatives 5b
(80% yield) and 5e (70% yield), respectively.
Scheme 6 summarizes the reaction of isoquinoline 13 with
PIFA leading first to the previously mentioned (see Scheme 3) tet-
racyclic product 11a (11% yield) and thence to pentacyclic
compound 17 (7% yield from 13). This process is believed to pro-
ceed through intermediates 16a, 16b, and 16c as depicted in
Scheme 6.
Colchicine exerts its cytotoxic activity through tubulin binding
that disturbs the tubulin-microtubule equilibrium.6 As we men-
tioned before, colchicine is highly potent against the colorectal
adenocarcinoma cell line HT-29. The synthesized colchicinoid
and related compounds were, therefore, assayed for cytotoxicity
against HT-29 cancer cells using the MTT assay [3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide]. The so obtained
IC50 values are shown in Figure 2, together with that found for col-
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11e, 11f, 11g, and 11h exhibited the highest cytotoxic activity in
this assay (IC50 values = 0.132–0.684 M, in red). Compounds 2a,
2e, 4c0, 5a, 8c, 10b, 11c, and 11d exhibited lower potencies (IC50
values = 0.99–9.10 M, in blue), while the rest of the compounds
lM) for comparison. Compounds 10a, 11a, 11b,
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l
l
showed either low activity (IC50 values <50
lM, in black) or their
activity was not determined (n.d., in black).
The bio-inspired investigation of the reactions of autumnaline
derivatives 1a–f led to series of novel colchicine-related
a
compounds. Biological evaluation of these compounds identified
several agents with significant cytotoxicity against HT-29 cancer
cells. Among them, the most potent ones were compounds 11a,
11b and 11e–h. These results suggest these molecular scaffolds
as leads for further studies aiming at new biological tools and
potential therapies for the treatment of cancer.
Acknowledgements
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We thank Drs. D.H. Huang and L. Pasternack for NMR spectro-
scopic assistance, Dr. G. Siuzdak for mass spectrometric assistance
and Dr. E. Hamel for helpful discussions. Financial support for this
work was provided by the Skaggs Institute for Research and the
National Institutes of Health, USA (Grant AI055475). We are grate-
ful to the NSF for a predoctoral fellowship (to V.C.), Merck for a
postdoctoral fellowship (to R.A.V.), and NIH for a Pathway to Inde-
pendence Award (K99EB011530; to K.P.).
15. (a) Stermitz, F. R.; Williams, D. K. J. Org. Chem. 1973, 38, 2099; (b) Pabuccuoglu,
V.; Hesse, M. Heterocycles 1997, 45, 1751.