Synthesis and evaluation of a series of C5′-substituted duocarmycin SA analogs

Article abstract of DOI:10.1016/j.bmcl.2010.03.078

The synthesis and evaluation of a key series of analogs of duocarmycin SA, bearing a single substituent at the C5′ position of the DNA binding subunit, are described.

Full text of DOI:10.1016/j.bmcl.2010.03.078

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2722–2725
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Bioorganic & Medicinal Chemistry Letters
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Synthesis and evaluation of a series of C50-substituted duocarmycin SA analogs
*
William M. Robertson, David B. Kastrinsky, Inkyu Hwang, Dale L. Boger
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and evaluation of a key series of analogs of duocarmycin SA, bearing a single substituent at
the C50 position of the DNA binding subunit, are described.
Received 7 March 2010
Revised 17 March 2010
Accepted 19 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Duocarmycin SA
Duocarmycin SA (1, IC50 = 10 pM)1 represents one of the most
cytotoxic members of a class of natural products that also include
duocarmycin A (2),2 yatakemycin (3),3 and CC-1065 (4, Fig. 1).4
Members of this family of natural products derive their biological
properties from a characteristic sequence-selective alkylation of
duplex DNA,5–9 in which a stereoelectronically controlled nucleo-
philic addition of adenine occurs at the least substituted carbon
of the activated cyclopropane within the deeper, narrower minor
groove at AT-rich sites in DNA.
flexible portion of the molecule.12,13,19 Both the C-terminus substi-
tuent (C6 methyl ester for 1) on the alkylation subunit and the
minor groove imbedded C50 substituent on the DNA binding sub-
unit contribute to the effective overall rigid length of the com-
pounds. Hence, both can impact the extent of the conformational
change or twist in the DNA bound compound, the degree of activa-
tion for nucleophilic attack, and the extent of the catalysis of the
Extensive investigations on the natural products in this class as
well as their synthetic analogs have defined key and subtle fea-
tures that contribute to their properties.9,10 Most notable of these
are the structural features that contribute to the AT-rich noncova-
lent binding selectivity dominating the alkylation selectivity,11
those that are responsible for the source of catalysis for the DNA
alkylation reaction,12,13 and those that subtly impact the unusual
and intrinsic stability of their alkylation subunits.9,13–17
Studies have shown that the role of the attached DNA binding
subunit goes beyond that of simply providing DNA binding affinity
and selectivity,11 but that it also contributes to and is largely
responsible for the DNA alkylation catalysis.12,18 We have sug-
gested that this catalysis is derived from a DNA binding induced
conformational change in the compound that serves to disrupt
the vinylogous amide stabilization of the alkylation subunit acti-
vating it for nucleophilic attack. Responsible for this conforma-
tional change and the resulting activation is the rigid extended
and planar structures of both the alkylation subunit and the at-
tached DNA binding subunit. The DNA bound molecule adopts a
bent versus planar conformation following the overall curvature
and helical pitch of the minor groove with the twist accommo-
dated by the region surrounding the linking amide, the only
MeO2C
Me
MeO2C
HN
O
1, (+)-Duocarmycin SA
2, (+)-Duocarmycin A
HN
OMe
OMe
OMe
OMe
N
O
N
O
O
O
N
H
N
H
OMe
OMe
OH
NH
SMe
OMe
O
3, (+)-Yatakemycin
HN
N
N
MeO
O
OH
O
N
H
CONH2
OH
O
N
Me
OMe
4, (+)-CC-1065
HN
O
NH
N
N
O
O
N
OH
H
OMe
* Corresponding author. Tel.: +1 858 784 7522; fax: +1 858 784 7550.
E-mail address: boger@scripps.edu (D.L. Boger).
Figure 1. Natural products.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.03.078

W. M. Robertson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2722–2725
NH2
2723
DNA alkylation reaction. As a result, minor groove bound substitu-
NH2
I
I2, Ag2SO4
EtOH, rt
ents on both the DNA binding subunit and the alkylation subunit
each have been shown to have a pronounced effect on the rate
and efficiency of DNA alkylation and the resulting biological po-
tency of the compounds. It has been shown that the substituent
at the C50 position of the indole DNA binding subunit of duocarmy-
cin SA is of predominant importance, and that it can alone provide
a fully active agent with little or no contribution derived from the
C60 and C70 substituents found in duocarmycin A and duocarmycin
SA (Fig. 2).12 Similarly, the removal of the C6 methyl ester from the
alkylation subunit of duocarmycin SA was shown to reduce the
rate (12–13-fold) and efficiency (10-fold) of DNA alkylation illus-
trating an important role for the minor groove imbedded substi-
tuent.15v Additionally, and as first systematically explored with
CBI derivatives, the nature of the C50 substituent proved to have
pronounced impact that correlated with its presence, size, rigidity
and length, but not electronic properties.18 Herein, we systemati-
cally explore the importance of the C50 substituent within duocar-
mycin SA analogs additionally bearing the minor groove imbedded
C6 methyl ester.
R
R
5−11
5, R = CO2Me, 70%
6
, R = CN, 90%
, R = COMe, 30%
7
8, R = OCF3, 63%
9, R = CF3, 84%
10, R = CO2H, 61%
11, R = CONHMe, 53%
1) SOCl2
2) MeNH2⋅HCl
O
H
N
NH2
I
Me
CO2H
CO2H
Pd(OAc)
2
R
R
DABCO
12 17
−
DMF, 105 °C
12, R = CO2Me, 64%
13, R = CN, 36%
14, R = COMe, 74%
15, R = OCF3, 84%
16
, R = CF3, 87%
17, R = CONHMe, 85%
H
H
N
The synthesis of the duocarmycin SA alkylation subunit was
carried out by a sequence first developed for the total synthesis
of duocarmycin SA,20 which relied on a late-stage chiral resolution
to provide optically active material. In most cases, a synthesis of
the C5-substituted indole-2-carboxylic acids was required to ob-
tain the appropriately substituted DNA binding subunit. Their syn-
N
LiOH
CO2X
CO2H
THF:MeOH:H2O
(3:2:1)
R
R
23−27
50 °C
18, R = X = H
19, R = Me, X = H
20, R = OH, X =H
21, R = OMe, X = H
22, R = F, X = H
thesis was initially pursued using
a Hemetsberger indole
synthesis21 followed by saponification of the methyl indole-2-car-
boxylate to provide the desired indole-2-carboxylic acid. However,
the Hemetsberger reaction, enlisting 3-substituted benzaldehydes,
often produced a near 1:1 mixture (by 1H NMR) of the C5- and C7-
substituted indoles and attempts to separate these regioisomers by
23
, R = NO2, X = Et
1) Zn, NH4Cl, 69%
2) Ac2O, Et3N, 95%
24, R = NHAc, X = Et
25, R = SO2Me, X = H, 82%
26, R = NO2, X = H, 91%
27, R = NHAc, X = H, 98%
chromatography proved challenging. Alternatively,
a
route
employing a palladium-catalyzed indole-forming reaction22 to
regioselectively access the desired C5-substituted indole-2-carbox-
ylic acids was explored and proved to be a synthetically attractive
route (Scheme 1).
Scheme 1.
EtOH, rt, 30–60 min, 30–90%)23 cleanly afforded the 4-substi-
tuted-2-iodoanilines (5–11). Treatment of the iodoanilines 5–11
with pyruvic acid (3.0 equiv), DABCO (3.0 equiv), and Pd(OAc)2
(0.05 equiv) at 105 °C for 4 h in a thoroughly degassed solution
of DMF cleanly provided the desired C5-substituted indole-2-car-
boxylic acids (12–17, 36–86%) as a single regioisomeric product.22
Most C5-substituted indole-2-carboxylic acids were prepared by
this method, with a few purchased from commercially available
sources either as the free acid (18–22) or obtained by hydrolysis
of the corresponding methyl or ethyl esters (23–27) (10 equiv
LiOH, THF/MeOH/H2O 3:2:1, 50 °C, 2 h, 57–91%). Boc deprotection
of enantiopure 2820 was achieved by treatment with 4 N
HCl/EtOAc (18 h, 25 °C) to afford the crude amine hydrochloride
salt. Without purification, subsequent coupling with the C5-substi-
tuted indole-2-carboxylic acid (1.4 equiv, 4.0 equiv EDCI, 2.0 equiv
NaHCO3, DMF, rt, 30–45 min, 19–98%) provided the benzyl pro-
tected coupled products 29–42 (Scheme 2).
Starting with the commercially available 4-substituted anilines,
electrophilic aromatic iodination (1.0 equiv I2, 1.0 equiv Ag2SO4,
DNA binding
subunit
DNA binding
subunit
OMe
OMe
6'
OMe
6'
DNA alkylation
subunit
OMe
OMe
DNA alkylation
subunit
OMe
NH
NH
N
N
O
6
O
MeO2C
N
H
O
CBI-TMI
O
1, (+)-duocarmycin SA
Hydrogenolysis of the benzyl ether to liberate the free phenol
(10% Pd/C, 1 atm H2, THF/MeOH, rt, 2 h, 11–66%) afforded deriva-
tives 43–55. In the case of 40, debenzylation of 28 (10% Pd/C,
25% aqueous HCO2NH4, THF, rt, 2 h, 28%) prior to Boc deprotection
and coupling was employed to avoid competitive reduction of the
nitro group under the hydrogenolysis conditions (Scheme 2). Final-
ly, spirocyclization was achieved with relative ease (1 equiv NaH-
CO3, DMF, H2O, rt, 30 min, 33–98%) to provide 56–69 (Scheme 2).
The results of the examination of the C50-substituted (+)-duo-
carmycin SA analogs in a L1210 cytotoxic assay are summarized
in Figure 3.
Substituent interplay effecting
twist in DNA bound agent?
Lack of substituent interplay...
more pronounced effect of R1
R1
R1
6'
6'
6
MeO2C
R2
R2
HN
N
N
R3
R3
N
H
N
H
O
O
O
O
From these data all analogs, except 65 (R = OMe) and 57
(R = CN), exhibit approximately equal potency (IC50 = 40–80 pM),
Figure 2. (+)-Duocarmycin SA and CBI analog series.

2724
W. M. Robertson et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2722–2725
R1
R1
R
R2
R2
Cl
NBoc 1) 4 N HCl, EtOAc
H
Cl
NH
R
Cl
NH
NH
MeO C
2
N
N
N
N
N
Boc
2)
O
O
O
CO H
MeO C
2
MeO2C
OBn
28
2
MeO2C
N
R
N
H
N
H
H
EDCI⋅HCl
NaHCO3
DMF, rt
OBn
O
OH
29−42
IC50, pMa
R1
(+)-duocarmycin SA
R2
1
-
6−10
Cl
NH
R
H2 (1 atm)
Pd/C
56 CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
47 (48)
N
N
57 CN
7 (9)
43 (38)
49 (85)
65 (75)
70 (61)
68 (72)
77 (78)
53 (50)
O
O
MeO C
2
58 COMe
THF:MeOH (9:1), rt
N
H
43−55
OCF3
CF3
CONHMe
59
60
61
OH
62 H
63 Me
64 OH
65 OMe
NH
NaHCO
3
7.5 (21)
DMF:H2O (2:1), rt
66
67
68
69
70 OMe
71 OH
MeO C
2
F
54 (79)
41 (35)
83 (81)
58 (58)
N
H
56−69
NO2
NHAc
SO2Me
H
H
OH
OMe
O
7 (18)
33 (41)
R
Compd
Compd
Compd
Yield (%)
Yield (%)
Yield (%)
aL1210 cytotoxic activity, average of 2−7 determinations run in duplicate.
Results of the examination of the seco derivative are in parentheses.
29
30
31
32
33
51
95
96
67
57
68
78
33
69
75
96
37*
98
70
CO2Me
CN
COMe
OCF3
CF3
CONHMe
H
Me
OH
OMe
F
NO2
NHAc
SO2Me
43
44
45
46
47
48
49
50
51
52
51
66
31
43
17
38
11
33
19
40
56
57
58
59
60
61
62
63
64
65
66
67
68
69
72
59
91
44
63
67
41
60
68
34
37
98
68
Figure 3. In vitro cytotoxic activity, L1210.
34
35
most closely related derivative (OH, OCF3). The latter incorporates
an electron-withdrawing versus electron-donating substituent,
and one that is sterically small, but extended linearly. Because
other electron-withdrawing substituents proved noticeably less
potent, it does not appear that it is electronic properties of these
two substituents that are responsible for their enhanced activity.
Additional potential contributing features including hybridization
(sp2 vs sp3) or hydrogen bond donor or acceptor properties do
not appear to account for the unique properties of 65 and 57.
Although it is easy to rationalize the observations that a C50 substi-
tuent does not have such a significant impact with duocarmycin SA
(10-fold difference between 1 and 62), at present it is difficult to
rationalize the origin of the observations with the two unique sub-
stituents (OMe, CN) that significantly impact the activity.
36
37
38
39
40
41
42
53
-
54
55
33
-
22
52
67
* = Debenzylated before coupling
Scheme 2.
all being 610-fold less potent than (+)-duocarmycin SA, (1,
IC50 = 6–10 pM). Additionally and according to expectations, the
spiro and seco analogs containing the same C50-substituent on
the DNA binding subunit exhibited equal potency and were essen-
tially indistinguishable. This indicates that the seco analogs,
regardless of the C50-substituent, are able to cyclize in situ to the
corresponding cyclopropane, the active DNA alkylating agent. Con-
trary to initial expectations, all C50-substituted analogues with the
exception of 65 and 57, were found to exhibit an approximately
10-fold decrease in cytotoxic potency as compared to 1 and to ap-
proach the potency of 62 lacking a C50 substituent altogether. This
is in contrast to observations18 made for the series of C50-substi-
tuted analogs containing the CBI alkylation subunit, where the
presence of a simple C50 substituent, regardless of that substitu-
ent’s electronic nature, typically produced analogs that substan-
tially increased the activity (as much as 100-fold) and some that
matched or even exceeded the potency of 1 (1000-fold increase).
This suggests that within the duocarmycin SA structure that al-
ready incorporates a more extended alkylation subunit and its
minor groove imbedded C6 methyl ester, the addition of a simple
indole C50 substituent typically does little to further enhance its
properties. The exceptions to this generalization are 65 and 57,
incorporating a C50 methoxy group or nitrile, respectively. The for-
mer incorporates a substituent (OMe) found in the natural prod-
ucts themselves, and it is significantly more potent than even its
Acknowledgments
We gratefully acknowledge the financial support of the National
Institutes of Health (CA041986) and the Skaggs Institute for Chem-
ical Biology. WMR and DBK were Skaggs Fellows.
Supplementary data
Supplementary data (full experimental details are provided)
associated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2010.03.078.
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