Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit

Article abstract of DOI:10.1016/j.bmcl.2010.01.145

The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in t

Full text of DOI:10.1016/j.bmcl.2010.01.145

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1854–1857
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of duocarmycin SA analogs incorporating
the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-car-
boxylate (COI) alkylation subunit
Kristopher E. Boyle, Karen S. MacMillan, David A. Ellis, James P. Lajiness, William M. Robertson,
*
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 design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-
one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an
oxazole replacement for the fused pyrrole found in the alkylation subunit.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 January 2010
Revised 26 January 2010
Accepted 29 January 2010
Available online 2 February 2010
Keywords:
Duocarmycins
DNA alkylating agents
Antitumor drugs
Duocarmycin SA (1)1 and duocarmycin A (2)2 represent the par-
ent members of a small class of naturally occurring antitumor anti-
biotics that additionally includes yatakemycin (3)3 and CC-1065
(4)4 and that derive their properties through a sequence-selective
alkylation of duplex DNA (Fig. 1).5–9 Substantial efforts have been
devoted to determining the origin of their DNA alkylation proper-
ties,9 including the preparation of derivatives possessing funda-
mental structural changes used to define relationships between
structure, functional reactivity, and biological properties.10 Most
notable of these are the structural features that contribute to the
AT-rich non-covalent binding selectivity dominating the minor
groove adenine N3 alkylation selectivity,11 those that are responsi-
ble for the source of catalysis for the DNA alkylation reaction,12,13
and those that subtly impact the unusual and intrinsic stability
of the alkylation subunits.10,13–17
oms. The oxazole oxygen potentially represents a cross-conjugated
vinylogous ester with the cyclohexadienone carbonyl and is posi-
tioned to be deeply imbedded in the minor groove at a site that
Herein, we report the synthesis of an analog of duocarmycin SA
in which the left-hand subunit pyrrole ring is replaced by an oxa-
zole, providing the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxaz-
olo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit (6
and 7, Fig. 2). This structural modification changes the hydrogen
bond donating pyrrole nitrogen of 1 into a Lewis basic oxazole
nitrogen, potentially provides an alkylation subunit heterocyclic
system capable of tunable metal cation activation,18 and changes
the electronic nature of the cyclopropylcyclohexadienone alkyl-
ation subunit by attaching two inductively withdrawing heteroat-
* Corresponding author. Tel.: +1 858 784 7522; fax: +1 858 784 7550.
E-mail address: bmcl@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.2010.01.145

K. E. Boyle et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1854–1857
1855
of aniline 8 produced 9, which provided aniline 10 (77%) when ex-
posed to concentrated sulfuric acid resulting from p-nitration and
O-tosylate deprotection.22 Acid-catalyzed condensation of 10 with
methyltrimethoxy acetate (1.8 equiv, 0.05 equiv TsOH, toluene,
DME, 80 °C, 87%) produced benzoxazole 11. Benzylation of the
remaining free phenol (1.5 equiv BnBr, 1.8 equiv K2CO3, DMF,
quantitative), nitro reduction (10 equiv Zn, 15 equiv NH4Cl, ace-
tone, H2O) and Boc protection of the resultant aniline (4.0 equiv
Boc2O, 2.2 equiv Et3N, dioxane, 60 °C, 51%, two steps) gave benzox-
azole 12. Regioselective iodination of 12 using N-iodosuccinimide
(1.4 equiv, 0.1 equiv TsOH, THF, MeOH, 87%) yielded aryl iodide
13. Alkylation of aniline 13 using P4-t-Bu phosphazene base and
1,3-dichloropropene (1.4 equiv P4-base, 1.8 equiv 1,3-dichloropro-
pene, benzene, 86%) produced vinyl chloride 14 as a mixture of al-
kene isomers.15m,n Once installed, the benzoxazole methyl ester
proved especially sensitive to hydrolysis and this influenced our
choice of reaction conditions, including the use of P4-base/benzene
for the N-alkylation of 13. Free radical 5-exo-trig ring closure of 14
using freshly prepared Bu3SnH (0.3 equiv AIBN, 1.2 equiv Bu3SnH,
benzene, 80%) produced 15.23 Debenzylation (10% Pd/C, 1 atm H2
gas, THF, MeOH, 50%) of 15 resulted in formation of phenol 16.
Exposure of phenol 16 to the basic conditions commonly
employed to effect spirocyclization in duocarmycin-like systems
(NaH, THF; NaHCO3, DMF, H2O; DBU, CH3CN) did not provide 6
and instead resulted in rapid hydrolysis of the methyl ester.
Replacement of the methyl ester with a tert-butyl ester, as in 17,
stabilized the molecule to competitive ester hydrolysis. However,
even exposure of 17 to basic spirocyclization conditions did not
result in ring closure, and the phenol starting material was recov-
ered. Deprotonation of the phenol precursors to the spirocyclopro-
pane alkylation units typically results in the formation of a yellow
reaction mixture, which changes to colorless upon formation of the
spirocyclopropane. Exposure of 17 to NaHCO3 in DMF and H2O
resulted in a bright yellow solution, but dissipation of the yellow
color and spirocyclization were not observed. This suggests that
the phenolate ion forms, but does not react to displace chloride
and form the cyclopropane.
Figure 2. Duocarmycin SA analog.
is sensitive to steric interactions contributing to the differences be-
tween the natural and unnatural enantiomers of the natural prod-
ucts.19 Consequently, the examination of COI and its derivatives
was anticipated to additionally probe the effect of replacing this
center (CH for 1 and C@O for 2) with the less sterically demanding
lone pair electrons on oxygen that would be directed into the DNA
minor groove.20
The synthesis21 of the duocarmycin SA analog 6 commenced
with protection of 2-nitroresorcinol as the ditosylate (2.05 equiv
TsCl, 3 equiv Et3N, THF, 23 °C, 5 h, 93%) followed by reduction of
the nitro group (10 equiv Zn, 15 equiv NH4Cl, acetone, H2O, quan-
titative) to provide aniline 8 (Scheme 1). Acetylation (1.5 equiv
AcCl, 0.2 equiv DMAP, 3.0 equiv pyridine, DMF, 80%) followed by
nitration (15 equiv Ac2O, 1.7 equiv HNO3, 0.5 equiv H2SO4, 99%)
Attempts to promote the spirocyclization of phenol 17 using sil-
ver salts or Bu4NI as additives were also unsuccessful. In order to
probe the impact of the ester on the problematic spirocyclization,
reduction of the methyl ester 15 (5.0 equiv NaBH4, MeOH) and
methylation of the resultant alcohol (2.0 equiv NaH, 10 equiv
MeI, THF, quantitative) produced methyl ether 18 (Scheme 2).
After debenzylation, exposure of phenol 19 to DBU in CH3CN
slowly produced spirocycle 20 in poor yield (ꢀ20%) and with
decomposition occurring during isolation and purification. Due to
this reactivity and despite our expertise in handling even the most
reactive alkylation subunits,24 it was not possible to isolate a pure
sample of 20.
The reactivity of 20 and the inability of 16 to spirocyclize to pro-
vide N-Boc-COI (6) suggest that there is an intrinsic reactivity of
this modified alkylation subunit that substantially exceeds that
of duocarmycin SA. To date, the spirocyclization precursors to the
Scheme 1.
Scheme 2.

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K. E. Boyle et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1854–1857
Scheme 3.
Table 1
In vitro cytotoxic activity, L1210 cell line
Compound
IC50 (pM)
(+)-5, (+)-N-Boc-DSA
16, seco-N-Boc-COI
(+)-1, (+)-duocarmycin SA
21, seco-COI–TMI
6000
550,000
10
5400
alkylation subunits containing the cyclopropane have displayed
biological properties indistinguishable from the final products.
Consequently, we elected to examine the cytotoxic activity of 16,
the seco precursor to N-Boc-COI (6), as well as 21 (Scheme 3),
the seco precursor to COI–TMI (Table 1, TMI = 5,6,7-trimethoxyin-
dole). Consistent with the indirect observations on their intrinsic
reactivity and the observation of a direct relationship between
chemical stability and cytotoxic potency,16 16 and 21 proved to
be 100 and 550 times less potent than (+)-N-Boc-DSA (5) or (+)-
duocarmycin SA (1), respectively. While this represents a substan-
tial reduction in the activity relative to duocarmycin SA, it is still of
a magnitude that is quite active (21, IC50 = 5.4 nM) and perhaps
surpasses the anticipated potency given its inferred reactivity.
The origin of the reactivity of the modified COI alkylation subunit
and the resulting loss in cytotoxic activity is not well understood,
especially when compared to the analogous CPyI,18 CBI,24,25 and
CTI17 alkylation subunit analogs.
To further characterize the modified alkylation subunit, the
DNA alkylation selectivity and efficiency of compound 21 were
examined using an assay previously described and singly 32P
end-labeled double-stranded w794 DNA.26 Figure 3 illustrates
the DNA alkylation selectivity of racemic seco-COI–TMI alongside
(+)- and ent-(À)-duocarmycin SA. Within w794 DNA, seco-COI–
TMI was found to alkylate the same site as (+)-duocarmycin SA,
and with an efficiency nearly identical to (+)-duocarmycin SA. In
this comparison, it is notable that the natural enantiomer of seco-
COI–TMI (in the racemic mixture) alkylates DNA much more effec-
tively than the unnatural enantiomer (not detected), and that its
natural enantiomer DNA alkylation properties (efficiency and
selectivity) are not readily distinguishable from those of (+)-duo-
carmycin SA (natural enantiomer).
What is remarkable is that the DNA alkylation selectivity and
efficiency of 21 nearly match those of (+)-duocarmycin SA when
conducted with cell free DNA, yet it fails to cyclize to the spirocy-
clopropane with the ease or facility of duocarmycin SA. Moreover,
the cytotoxic potency of 21 does not reflect its DNA alkylation
efficiency. Not only is it difficult to rationalize the origin of these
observations, but to our knowledge it represents the first instance
of such a dramatic lack of correlation between DNA alkylation
efficiency and biological activity.
Figure 3. Thermally-induced strand cleavage of w794 DNA (144 bp. nucleotide no.
5238–138) after DNA-agent incubation with (+)- or ent-(À)-duocarmycin SA and
COI–TMI (48 h, 23 °C), removal of unbound agent by EtOH precipitation and 30 min
thermolysis (100 °C), followed by denaturing 8% PAGE and autoradiography. Lane 1,
control DNA; lanes 2–5, Sanger G, C, A, and T sequencing standards; lane 6, (+)-
duocarmycin SA (1 Â 10À5 M, natural enantiomer); lane 7, (À)-duocarmycin SA
(1 Â 10À4 M, unnatural enantiomer); lane 8, seco-COI–TMI (21, 1 Â 10À5 M, racemic
mixture).
Acknowledgments
Supplementary data
We gratefully acknowledge the financial support of the National
Institutes of Health (CA041986) and the Skaggs Institute for Chem-
ical Biology. K.S.M., J.P.L., and W.M.R. were Skaggs Fellows.
Supplementary data (synthesis of 16 and 21 and their experi-
mental examination) associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.01.145.

K. E. Boyle et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1854–1857
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