4
Tetrahedron
towards MCF-7 and NCI-H460 cancer cell lines than its benzyl result obtained with the 4-carboxylate-3HQ series (Table 2).
ester counterpart 11, while being clearly less toxic to CHOK1 Consistently with what observed for the previously tested
cells at a concentration of 20 µM than compound 11 (Table 3).
compounds, also this series of 3HQ derivatives did not elicit any
anti-proliferative activity on HT-29 cancer cells. Due to their
interesting activity both in NCI-H460 and MCF-7 cells, compound
13 and 32 were further tested for to their ability to induce cell death
in these cell lines as measured by Lactate dehydrogenase (LDH)
release, which is an indicator of plasma membrane damage.
Interestingly, exposure to compound 13 or 32, at IC50 and 2x IC50,
significantly increased general cell death in both cell lines,
confirming the anticancer potential of these compounds (Figure 1,
SI).
3. Conclusion
In this study, we address for the first time the cytotoxic potential
of 3HQs. The Eistert ring-expansion reaction of isatins with diazo
compounds catalysed by Rh2(OAc)4 was shown to be a versatile
methodology to prepare 3HQs. The direct addition of structurally
diverse diazo compounds to isatins enabled the construction of a
series of 4-carboxylate-3HQs (in yields up to 86%) which were
shown to present anti-proliferative activity against a panel of MCF-
7, NCI-H460 and HT-29 cancer cell lines. Regrettably, this series
of compounds also induced severe cytotoxicity against a model of
non-cancer cell lines, which motivated us to evaluate the 4-
carboxamide-3HQ counterparts. The troublesome preparation of
these compounds was simplified by performing a ring expansion
reaction of isatin derivatives with NHS-diazo acetate. This
methodology afforded the targeted 4-carboxamides-3HQs in yields
up to 90%, and this series of cytotoxic 3HQs were shown to have
an improved selectivity towards MCF-7 (3HQ 23, IC50 of 4.8 µM)
and NCI-H460 (3HQ 26, IC50 of 7.3 µM) cancer cell lines.
Scheme 6. Synthesis of 4-carboxamide-3HQs based on Eistert ring-expansion
reaction of 5- trifluoromethoxy -isatin with NHS-diazo acetate, followed by an
amidation step.
4. References and notes
[1]
K.G. Cunningham, G.G. Freeman, , Biochem. J. 53 (1953)
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This profile was even more pronounced in the case of amides 23
and 26 that showed a good selectivity towards the MCF-7 (IC50 of
4.8 µM) and NCI-H460 (IC50 of 7.3 µM) cancer cell lines
respectively (Table 3), with negligible toxicity towards the CHOK1
cells. The “peptidic-like” 4-carboxamides-3HQs 30-32 were also
active against the MCF-7 and NCI-H460 cell lines.
[3]
[5]
[6]
Table 3. Anti-proliferative evaluation of compounds 21-32
against MCF-7, NCI-H460 and CHOK1 cell lines.
M.Y. Wei, R.Y. Yang, C.L. Shao, C.Y. Wang, D.S. Deng,
Z.G. She, Y.C. Lin, 47 (2011) 322–325.
C
OMPOUND
MCF-7
NA
12.0±1.0
4.8±1.2
17.5±2.4
NA
NCI-H460
NA
9.5±1.2
NA
NA
NA
7.3±1.2
NA
NA
CHOK1
NA
NA
NA
NA
ND
NA
ND
NA
ND
NA
NA
NA
[7]
[8]
D. Austin, M. Myers, J. Chem. Soc. 1 (1964) 1197–1198.
I.Z. El Euch, M. Frese, N. Sewald, S. Smaoui, M. Shaaban,
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21
22
23
24
25
26
27
28
29
30
31
32
Lett. 17 (2007) 5523–5524. [10]
A. Heguy, P. Cai,
NA
NA
P. Meyn, D. Houck, S. Russo, R. Michitsch, C. Pearce, B.
Katz, G. Bringmann, D. Feineis, D.L. Taylor, A.S. Tyms,
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A.J. Duplantier, S.L. Becker, M.J. Bohanon, K.A.
Borzilleri, B.A. Chrunyk, J.T. Downs, L.Y. Hu, A. El-
12.6±1.1
NA
9.4±7.5
9.5±1.0
15.1±1.9
NA
8.4±1.7
11.4±1.1
2.7±1.4
[11]
[12]
[13]
[14]
Determined IC50 of the compounds in MCF-7 and NCIH460 cancer cell lines and
CHOK1 non-cancer cell model after 48 hours of incubation; NA – Non-active at
the concentration of 20 µM; ND – Not determined
In particular, compound 32 elicited an IC50 of 2.7 µM against the
NCI-H460 cells (Table 3), which compares well with the best