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J. M. Padron et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2487–2490
2489
a difference is not observed for compounds 2a and 2c,
when compared to 2e and 2m.
Although the experiments are preliminary, we found
that these synthetic derivatives considerably induced
growth inhibition in HL60 human leukemia cells in
vitro. The observation that the major part of the deriva-
tives evaluated in this study present antiproliferative
activity is consistent with considering pyrrole as a privi-
leged structure with the substituents on the pyrrole ring
modulating the biological activity.
In summary, we have constructed a 20-member library
of tetrasubstituted pyrroles in a simple and direct way.
On the basis of GI50 and TGI data, a structure–activity
relationship was obtained. Some derivatives showed
promising antiproliferative activity against HL60 cells.
This general methodology allows the quick production
of a variety of pyrrole synthons that are useful in com-
binatorial syntheses for the discovery of novel bioactive
compounds.
Scheme 3. Synthesis of pyrrole 2k bearing two different ester groups.
curves. Growth inhibition of 50% (GI50), which is the
drug concentration resulting in a 50% reduction of cellu-
lar net growth when compared with values of untreated
control cells, the drug concentration resulting in total
growth inhibition (TGI), and the net loss in 50% of cells
following treatment (LC50) denoting cell kill.
Acknowledgements
The GI50 and TGI data are listed in Table 1. The results
allow us to classify the compounds in two groups
according to their antiproliferative profile. The group
of active compounds comprises 15 products, which show
GI50 values in the range 4–45 lM. From this series,
compounds 2h and 2n were the most active against
HL60 cells, with GI50 values of 4.8 and 5.1 lM, respec-
tively. The remaining active derivatives showed modest
activity with GI50 values in the range 15–45 lM. Only
five products proved to be inactive at the maximum test
concentration, that is, 100 lM. Interestingly, com-
pounds 2a, 2c, 2j–l, and 2n were the only products from
the active group series that reached a TGI value. The
TGI values for those products were in the range 80–
95 lM. None of the evaluated pyrroles was able to show
a LC50 value. Morphological changes were observed in
cells treated with active compounds at 100 lM (results
not shown), being shrinkage the sole effect. At
lower drug concentrations no clear difference could be
observed from control cells.
This research was supported by grants PPQ2002-04361-
C04-02 and PPQ2002-04361-C04-03 from the Spanish
MEC and the Canary Islands Government. We are in-
´
debted to Dr. Raquel Dıaz Pen˜ate for providing us with
HL60 cells. We are grateful to ICIC, for the award of
postdoctoral research fellowships to J.M.P. and D.T.
F.G.T. also thanks ICIC for financial support (ISCiii,
RTICCC C03/10).
References and notes
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activity relationship is obtained: (a) the aliphatic substi-
tuent on the nitrogen atom of compound 2t decreases
activity when compared to compounds 2f and 2s, which
posses aromatic side chains; (b) the absence of a substi-
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Padron, Jose M.
