MedChemComm
Concise Article
ring. This could partially explain the good results obtained with
alkenes 3 and 4 on LNCaP cells. Finally, isosteric replacement
with sulfur was not tolerated. Compound 7 was inactive against
these four cell lines. The larger size of sulfur as compared to
oxygen or oxidation at sulfur may be responsible for the inac-
tivity of compound 7. This steric effect is in accordance with
previous observations that ortho-substituted compounds are
inactive.
Compounds 1, 3 and 4 were incubated at 50 mM with HL60 or
MDA-MB231 cells. Aer 24 h, DNA fragmentation was evaluated
(Fig. 8). Signicant increases in DNA fragmentation were
detected aer treatment with all compounds at 50 mM in HL60
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MDA-MB231 cells. Considering HL60 cells, compound
induced more DNA fragmentation in comparison with 3 and 4.
1
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Thus, the –OCH2– spacer is favorable to enhance the pro- 12 M. C. X. Pinto, D. F. Dias, H. L. del Puerto, A. S. Martins,
apoptotic potential. In comparing isomers 3 and 4, isomer Z 3
had more pro-apoptotic potential than E 4 in this case. It is
possible that these compounds are involved in the same
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does not appear to be important in MDA-MB231 cells. Thus,
apparently this class modulates more than one pathway.
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Conclusions
In summary, we described herein the synthesis and cyto-
toxic evaluation of a series of analogues of chiral oxazoli-
dine
1 and 2 designed by isosteric replacement or
rigidication of the oxymethylene spacer. Introduction of a
double bond was well tolerated in almost all cases. Alkene E
4 had a relevant activity against LNCaP with an IC50 value of
11 mM without affecting Vero or PBMC cell proliferation. It
was about 3 times more active than the Z-isomer on this
cancer cell line. Besides, compound 4 has drug-like physi-
cochemical properties. Thus, compound 4 has potential for
further development as an anticancer agent. Rigidication
using amide or isosteric replacement did not enhance the
activity of this class and will not be considered for further
modications.
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