SAR Study on Thiolato-Bridged Triosmium Carbonyl Clusters: Higher Reactivity Does Not Equal Higher Antiproliferative Activity

A structure–activity relationship
study on triosmium clusters
of the general formula Os3(μ-H)(μ-SC6H4X)(CO)10 (2-X, where X = o-, m- or p-NH2; o-, m- or p-
OH; p-H, -Br, -NO2, -COOH or -CH2COOH) show
that their antiproliferative activity is through the cluster core,
and the nature and position of the phenyl ring substituent X shows
a significant impact on the activity. Clusters with an electron-withdrawing
group are more reactive but are thus quickly consumed through reaction
with serum, while those with an electron-donating group persists sufficiently
to enter the cells and result in higher antiproliferative activity.
Interestingly, m-substituted clusters and those with
lipophilicity >6.0 also exhibit higher antiproliferative activity.
In contrast, o-substituted clusters capable of intramolecular
hydrogen bonding have lower cytotoxicity. The cluster 2-m-OH, with higher antiproliferative
activity and lower reactivity with serum, is a potential lead compound
for further mode of action studies.