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.