Synthesis and in vitro characterization of anticancer platinum(II) coordinates: NCI Compare and FTIR spectroscopy for drug candidate profiling

Platinum-based drugs have been used for several decades to successfully treat diverse cancers. Cisplatin, the original compound of this class, is effective against various tumor types, yet it exhibits toxic side effects and tumors often develop resistance. We developed an original in vitro approach to rapidly determine whether platinum compounds could at least partially overcome these limitations by exhibiting a modified activity pattern. From preliminary studies on a twenty compounds series by our group, five compounds were selected for further investigation. After having determined their anticancer potencies through MTT growth inhibition assays, the two most potent compounds (IC50 = 2 µM) were evaluated using the 60 human tumor cell line panel from the NCI and the results were compared to those of the NCI database using the COMPARE algorithm. To complete this approach, the products were compared to cisplatin and oxaliplatin using a FTIR spectroscopy technique allowing the fingerprinting of metabolic changes arising upon drug treatment inside cells.
Results interestingly show a relatively low correlation of the tested compounds to Pt(II) compounds from the NCI database (and obviously to marketed Pt drugs), although they correlate to DNA targeting compounds as expected. Beside this, FTIR experiments indicate a probably different biochemical impact on cells after treatment compared to cisplatin and oxaliplatin, which supports the correlation data from the NCI60 panel. In conclusion, this original approach may be effective for the early screening of a research compounds series and could therefore help for lead identification of new metallodrug intended for cancer treatment. In addition, a convenient synthesis of enantiopure diamines allowing the production of both diastereomeric series from the same precursors is reported.