Novel C,N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant

The novel steroidal carrier ligand 17-α-[4′-ethynyl-dimethylbenzylamine]-17-β-testosterone (ET-dmba 1) and the steroid — C,N-chelate platinum(II) derivatives [Pt(ET-dmba)Cl(L)] (L = DMSO (2) and PTA (3; PTA = 1,3,5-triaza-7-phosphaadamantane)) have been prepared. Values of IC50 were calculated for the new platinum complexes 2 and 3 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48 h incubation time complexes 2 and 3 show very low resistance factors (RF of < 2) against an A2780 cell line which has acquired resistant to cisplatin and were more active than cisplatin (about 4-fold for 3) in T47D (AR+, AR = androgen receptor). Compound 1 retains a moderate degree of relative binding affinity (RBA = 0.94%) for androgen receptors. The cytotoxicity of the non steroidal platinum analogues [Pt(dmba)Cl(L)] (dmba = dimethylbenzylamine; L = DMSO (4) and PTA (5)) has also been studied for comparison purposes. Theoretical calculations at the BP86/def2-TZVP level of theory on complex 3 have been undertaken.

Graphical AbstractTwo novel cytotoxic steroids — C,N-chelate platinum(II) conjugates with DNA binding and an enhanced lipophilicity for breast cancer cells are described.Figure optionsDownload as PowerPoint slide