Conjugates of Pyropheophorbide α with 17-substituted Steroidal Androgens. Synthesis, Molecular Modeling, Interaction with Some Cancer Cells

Five new bifunctional conjugates of pyropheophorbide a with 17-substituted testosterone, dihydrotestosterone and epitestosterone differing in the length of linker ( 1–5 ) and two new complex conjugates 6 and 7 (containing three functional units: pyropheophorbide a , 17α-substituted testosterone, and lipophylic hexadecyl chain) were synthesized. Mutual influence of steroidal and macrocyclic fragments in conjugates 1–7 was established by analysis of 1 H NMR spectra and molecular models of conjugates. The uptake and internalization of conjugates 1–5 by prostate carcinoma cells were dependent on the stereochemical configuration of 17-hydroxyl group in steroidal moiety, and the length of linker. Conjugates 1–5 significantly decreased the LNCaP and PC-3 cells growth and proliferation at 96 h incubation; the anti-proliferative activity of epitestosterone derivative comprising short linker 3 was superior. Irradiation of cells labeled with conjugates with light (λ = 660 nm) significantly increased cytotoxicity. Trifunctioal conjugates 6 and 7 easily formed mixed micells with phosphatidyl choline and pluronic F68; these mixed micelles efficiently internalized by human hepatocarcinoma Hep G2 cells, herewith the internalization was dependent on the conjugate structure, rather than on the method of solubilization.