Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4

The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step reaction sequence with 28% and 38% overall yield for the testosterone and dihydrotestosterone dimer, respectively. The dimerization reaction was achieved by an olefin metathesis reaction with 2nd generation Hoveyda-Grubbs catalyst. The dimers and their corresponding 17α-allyl precursors were tested for the antiproliferative activity on androgen–dependent (LNCaP) and androgen–independent (PC3) prostate cancer cell lines. The effects on cells were compared with that of the antiandrogen cyproterone acetate (CPA). The results showed that the dimers were active on both cell lines, with an increased activity towards androgen–dependent LNCaP cells. However, the testosterone dimer (11) was fivefold more active than the dihydrotestosterone dimer (15), with an IC50 of 11.7 μM vs. 60.9 μM against LNCaP cells, respectively, and more than threefold more active than the reference drug CPA (IC50 of 40.7 μM). Likewise, studies on the interaction of new compounds with drug-metabolizing cytochrome P450 3A4 (CYP3A4) showed that 11 was a fourfold stronger inhibitor than 15 (IC50 of 3 μM and 12 μM, respectively). This suggests that changes in the chemical structure of sterol moieties and the manner of their linkage could largely affect both the antiproliferative activity of androgen dimers and their crossreactivity with CYP3A4. [Display omitted] •Synthesis and properties of original androgen-based dimers are reported.•The TS dimer exhibits IC50 of 11.7 μM on AR + prostate cancer cells (LNCaP).•This dimer is ∼3.5 times more active than the reference drug cyproterone acetate.•Cross-reactivity of androgen-based dimers with CYP3A4 was also examined.•The TS dimer had a 40-fold higher affinity towards CYP3A4 compared to the DHT dimer.