Design, Synthesis, and Biological Evaluation of Ferrocenyl–Cyclo-(Gly‑l‑Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents

Ferrocenyl–cyclo-(Gly-l-Pro) hybrids
as novel inhibitors
of ABCB1 and ABCG2 transporters were developed. These organometallic
compounds were virtually nontoxic to colon cancer cells, their multidrug-resistant
(MDR) variants, and normal fibroblasts. Derivatives bearing o-, m-, or p-ferrocenylphenyl
groups significantly sensitized ABCB1- and ABCG2-overexpressing cells
to chemotherapeutics such as vincristine, mitoxantrone, and doxorubicin,
reducing IC50 values by up to 12.7- and 10.3-fold, respectively.
Notably, (S,Z)-4b,
(S,Z)-4c, and (S,Z)-4d showed the strongest
effects. Drug combination studies revealed synergistic interactions,
particularly in vincristine-, mitoxantrone-, and etoposide-resistant
cells (synergy scores: 13.6–17.05). Accumulation assays confirmed
ABC transporter inhibition, with (S,Z)-4b and (S,Z)-4d increasing intracellular retention of calcein and pheophorbide
A up to 3.4- and 2.9-foldcomparable to those of verapamil
and Ko143. Antibody-binding assays further indicated that these hybrids
act as substrates of ABCB1 and ABCG2.