Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells

作者：Cai Bangrong; Liao Aimei; Lee Kyung Ku; Ban Jae Sam; Yang Hyun Sam; Im Young Jun^*; Chun ChangJu^*

来源：Steroids, 2016, 116: 45-51.

DOI：10.1016/j.steroids.2016.10.006

• Methotrexate
• Diosgenin
• Transport resistance
• Methotrexate-diosgenin conjugates
• MDA-MB-231 cells

A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) into transport-resistant cells. The inhibitory effects of these conjugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate-resistant MDA-MB-231 cells than MTX. Conjugate 18, containing a disulfide bond, exhibited the most potent anti-proliferative and DHFR inhibitory effects (IC50 = 4.1 mu M and 17.21 nM, respectively). Anti-proliferative activity was higher in the conjugate with a longer space linker (conjugate 21) than those with shorter linkers (conjugates 19 and 20). These results suggest that diosgenin conjugation of MTX may be an effective way to overcome its transport resistance in cancer cells.

• 出版日期2016-12