title: Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells.
abstract: 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=4.1μM and 17.21nM, 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.
authors: Research Institute of Drug Development, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
authors: Bangrong
authors: B
authors: Cai
authors: Research Institute of Drug Development, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
authors: Aimei
authors: A
authors: Liao
authors: Biomedical Material and Component Service Center, Gwangju Technology Park, Gwangju 62253, Republic of Korea.
authors: Kyung-Ku
authors: KK
authors: Lee
authors: Biomedical Material and Component Service Center, Gwangju Technology Park, Gwangju 62253, Republic of Korea.
authors: Jae-Sam
authors: JS
authors: Ban
authors: Department of Automotive & Mechanical Engineering, Nambu University, Gwangju 506-706, Republic of Korea.
authors: Hyun-Sam
authors: HS
authors: Yang
authors: Research Institute of Drug Development, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: imyoungjun@jnu.ac.kr.
authors: Young Jun
authors: YJ
authors: Im
authors: Research Institute of Drug Development, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: cchun1130@jnu.ac.kr.
authors: ChangJu
authors: C
authors: Chun
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004144:Diosgenin / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008727:Methotrexate / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004144:Diosgenin; D008727:Methotrexate
keywords: Diosgenin; MDA-MB-231 cells; Methotrexate; Methotrexate-diosgenin conjugates; Transport resistance