title: Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate-taxoid conjugate.
abstract: The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate-drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next-generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free 'click' chemistry. The synthesis was highly convergent and required no HPLC purification to obtain the final folate-taxoid conjugate 1. Conjugate 1 demonstrated highly FR-specific potency (IC₅₀ 2.1-3.5 nM) against a panel of cancer cell lines, with a >1000-fold decrease in cytotoxicity against normal human cells (IC₅₀>5000 nM). The remarkable potency and selectivity of conjugate 1 can be attributed to highly FR-specific receptor-mediated endocytosis as well as efficient release of the unmodified cytotoxic warhead using a mechanism-based self-immolative linker.
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Seitz
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Vineberg
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Evan
authors.initials: E
authors.lastname: Herlihy
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Bora
authors.initials: B
authors.lastname: Park
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors.forename: Eduard
authors.initials: E
authors.lastname: Melief
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, United States. Electronic address: iwao.ojima@stonybrook.edu.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D005492:Folic Acid
keywords: Anticancer agent; Drug conjugate; Folic acid; Taxoid; Tumor-targeted
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