کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1357776 981276 2015 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate–taxoid conjugate
ترجمه فارسی عنوان
طراحی، سنتز و ارزیابی بیولوژیکی یک پلی اتیل مخزن انتخابی بسیار قوی و سلول سرطانی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
چکیده انگلیسی

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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 23, Issue 9, 1 May 2015, Pages 2187–2194
نویسندگان
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