The design and synthesis of non-natural polyenes for the reversal of multidrug resistance
Abstract
The synthesis of new non-natural polyenes derived from (−)-stipiamide is reported that effectively reverses multidrug resistance (MDR) in adriamycin resistant human breast cancer cell lines (MCF7-adrR) at low concentrations (4–22 μM). These compounds were shown to bind directly to P-glycoprotein (Pgp), a transmembrane bound efflux pump responsible for extruding toxic entities. Significantly, these stipiamide analogs possess cytotoxicities (ED50 = 5–19.5 μM) which are four orders of magnitude less than that of stipiamide (ED50 = 0.01 nM). A solution-phase indexed combinatorial library of polyenes, based on 4,5-dihydro-stipiamide 2.1, was constructed and evaluated for the discovery of new MDR reversal agents. Six vinyl iodides and seven terminal alkynes were prepared individually following new and established routes. Optimized Sonogashira coupling conditions were used to generate 13 pools of enynes, having different end groups, indexed in two dimensions for a total of 42 compounds. The pools were screened and intersections of potent pools within the library identified new individual compounds with potent MDR reversal efficacy (1–2 μM). Potent compounds were further investigated for their ability to stimulate ATPase activity. Additionally, competitive displacement studies with labeled IAAP were conducted to measure IC50 concentrations for the modulators. Dual domain dimers were synthesized in an effort to achieve enhanced MDR sensitization. Naphthyl-4,5-dihydro-DHS was linked to itself using polyethylene glycol (PEG) linkers of various sizes to form homodimers. Studies revealed that homodimer (n = 5) afforded MDR reversibility at nanomolar concentration levels (ED 50 = 260 nM). Finally, a heterodimer synthesis of naphthyl-4,5-dihydro-DHS linked to the cancer drug, adriamycin, was performed. Initial studies suggest that this heterodimer effectively accumulates at cytotoxic levels in cancer resistant cell lines.
Degree
Ph.D.
Advisors
Andrus, Purdue University.
Subject Area
Organic chemistry|Pharmacology
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