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    Anticancer pharmacology of natural and semi-synthetic lignansfrom Larrea tridentata (Moc and Sess) cov. (Zygophyllaceae)

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    Author
    Lambert, Joshua David
    Issue Date
    2001
    Keywords
    Health Sciences, Pharmacology.
    Chemistry, Organic.
    Advisor
    Timmermann, Barbara N.
    
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    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    The objective of this dissertation was to isolate, identify, modify, and pharmacologically characterize lignans from Larrea tridentata (Zygophyllaceae) which possessed antitumor activity. Seven lignans including the novel 3,4'-dihydroxy-3 ',4-dimethoxy-6,7'-cyclolignan ( 3), and one flavanone were isolated. Although 1-(3-hydroxy-4-methoxyphenyl)-4-(3-methoxy-4-acetoxyphenyl)2,3-dimethylbutane (1) was previously reported, the spectroscopic data is reported here for the first time. Eight acyl and alkyl derivatives of nordihydroguaiaretic acid (NDGA) were prepared to determine the effect of additions to the catechol hydroxyl on tumor cell cytotoxicity. All of the compounds were assessed for their cytotoxicity in human tumor cell lines. NDGA and compounds 1--14 had IC₅₀ values ranging from 6--60 μM in all cell lines. Compounds 2 and 15 were active only against human breast cancer cells. There appeared to be a positive correlation between the number of O-methyl substitutions on the NDGA molecule and potency against breast cancer cells. NDGA and tetra-O-methylnordihydroguaiaretic acid (M₄N) were chosen for further study based on cytotoxicity results and compound availability. Both compounds inhibited DNA synthesis, but only M₄N demonstrated antitumor activity in vivo. M₄N induced cell cycle arrest in the G₀/G₁ and the G₂/M phases and induced apoptosis in melanoma cells. Myeloma cells with decreased topoisomerase IIα levels exhibited increased sensitivity to M₄N, although M₄N inhibited neither topoisomerase IIα or topoisomerase I in a cell-free system. In cells with decreased topoisomerase IIβ levels, the increased sensitivity to M₄N was ablated. This suggests topoisomerase IIβ partially mediates M₄N cytotoxicity. NDGA was hepatotoxic both in vitro and in vivo (LD₅₀ = 75 mg/kg (i.p.) in the mouse). M₄N was non-toxic in vivo and did not alter hepatic enzymes. This demonstrates the importance of the catechol hydroxyls in causing hepatotoxicity. NDGA (i.v.) exhibited two-compartment pharmacokinetics with a distribution half-life of 30 min and a terminal half-life of 135 min in mice. The peak plasma concentration was 14.7 μg/mL and the clearance was 201.9 mL/(min*kg). Overall, several new compounds were identified from L. tridentata that have an improved therapeutic index, compared with NDGA, against human cancer cells. This growth inhibition may involve topoisomerase II inhibition leading to cell cycle arrest and impaired DNA synthesis.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmacology & Toxicology
    Degree Grantor
    University of Arizona
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