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Design, synthesis, and evaluation of...

Cogan, Peter Smith.

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Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin./
作者:	Cogan, Peter Smith.
面頁冊數:	281 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1245.
Contained By:	Dissertation Abstracts International64-03B.
標題:	Chemistry, Organic. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3086273

Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin.
Cogan, Peter Smith.

Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin. - 281 p.

Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1245.

Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2003.

The anthracycline antibiotic doxorubicin has maintained its status as one of the most clinically useful antineoplastic agents for over three decades. While the drug has been used to treat cancers of various somatic origins, it is also known to induce several systemic side effects; most notably, acute and chronic cardiotoxicity. Although extensive research into the mechanism of action of doxorubicin has suggested several pathways by which the drug acts to inhibit tumor growth, the ultimate mode of action of the drug remains unclear. Likewise, efforts aimed at the identification and development of novel derivatives of doxorubicin which exhibit an improved therapeutic index have been almost entirely fruitless. Recent work in several laboratories has suggested that a key event in the mechanism of both the antitumor effects and the toxicity of the anthracyclines is the induction of oxidative stress. In the presence of ferric iron, doxorubicin has been shown to catalyze the generation of formaldehyde in both whole cells and cell free systems. The formaldehyde thusly produced is then employed by doxorubicin for the generation of covalent drug-DNA adducts. A remarkably active, semi-synthetic, dimeric prodrug of doxorubicin, known as doxoform, which delivers 1.5 equivalents of formaldehyde with each molecule of doxorubicin, has also been shown to generate covalent drug-DNA adducts, which translates into superior inhibition of tumor growth. Unfortunately, poor aqueous solubility, inherent instability, and excessive systemic toxicity limit the usefulness of the prodrug.Subjects--Topical Terms:

516206
Chemistry, Organic.

Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin.
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245 1 0 $a Design, synthesis, and evaluation of potent androgen receptor targeted prodrugs of doxorubicin.
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500 $a Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1245.
500 $a Director: Mark Duncan.
502 $a Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2003.
520 $a The anthracycline antibiotic doxorubicin has maintained its status as one of the most clinically useful antineoplastic agents for over three decades. While the drug has been used to treat cancers of various somatic origins, it is also known to induce several systemic side effects; most notably, acute and chronic cardiotoxicity. Although extensive research into the mechanism of action of doxorubicin has suggested several pathways by which the drug acts to inhibit tumor growth, the ultimate mode of action of the drug remains unclear. Likewise, efforts aimed at the identification and development of novel derivatives of doxorubicin which exhibit an improved therapeutic index have been almost entirely fruitless. Recent work in several laboratories has suggested that a key event in the mechanism of both the antitumor effects and the toxicity of the anthracyclines is the induction of oxidative stress. In the presence of ferric iron, doxorubicin has been shown to catalyze the generation of formaldehyde in both whole cells and cell free systems. The formaldehyde thusly produced is then employed by doxorubicin for the generation of covalent drug-DNA adducts. A remarkably active, semi-synthetic, dimeric prodrug of doxorubicin, known as doxoform, which delivers 1.5 equivalents of formaldehyde with each molecule of doxorubicin, has also been shown to generate covalent drug-DNA adducts, which translates into superior inhibition of tumor growth. Unfortunately, poor aqueous solubility, inherent instability, and excessive systemic toxicity limit the usefulness of the prodrug.
520 $a The work herein describes the design, synthesis, and primary evaluation of a second generation prodrug of doxorubicin. We have developed a novel N-Mannich base "trigger" mechanism by which doxorubicin and formaldehyde can be concurrently delivered to targeted tumor cells. The prodrug exhibits superior solubility relative to doxoform while the N-Mannich base moiety allows for facile control of the stability of the construct through either variance of pH or covalent modification. We have also successfully targeted the prodrug to the androgen receptor via the tethered attachment to a non-steroidal anti-androgen. The androgen receptor is known to be overexpressed in advanced prostate cancer and should, therefore, serve as an ideal target for the preferential accumulation of the novel prodrug.
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791 $a Ph.D.
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