Mechanism-based rational design of cisplatin analogues

The success of cisplatin as an anticancer drug is attributed to the ability of the platinum compound to damage DNA and subsequently induce apoptosis. Details of the cellular processing of cisplatin-damaged DNA can provide invaluable insight into the rational design of cisplatin analogues or combination therapies. Chapter I provides a survey of recent developments in the understanding of the mechanism of cisplatin action and summarizes relevant platinum-based anticancer compounds. Chapter 2 describes a series of estrogen-tethered platinum(IV) complexes (BEPn, n=l -5) that were synthesized, evaluated for their ability to upregulate HMGB1 and screened for cytotoxicity against human breast cancer cell lines. All BEPn complexes induced the overexpression of HMGB I in ER(+) MCF-7 cells. BEP3 was nearly twice as cytotoxic in ER(+) MC'F-7 cells than in ER(-) HCC-1937 cells. This result suggests the possibility of using compounds in this class specifically to target ER(+) malignancies, such as breast and ovarian cancers. In addition, the series of BEPn compounds provide an example of a useful strategy in the development of platinum-containing anticancer agents, namely, using mechanistic insights to aid in the rational design of new complexes.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Barnes, Katie R., 1978-

Advisor dc:contributor.advisor

• Stephen J. Lippard.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/33647
• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Identifier URI

http://dspace.mit.edu/handle/1721.1/33647

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/33647