Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti-cancer agents.
A series of bifunctional compounds was prepared consisting of 17beta estradiol linked to a DNA damaging N,N-bis-(2-chloroethyl)aniline. The objective of our studies was to determine the characteristics of the linker that permitted both reaction with DNA and binding of the resultant covalent adducts to the estrogen receptor. Linker characteristics were pivotal determinants underlying the ability of the compounds to kill selectively breast cancer cells that express the estrogen receptor.
Sharma
U
U
Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Marquis
J C
JC
Nicole Dinaut
A
A
Hillier
S M
SM
Fedeles
B
B
Rye
P T
PT
Essigmann
J M
JM
Croy
R G
RG
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000816:Aniline Mustard; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D011960:Receptors, Estrogen; D004958:Estradiol; D000816:Aniline Mustard