Synthesis and biological activity of DNA damaging agents that form decoy binding sites for the estrogen receptor.
It is a goal of cancer chemotherapy to achieve the selective killing of tumor cells while minimizing toxicity to normal tissues. We describe the design of selective toxins forming DNA adducts that attract the estrogen receptor (ER), a transcription factor that is overexpressed in many human breast and ovarian tumors. The compounds consist of 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline linked to 2-(4'-hydroxyphenyl)-3-methyl-5-hydroxy-indole. The former moiety is a DNA damaging nitrogen mustard and the latter is a ligand for the ER. The connection between these groups was refined to permit DNA adducts formed by the mustard portion of the molecule to present the ligand domain so that it was able to interact efficiently with the ER. By using 16-mers containing specific DNA adducts, it was determined that monoadducts and putative intrastrand crosslinks were preferred targets for the ER over interstrand crosslinks. A series of structurally related 2-phenylindole mustards was prepared, some of which were selectively toxic to the ER-positive breast cancer cell line MCF-7, as compared with the ER(-) negative line MDA-MB231. The ability both to bind to DNA and to interact significantly with the ER were essential to achieve selective lethality toward ER(+) cells. Compounds forming DNA adducts without the ability to bind receptor showed similar toxicities in the two cell lines. Several models could explain the selective toxicity of the mustard-phenylindole compounds toward ER(+) cells. The favored model suggests that a mustard-DNA adduct is shielded by the ER from DNA repair enzymes and hence cells possessing an abundance of the ER selectively retain the adduct and are killed.
Rink
S M
SM
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Yarema
K J
KJ
Solomon
M S
MS
Paige
L A
LA
Tadayoni-Rebek
B M
BM
Essigmann
J M
JM
Croy
R G
RG
D000816:Aniline Mustard / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004249:DNA Damage; D015195:Drug Design; D005260:Female; D006801:Humans; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D009838:Oligodeoxyribonucleotides; D010051:Ovarian Neoplasms / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D009838:Oligodeoxyribonucleotides; D011960:Receptors, Estrogen; D014157:Transcription Factors; D004247:DNA; D000816:Aniline Mustard