Design, synthesis, and bioactivities of steroid-linked taxol analogues as potential targeted drugs for prostate and breast cancer.
The female steroid hormone 3,17beta-estradiol (2) was selected as an agent to target taxol (1) to estrogen receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through linkages from the 11- or 16-position of estradiol to the 2'-, 7-, or 10-position of taxol. All conjugates were cytotoxic to the A2870 ovarian cancer cell line, although less so than taxol. The MCF-7 breast cancer cell line (ER-alpha positive) and MDA-MB-231 breast cancer cell line (ER-alpha negative) were also used to evaluate the selectivity and cytotoxicity of these conjugates. One conjugate showed some selectivity for ER positive cells, but it was less potent than taxol. Two ETC hemisuccinates were also prepared to improve the solubility of the conjugates. The corresponding Na and triethanolammonium salts were slightly more cytotoxic than the acid form but were much less cytotoxic than the corresponding ETC.
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute & State University, Blacksburg, Virginia 24061, USA.
Changhui
C
Liu
Jeannine S
JS
Strobl
Susan
S
Bane
Jennifer K
JK
Schilling
Meredith
M
McCracken
Sabarni K
SK
Chatterjee
Rayhana
R
Rahim-Bata
David G I
DG
Kingston
D001943:Breast Neoplasms; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D011467:Prostate; D013237:Stereoisomerism; D013386:Succinates / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D013386:Succinates; D004958:Estradiol; D017239:Paclitaxel