ABSTRACT
In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their inâ vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines - for example, EC50 (PC-3) down to 1.07â µM, and EC50 (MCF-7) down to 2.08â µM - thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC50 =75.1 (PC-3) and 19.3â µM (MCF-7)), dihydroartemisinin (2; EC50 =263.6 (PC-3) and 49.3â µM (MCF-7)), and artesunic acid (3; EC50 =195.1 (PC-3) and 32.0â µM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50 =1.18 and 1.07â µM, respectively) against prostate cancer, and hybrid 23 (EC50 =2.08â µM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.
Subject(s)
Antineoplastic Agents/pharmacology , Artemisinins/pharmacology , Breast Neoplasms/drug therapy , Estrogens/pharmacology , Prostatic Neoplasms/drug therapy , Tamoxifen/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Artemisinins/chemistry , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Estrogens/chemistry , Female , Humans , MCF-7 Cells , Male , Molecular Structure , PC-3 Cells , Prostatic Neoplasms/pathology , Structure-Activity Relationship , Tamoxifen/chemistryABSTRACT
Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17ß-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes.
Subject(s)
Antioxidants/pharmacology , Estrogens/pharmacology , Lipoproteins, LDL/drug effects , Antioxidants/chemistry , Estrogens/chemistry , Humans , Lipoproteins, LDL/blood , Male , Molecular StructureABSTRACT
To investigate the relationship between structure and biological activity of analogues of steroid estrogens we have developed the synthesis of 7α-methyl-6-oxa-estra-1,3,5(10),8(9)-tetraenes with cis- and trans-junction of C and D rings. We found that such compounds have stronger osteoprotective, cholesterol-lowering and antioxidant properties in comparison with uterotrophic activity; that is the advantage in comparison with clinically used 17α-ethynylestradiol.
