Abstract |
An integrated QSAR model has been formulated to predict estrogenic, carcinogenic, and cancer protective effects of phytoestrogens (PE). Relative binding of PEs to estrogen receptors ER alpha and ER beta exhibited a parabolic relationship with dipole moment (mu). The high-affinity binding of PEs to ER alpha correlated with Dif0 (0 chi-0 chi v difference index encoding nonsigma electronic charge), while the low-affinity binding of PEs to ER alpha correlated with H bonding (positive coefficient) and % hydrophilic surface (negative coefficient). The high-affinity binding of PEs to ER beta correlated with molecular with (MWd) and Dif0, while the low-affinity binding of PEs to ER beta correlated with H bonding (positive coefficient) and hydrophilic-lipophilic balance (negative coefficient). Thus an increase in electronic or ionic charge, formation of H bonds, or a decrease in hydrophilic property of PEs may increase their binding to ER. The relative transcription activity (RTA) of ER alpha correlated with Dif0-Dif1, while RTA of ER beta correlated with H bonding and polarity. The PE-induced stimulation of DNA synthesis in estrogen-sensitive breast cancer (BC) cells correlated positively with (MD*4 chi v) where MD is molecular depth and 4 chi v is the valence of a 4th order fragment. IC50 for PE-induced inhibition of DNA synthesis in estrogen-sensitive BC cells correlated with (MD*Log P) and Dif3 (3 chi-3 chi v difference index encoding nonsigma electronic charge of fragments consisting of four atoms and three bonds) and Dif3(2). IC50 for PE-induced inhibition of DNA synthesis in estrogen-independent cancer cell lines correlated with (MD*Log P) and 1/water solubility. Thus molecular shape and molecular connectivity of PEs play a key role in modulating estrogen-induced transactivation activity and DNA synthesis in BC cells.
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Authors | A K Singh |
Journal | Cancer investigation
(Cancer Invest)
Vol. 19
Issue 2
Pg. 201-16
( 2001)
ISSN: 0735-7907 [Print] England |
PMID | 11296624
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Anticarcinogenic Agents
- Carcinogens
- Estrogen Receptor alpha
- Estrogen Receptor beta
- Estrogens
- Estrogens, Non-Steroidal
- Isoflavones
- Phytoestrogens
- Plant Preparations
- Receptors, Estrogen
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Topics |
- Amino Acid Sequence
- Animals
- Anticarcinogenic Agents
(pharmacokinetics)
- Breast Neoplasms
(drug therapy, pathology)
- Carcinogens
(pharmacokinetics)
- Estrogen Receptor alpha
- Estrogen Receptor beta
- Estrogens
(pharmacokinetics)
- Estrogens, Non-Steroidal
(chemistry, pharmacokinetics, therapeutic use)
- Female
- Humans
- Isoflavones
- Molecular Sequence Data
- Neoplasms
(drug therapy, pathology)
- Phytoestrogens
- Plant Preparations
- Quantitative Structure-Activity Relationship
- Rats
- Receptors, Estrogen
(chemistry, metabolism)
- Sequence Alignment
- Sequence Homology, Amino Acid
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