Synthesis and structure-affinity of a series of 7.alpha.-undecylestradiol derivatives: a potential vector for therapy and imaging of estrogen-receptor-positive cancers

Abstract

A series of 7 alpha-undecylestradiol derivatives, featuring various substituents at the end of the undecyl spacer chain, were synthesized and evaluated for their interaction with the estrogen receptor and nonreceptor sites. Their relative binding affinities (RBA) for calf uterine estrogen receptors were measured by competitive binding assays and varied between 0.5 and 8.4% of that of unlabeled 17 beta-estradiol. Enhanced lipophilicity and steric hindrance of the substituent on the end of the spacer chain resulted in decreased binding affinity for the estrogen receptor, while interactions with nonreceptor sites increased. RBA values were not affected by prolonged incubation times, suggesting a stable ligand-receptor complex. The potential to use the 7 alpha-undecylestradiol as a vector for site-selective delivery of diagnostic and therapeutic moieties to estrogen-receptor-positive human cancers is discussed.

Synthesis and evaluation of 7α-(3-[18F]fluoropropyl) estradiol

“…It has been proposed that grafting of the C-7α-spacer away from the two hydroxyl groups could lead to high-affinity derivatives for ER [13][14][15][16][17]. On the other hand, 7α-methyl-estradiol has high affinity (K i = 0.1-1 nM) for the receptor [28].…”

“…In another approach, several lines of evidence suggest that C-7α-substituted estradiol derivatives are well tolerated by the ER [13][14][15][16][17]. In line with this hypothesis, we are interested in the design and synthesis of C-7α-substituted estrogens as molecular probes to visualize ER function.…”

C7-Substituted Estranes and Related Steroids

“…Further elaboration to the target compounds involve functional group interconversions including the manipulation of protective groups at C17 within the steroidal frame, as well as the terminus of the C7 side chain. A number of groups [47][48][49][50][51][52][53] . In the first case, much 1,2-addition product is isolated, while in the latter case the reaction temperature plays a significant role for the outcome of the reaction.…”

Derivatization of Steroids for Obtaining Conjugates: Use as Vectors for Drug Delivery

“…Derivatization of steroids has been carried out for desired pharmacological applications. This includes preparation of more potent molecules, 1-3 antihormones, [4][5][6] steroidal drugs such as anticancer, [7][8][9][10][11] anti-inflammatory, 12 immunosuppressent, 13 antihyperglycemic, 13 antiobesity, 14 antidiabetic, 15 enzyme inhibitors, [16][17][18] muscle relaxant 19 and steroidal antibodies 20 etc. Transformations of steroids have also been carried out for mapping the distribution of steroid receptors 21 and their labeling for antibody production, 22 and recently for use as vectors for anticancer moieties/ molecules.…”

“…This approach is getting more importance due to the discovery of steroidal receptors in cancers of different organs e.g., Lung cancer, 23 meningiomas, 24 in addition to brain, kidney, and prostate cancers where the expression of receptor gene is well documented. [7][8][9][10][11] Some of the potential anticancer steroids and steroidal conjugates introduced in the recent past include estradiol and cholesterol derivatives (1-11). Among these, the compound (7) is a nitrogen mustard conjugate of a bile acid, whereas (6), an antiesterogenic aromatase inhibitor is used to treat hormone dependent tumors.…”