On Doisynolic Acids, A New Class of Estrogens.

Absolute Structure Determination of the Highly Biologically Active Bisdehydrodoisynolic Acids

“…Alkali fusion of equilenin provides two: a (−) enantiomer, originally characterized as cis-1a, and a (+) enantiomer, originally characterized as trans-2a (Scheme 1). 1 Of the four isomers, 1a [as well as its 3-methyl ether (4a)] was found to be the most estrogenic, in some cases exhibiting a potency in animals surpassing that of estradiol (E2) and other doisynolic acids. 1,[13][14][15]18,20 A number of studies comparing the estrogenic doisynolic-type acids with E2 has revealed surprising paradoxes: (1) Our initial results with doisynolic-type acids indicated that their in vivo estrogenic activity was not reflected in their ER binding affinity, which was in the order of 10 −2 that of E2 whose estrogenicity was similar to or even less than that of some of these estrogenic acids.…”

“…10,11,13,18 (2) In animals (±)-cis-bisdehydrodoisynolic acid [(±)-1] and its 3-methyl ether [(±)-4] are highly estrogenic. 1,3,5,7,[13][14][15][16]20 However, a sensitive transcription assay showed that (±)-4 was 250-fold less active in human cell lines than in a nonhuman cell line. 11 This human-specific difference in estrogenicity may be apparent clinically as poor activity of (±)-4 in human females, as indeed reported, 21 and as a lack of the proliferative response to (±)-4, but not (±)-1, in human MCF-7 breast cancer cells.…”

Ab → Abc → Abcd

“…Anner and Miescher [52,69] also synthesized "estrone-d" (93) and "estrone-e" (96) starting from the lower-melting unsaturated diester 95. The same isomers 93 and 96 could also be obtained by construction of ring D onto the keto ester 92.…”

“…In a brilliant series of papers [86][87][88][89][90][91][92][93][94] they also described the total synthesis of this compound (Scheme 3-11). The keto ester 15, an intermediate in Bachmann's synthesis of equilenin (Scheme 3-2), was treated with ethylmagnesium bromide to form the hydroxy ester 117.…”

A possible basis for structure–function relationship of estrogens

“…It is widely accepted that the OH groups of E2 are involved in the formation of hydrogen bonds at the receptor site, and are thus important for its high receptor affinity and activity [4-61. If simulation of the E2 structure on the receptor site is to be taken as the criterion for estrogenic activity, then perhaps the activity of diethylstilbestrol (DES) [7] and doisynolic acid [8] can be explained. E2, DES, and diosynolic acid all share an essentially planar and linear hydrocarbon skeleton and two hydrogen bonding functions in a similar stereochemical relationship.…”