Trifluoromethylacetylenic alcohols as affinity labels: inactivation of estradiol dehydrogenase by a trifluoromethylacetylenic secoestradiol

Abstract

This investigation is continuing despite an elegant total synthesis of (-)-N(8)-norphysostigmine just published by Japanese scientists.71 ConclusionAnalogues of colchicine (ethyl carbamate) and thiocolchicine (3-demethylthiocolchicine) which show interesting biological properties have to await further pharmacological and toxicological evaluation to establish their potential clinical usefulness.The finding, that natural colchicinoids and derived alio congeners bind to tubulin as aS-configurated biaryls, will greatly help in further study of elucidating the mechanism by which they bind to the colchicine binding site on the protein. Systematic efforts to structurally modify compounds of the alio series paid off, since it clearly showed that the methoxy groups at C(l), C(2), and C(9) are required for the binding to tubulin and shifting the acetamido group from C(7) to C(5) afforded an inactive compound.With efficient synthesis of Calabar alkaloids leading to both optical isomers on hand, it now is up to medicinal chemists to make further molecular changes, which (71) Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109. hopefully may lead to clinically useful analgesics and cholinergic agents. Further pharmacological evaluation of (+)-physostigmine and of (-)-Ml)-norphysostigmine, which emerged as interesting compounds, is indicated. In both series of alkaloids discussed, the colchicines and the physostigmines, optical resolution of racemic mixtures and testing optically active isomers instead of racemic mixtures, was pivotal for obtaining useful information.Acknowledgment. The research presented here could not have been accomplished without the input made by many devoted and hard working scientists. This, in the case of colchicine, included the following Ph.D's: H.

Cutaneous Androgen Metabolism: Basic Research and Clinical Perspectives

“…Well characterized 17b-HSD1 inhibitors include estradiol derivatives containing a bromopropyl/or iodopropyl group at position 16a such as 16 -(bromoalkyl)-estradiols (Luu-The et al, 1995;Tremblay et al, 1995), phytoestrogens such as £avonoids (including £avone, £avanone, and iso£avone), iso£avonoids, and lignans (Evans et al, 1995;Makela et al, 1995Makela et al, , 1998; Le Bail et al, 1998), tri£uoromethylacetylenic secoestradiol (Lawate and Covey, 1990), and 6b -(thiaheptanamide) derivatives of estradiol (Poirier et al, 1998). Compounds belonging to this group might also include those described to inactivate ovarian 17b-HSD isoenzyme, such as glycyrrhizin and glycyrrhetinic acid (Sakamoto and Wakabayashi, 1988;Armanini et al, 1999) or to inhibit the enzyme activity in breast cancer cell lines, such as medrogestone (Chetrite et al, 1999).…”

17 -Hydroxysteroid dehydrogenase: inhibitors and inhibitor design

“…1 l(XIV)). This compound did not require oxidation to a ketone to cause enzyme inactivation, indicating that the powerful electron-withdrawing properties of the trifluoromethyl group were suffi¬ cient to activate the compound (Lawate & Covey 1990 (Ricigliano & Penning 1989 …”

New cancer drugs targeting the biosynthesis of estrogens and androgens

“…5). Developed by Covey's group to reduce the level of potent estrogen E2, 16-methylene-estradiol (25) is the first of a series of suicide inhibitors of 17b-HSD1 [Thomas et al, 1983;Lawate and Covey, 1990]. Despite an appealing concept for the development of selective inhibitors, these suicide inhibitors have not proven worthy of therapeutic use.…”