Steroid-Derived Scaffolds

Early exploration of derivatives of the natural estrogens failed to provide the necessary tissue selectivity, but an example of successful application of the steroid-like scaffold was realized with fulvestrant (10), which has been used in breast cancer therapy since the early 2000s. Fulvestrant (10) is a full ER antagonist that displays no agonistic effects, and it works both by down-regulating and by degrading the ER.1,19,20... 

The steroid-based scaffold was also used by Davis and coworkers to effect the enantioselective extraction of N-acyl a-amino acids from aqueous media. " Synthetic manipulation of cholic acid delivers a family of steroid-type derivatives (4) with different binding units at C3, Cl. and C12, which are predisposed to facilitate binding. A guanidinium group embedded in a six-membered ring was incorporated at C3 to enhance lipophilicity of the receptor. Variations in the asymmetry of the receptors using a variety of phenyl substituents permitted the researchers to tune the receptor for extraction of different amino acids. 

A one-pot titanium-catalyzed tandem sulfoxidation-kinetic resolution process was developed by Chan using TBHP as the oxidant This process combines asymmetric sulfoxidation (at 0°C) and kinetic resolution (at room temperature). Excellent enantiomeric excesses (up to >99.9%) and moderate to high chemical yields of sulfoxides were obtained [270] (Scheme 14.113). The effect of fluorine substitution at the backbone of BINOL on the catalytic activity in titanium-catalyzed sulfide oxidation with TBHP or cumyl hydrc en peroxide (CHP) was studied by Yudin [271]. Introduction of fluorines into the BINOL scaffold was found to increase the electrophilic character of the Lewis acidic titanium center of the catalyst The most intriguing difference between the FsBINOL and BINOL systems is the reversal in the sense of chiral induction upon fluorine substitution. A steroid-derived BINOL ligand has also been used for the same reaction [272]. 

Combination of microbiological chemistry, often yielding scaffolds not easily obtained by purely chemical means, and combinatorial chemistry, enabling rapid and efficient synthesis of analogs, provides a valuable tool for generation of novel test compounds. As an example [24] we describe here the application of our lipoic acid-derived thioketal linker [25] to the solid-phase synthesis of A4-3-keto steroidal ureas from / -sitosterol. 

Using steroid as supporting scaffold, the reaction of diamine 67, diisocyanide 68 (both being derived from lithocholic acid), acetic acid and formaldehyde afforded the macrocycle 69a in 58% yield as a mixture of head-to-tail and head-to head cyclic dimers ((1), Scheme 20 for the sake of clarity, only the head-to-tail regioi-somer was shown) [96-98]. On the other hand, the reaction of diacid 70, diisocyanide 68, isopropylamine and formaldehyde afforded the steroid-peptoid conjugate... 

Steroidal agents such as 5a-androstan-17P-ol-3-one (Fig. 4.5,1) and selected analogues (Fig. 4.5, 2-4) dissociate efficiently upon ESI and CID as shown exemplarily for 5a-androstan-17P-ol-3-one (Fig. 4.6a). Commonly, the saturated scaffold of cyclopenta[a]phenanthrene-derived compounds results in product ion mass spectra predominantly containing ions of low specificity, which are separated by methylene units (14 Da). Although a,P-unsaturated 3-keto-steroids also yield such product ions, the presence of double bonds commonly directs the dissociation pathway to specific and more characteristic fragments vide infra). 

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