The present disclosure relates to stereodefined polycyclic (e.g., tetracyclic) compounds that contain quaternary centers at one or multiple ring fusions, synthetic methods for preparing such compounds, and methods of using such compounds to treat a disease, such as a brain tumor and, particularly, a glioma.

The technology disclosed herein provides (4aR,4bS,6aS,9aS,9bS)-1-(4-chlorobenzyl)-4a,6a-dimethyl-3,4,4a,6,6a,8,9,9a,9b,10-decahydro-1H-indeno[5,4-f]quinoline-2,5,7(4bH)-trione, identified as compound IB:10:D, and related compounds. Compound IB:10:D was discovered though screening a compound library for inhibitors of the enzyme SULT2B1b. This enzyme, which produces the product cholesterol sulfate, is overexpressed in cancer. The product acts as an immunosuppressant that results in suppression of the immune system's ability to clear tumor cells. Compounds related to IB:10:D were synthesized and shown to inhibit production of cholesterol sulfate. The discovered inhibitors of SULT2B1b provide new compounds and methods for immunotherapy and cancer treatment.

Provided are steroid analogues functionalized with polar substituents at the C3 and/or C20 positions of the steroid ring system that exhibit improved water solubility. Also provided are pharmaceutical compositions comprising the steroid analogues and methods using the novel steroid analogues for the treatment and prevention of neurodegeneration in a patient following injury to the central nervous system.

Methods for producing enantiodefined polycyclic compounds, particularly tetracyclic compounds, are provided. More particularly, synthetic methods for producing biologically active enantiodefined steroidal compositions of both natural (nat-) and unnatural (ent-) absolute stereochemistry are provided. An exemplary method for manufacturing a tetracyclic compound comprises a step of forming a hydrindane intermediate through coupling of a suitably functionalized enyne with a suitably functionalized alkyne and subsequently performing an intramolecular ring-closing reaction to form the tetracyclic compound. Steroidal compounds obtained by this method and methods of using such steroidal compounds in human and/or animal therapeutics and medicines are also provided.

A method of reducing an aromatic ring or a cyclic, allylic ether in a compound includes preparing a reaction mixture including a compound including an aromatic moiety or a cyclic, allylic ether moiety, an alkali metal, and either ethylenediamine, diethylenetriamine, triethylenetetramine, or a combination thereof, in an ether solvent; and reacting the reaction mixture at from 20 C. to 30 C. for a time sufficient to reduce a double bond in the aromatic moiety to a single bond or to reduce the cyclic, allylic ether moiety.

Provided herein is a compound of Formula (I-I) ##STR00001##
or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I), and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

The present application discloses, among other things, asymmetric synthesis a diastereomeric compound of formula (I) (e.g., -anordrin) or salt thereof. Also provided are methods and compositions for treatment of estrogen deficiency as well as preventing or reducing an estrogen deficiency symptom using a diastereomeric compound of formula (I) (e.g., -anordrin) or salt thereof alone or in combination with at least one additional agent. Further provided are methods and compositions for reducing a side effect of an additional agent in the context of combination therapy with a diastereomeric compound of formula (I) (e.g., -anordrin) or salt thereof.