Azasteroids are steroid mimics, a class of natural or synthetic compounds, containing nitrogen in a cyclopentenophenanthrene steroidal nucleus. The replacement of one or more carbon atoms of a steroidal molecule with a heteroatom affects chemical properties and can produce useful alterations in its biological activities. Heterosteroids, and specifically azasteroids, have received much attention among structurally modified natural steroids because of their wide variety of biological activities, often free from undesirable or harmful side effects. One could divide azasteroids into two categories, nuclear and exonuclear, based on the position of heteroatoms. The compounds in which replacement of carbon atoms in the steroidal skeleton at positons 1-17 are nuclear, whereas, when in the side chain or in extra rings the compounds are exonuclear. Nuclear azasteroids are further classified by the position (1-17) of heteroatom or by the ring (A-D) of the steroidal skeleton. For example, the drugs Finasteride and Dutasteride (Avodart) are synthetic, A-ring 4-azasteroids used as 5α-reductase inhibitors. The series of A25822 (A, B, D, L, M, N), natural, homo-D-ring 15-azasteroids was isolated from the mold Geotriclzum flavor-brunneum in 1975. (Chamberlin et al., J Antibiot (Tokyo) 1974, 27 (12), 992-3)
In order to find new steroidal molecules with desirable biological effects, natural steroids are often modified at several positions, especially in the cyclopentenophenanthrene ring system with heteroatoms or rings. Replacement of one or more atoms in steroids with heteroatoms (nitrogen) generates new molecules called azasteroids with such diverse biological properties as cytotoxicity, anti-atherogenicity, anti-carcinogenicity, antifungal, antilipemic, local anesthetic, neuromuscular blocking activity, inhibition of steroidal reductases, and more. Certain azasteroid pills are well known contraceptive drugs, due to their binding with steroid receptors, thereby blocking the binding of the actual steroids. Enzymes that normally transform steroids may bind with substrates and form undesirable steroids. Certain azasteroids have an ability to block the biosynthesis of physiologically undesirable steroids.
Selective androgen receptor modulators (SARMs) (non-steroidal) are a novel class of therapeutic compounds having properties similar to anabolic-androgenic steroids (AAS) but more selective in their action. Such selectivity includes androgen receptor specificity, tissue selectivity, fewer steroid-related side effects and, most importantly, an ability to differentiate between anabolic and androgenic activities. These exceptional properties make SARMs unique in the treatment of androgen related complications although they do have the potential for misusage as performance enhancement drugs in sports due to their anabolic properties and an ability to stimulate androgen receptors.
In the process of finding new SARMs, several azasteroidal androgen receptor agonists were designed and synthesized from dihydrotestosterone (DHT). The new azasteroidal selective androgen receptor modulators showed potent human androgen receptor (hAR) binding and low virilizing. Some are useful for the enhancement of weakened muscle tone and amelioration of complications generated by androgen deficiency such as osteoporosis, atherosclerosis, obesity, benign prostatic hyperplasia (BPH), prostate cancer, etc.
Heterosteroids, particularly azasteroids, present challenges in their synthesis, which have prompted synthetic chemists to initiate studies in the total or partial synthesis of these compounds. Most of the synthetic approaches performed on azasteroids followed ring contraction and expansion strategies by using oxidative cleavages or Beckmann rearrangements. The direct synthetic methods leading to the azasteroids are very limited. Intramolecular Diels-alder and cyclization strategies are used in the synthesis of azasteroids as they form cyclic ring structures of the steroidal backbone. Electrocylization involving Stille and Heck coupling as key steps have been used to synthesize azasteroidal compounds.
The design various novel azasteroids with concise synthetic routes to such compounds is desired. The challenges in the synthesis of azasteroids, and the potential of azasteroids as novel drugs have prompted numerous investigations in this field. The synthetic methods leading to steroidal derivatives (azasteroids) with one or more nitrogen atoms are very limited. Generally, oxidative cleavage of the steroidal rings is needed to introduce nitrogen atom(s) in order to synthesize azasteroids. Even though several azasteroidal syntheses have been reported, there is still a need for the development of new methodologies as the previous synthetic methods are limited to particular steroidal structures. Anhydrobases, a class of heterocyclic compounds, are known for their extreme instability. Becker et al., Synlett 1993, (11), 866-8 discloses the synthesis and chemistry of anhydrobases in the isoxazole series because of their weak nitrogen-oxygen bond.
Additionally, an azasteroid mimic with heterocyclic ring substitution at the C-17 position may have biological properties similar to VT-1161, a novel oral agent synthesized by Viamet pharmaceutical company, developed for the treatment of onychomycosis, a very common fungal infection of the nail. VT-1161 is a tetrazole derivative and Viamet has other tetrazoles in development.
Prostate cancer is second most common type of cancer and fifth leading cause of cancer related deaths in men. Abiraterone, a steroidal anti-androgen, is a successful drug that is used in the treatment of prostate cancer. Currently, the FDA has approved only one CYP17A1 inhibitor, Abiraterone, which contains a steroidal scaffold that is similar to the endogenous CYP17A1 substrates. It binds in the active site of the enzyme and coordinates the heme iron through its pyridine nitrogen, mimicking the substrate. Galeterone, developed by Tokai pharmaceutical company, has been in phase III clinical trials for castration-resistant prostate cancer. This company announced the discontinuation of its clinical trials on Jul. 26, 2016, after a data of the trial was unlikely to meet its endpoint. Cytochrome P17A1 (CYP17A1) is an enzyme catalyzing biological reactions involved in drug metabolism, synthesis of steroids and other lipids in humans. CYP17A1 is responsible for the production of androgens that are required for the tumor cell growth and became an important target in the treatment of prostate cancer. It possesses an active site that associates with a heme prosthetic group to catalyze biosynthetic reactions. Abiraterone contains a steroidal scaffold that is similar to the endogenous CYP17A1 substrates.
To this end, preparation of novel azasteroidal compounds via an intermediate anhydrobase to a steroidal skeleton and the modification of substituents on the steroidal skeletons might provide congeners with useful biological properties.
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