No regioselectivity for the steroid α-face in cocrystallization of exemestane with aromatic cocrystal formers based on phenanthrene and pyrene

The anti-cancer steroidal drug exemestane presents significantly different behavior in cocrystallization with arenes compared with the previously explored steroid progesterone. Mechanochemical and solution-based cocrystallization of exemestane with hydroxy derivatives of phenanthrene and pyrene leads to the formation of cocrystals exhibiting clear O–H···O type arene-steroid hydrogen bonds. So far, exemestane and 1-hydroxypyrene have been observed to form only one type of cocrystal, with the 1:1 stoichiometric ratio of the two components. However, there are two stoichiometric variations of the cocrystal of 9-hydroxyphenanthrene and exemestane, with the arene:steroid stoichiometric ratio of either 1:1 or 1:2. Importantly, although cocrystallization of progesterone with the same arene cocrystal formers was previously reported to take place regioselectively through α···π contacts between the α-face of the steroid and the π-electron surface of the arene, the herein explored cocrystals of exemestane reveal α···π and β···π contacts, as well as sidewise interactions involving the arene π-system and different edges of the steroid molecule. The loss of regioselectivity for the steroid α-face in cocrystallization with the two monohydroxylated arenes is tentatively explained by the highly positive electrostatic surface potential of the steroid β-face and a diminished number of C–H groups on the α-face of exemestane compared with progesterone.

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T and T-A pairings, which has only two internal hydrogen bonds whereas C-G and G-C have three hydrogen bonds. It is shown that the third hydrogen bond for A-T and T-A is formed when the A-T and T-A nucleotides are coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca$^{2+}$ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO$_4^-$ ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. Additionally, the basis of initiating the transcription process is described in which the energy stabilization due to the binding of the ion-steroid complex to DNA is dissipated through the DNA molecule to initiate strand separation locally by increasing the length of hydrogen bonds, thus allowing RNA polymerase action. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T and T-A pairings, which has only two internal hydrogen bonds whereas C-G and G-C have three hydrogen bonds. It is shown that the third hydrogen bond for A-T and T-A is formed when the A-T and T-A nucleotides are coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca$^{2+}$ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO$_4^-$ ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. Additionally, the basis of initiating the transcription process is described in which the energy stabilization due to the binding of the ion-steroid complex to DNA is dissipated through the DNA molecule to initiate strand separation locally by increasing the length of hydrogen bonds, thus allowing RNA polymerase action. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T pairing, which has only two internal hydrogen bonds whereas C-G has three hydrogen bonds. It is shown that the third hydrogen bond for A-T is formed when the A-T nucleotide is coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca2+ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO4- ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.

One-pot Synthesis of Hollongdione from Dipterocarpol

A one-pot synthesis of a hybrid triterpenoid-steroid molecule, hollongdione (22,23,24,25,26,27-hexanordammar-3,20-dion), was achieved in a yield of 89%, based on the selective dehydration of dipterocarpol following ozonolysis. The structure of hollongdione was confirmed by X-ray analysis for the first time. Dammar-20(22),24(25)-dien inhibited the growth of Mycobacterium tuberculosis (strain H37Rv) in vitro with a MIC of 50 μg/mL.

The role of 5a-reduction in steroid hormone physiology

A role for 5α-reduction in androgen physiology was first established with the recognition that dihydrotestosterone, the 5α-reduced metabolite of testosterone, is formed in many androgen target tissues, binds to the androgen receptor with greater affinity than testosterone, and plays an essential role in virilization of the urogenital sinus and urogenital tubercle during male development. Two 5α-reductases perform this reaction, and both isoenzymes utilize NADPH as cofactor and have broad specificity for steroids containing a Δ4, 3-keto configuration. 5α-Reduction, which is essentially irreversible, flattens the steroid molecule because of altered relation of the A and B rings, and stabilizes the hormone–receptor complex. Studies involving in vitro reporter gene assays and intact mice in which both isoenzymes are disrupted, indicate that the fundamental effect of dihydrotestosterone formation is to amplify hormonal signals that can be mediated by testosterone at higher concentrations. 5α-Reduction also plays a role in the action of other steroid hormones, including the plant growth hormone, brassinolide, the boar pheromones, androstanol and androstenol, progesterone (in some species), and, possibly, aldosterone and cortisol. The fact that the reaction is important in plants and animals implies a fundamental role in steroid hormone action.

Metabolism of anabolic androgenic steroids

Anabolic androgenic steroids (AAS) are misused to a high extent in sports by athletes to improve their physical performance. Sports federations consider the use of these drugs in sports as doping. The misuse of AAS is controlled by detection of the parent AAS (when excreted into urine) and (or) their metabolites in urine of athletes. I present a review of the metabolism of AAS. Testosterone is the principal androgenic steroid and its metabolism is compared with that of AAS. The review is divided into two parts: the general metabolism of AAS, which is separated into phase I and phase II metabolism and includes a systematic discussion of metabolic changes in the steroid molecule according to the regions (A-D rings), and the specific metabolism of AAS, which presents the metabolism of 26 AAS in humans.