Inquiries regarding the use of the book should be directed to the rights and permissions department of INTECHOPEN LIMITED ([email protected]). She holds a position as Assistant Professor at the Faculty of Pharmacy of the University of Coimbra, Portugal.
Introduction
The book Chemistry and Biological Activity of Steroids aims to provide an up-to-date overview of recent developments in the medicinal chemistry of steroids. The renewable and economical natural steroid compounds can be used as building blocks in the design and construction of steroid-based supramolecular systems.
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Microbiological transformations of steroids
This marked the beginning of a very important phase in the development of the synthesis of steroids with biological activity [4, 5]. The presence of a hydroxyl group at C-17 in the androstane skeleton appears to direct the hydroxylation to C-7 with a β orientation (Figure 15) [53].
Conclusions
Transformation of steroids by Bacillus strains isolated from the foregut of water beetles (Coloptera: Dytiscidae): II. Microbial transformation of the anti-cancer steroid exemestane and cytotoxicity of its metabolites against cancer cell lines.
Approaches for the manipulation of estrogen level in tumors 1 Endocrine therapy
- Inhibitors of enzymes responsible for the estrogen formation in tumors The aromatase enzyme is responsible for the conversion of testosterone and
- Steroid sulfatase enzyme (STS)
- Mechanisms of inactivation of steroid sulfatase
- Nonsteroidal STS inhibitors
- Steroidal STS inhibitors
The topology of the active site of the steroid sulfatase and the arylsulfatases A and B is similar [66]. The knowledge of the crystal structure opens up the rational design of molecules for the inactivation of steroid sulfatase. The significance of steroid sulfatase and sulfotransferases in gynecological disorders is summarized in the review [57].
IRIS study: A phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients. In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase.
A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for breast cancer.
The liver is as sex steroid-responsive organ
- Direct regulation of liver gene expression by sex steroids
- Indirect regulation of liver gene expression by sex steroids
- The GHR-STAT5b signaling pathway
- The SOCS family
- Protein phosphatases and signal regulatory proteins (SIRPs)
- Sirtuins
- Protein inhibitors of activated STAT (PIAS)
- STAT5 interacts with Oct-1 to regulate cell cycle
- STAT5 associates with steroid receptors
- Epigenetic modulation of STAT5 transcriptional activity: a cross talk with xenobiotics
This is consistent with GH's role in the regulation of somatic growth and composition. Intriguingly, as mentioned above, a direct ER-STAT5 interaction can directly control STAT5-dependent transcriptional activity in the liver [ 50 ]. Interestingly, the GH-IGF-1 axis has been reported to be positively involved in the growth-promoting and metabolic effects mediated by T [ 5 ].
However, further studies are still needed to better understand molecular interactions between sex steroids and GHR-STAT5b-dependent transcription in the liver. SOCS2 is, among other things, responsible for regulating IGF-1 expression in the liver, which is mediated by STAT5b. The clinical role of SHP-2 in the regulation of GH signal transduction is confirmed by Noonan [93] and Leopard [94] syndromes.
The inhibitory effect of SIRT1 was also observed on STAT3 protein activity in the liver.
STAT5b in liver physiology
- Postnatal body growth
- Lipid and glucose metabolism
- STAT5b is a master regulator for “liver sexuality”
Interestingly, GR acts as a positive regulator (co-activator) for STAT5b transcriptional activity in promoting body growth and sexual maturation. As mentioned above, not only STAT5b but also other transcription factors that interact with STAT5b can affect body growth, including GR, a critical coactivator of STAT5b in the liver [119], or ER, which interacts with E2 and STAT5 [50]. These findings highlight the molecular interactions of LXR with GH-STAT5 signaling in the liver.
Most of the gender dimorphism in the liver can be explained by the female-specific pattern of pituitary gh secretion, through the induction and repression of female- and male-dominant transcripts, respectively. A consensus exists that the response to sex-different pattern of pituitary GH secretion is the main cause of sex dimorphism in the liver. In addition, SREBP1c induction, as well as hepatic triglyceride synthesis and VLDL secretion, and PPARα inhibition can be observed in the liver after continuous GH administration [ 47 , 123 ].
However, it is likely that other factors account for some of the sex differences in the liver.
Sex steroids in liver physiology
- Body growth and composition
- Lipid and glucose metabolism
GHRKO- and GH-deficient mice show improved insulin sensitivity and increased hepatic insulin signaling, suggesting that GH locally antagonizes insulin signaling in the liver [129]. This may affect hepatic insulin sensitivity, leading to insulin resistance and upregulation of gluconeogenic genes (eg, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase), essential for hepatic glucose homeostasis. In addition to free fatty acids, the SOCS family of proteins, whose expression is induced by both GH and insulin in the liver, is thought to contribute to insulin resistance [79, 128].
Several female-predominant repressors show increased expression in STAT5b-deficient male mice; these may contribute to the large loss of male gene expression found in the absence of STAT5b. In addition, E2 can induce IGF-1 gene expression in the liver of the hypothyroid male rat, accompanied by low or. This inhibition may be explained by E2 induction of SOCS2 and SOCS3, which are negative regulators of GHR-JAK2-STAT5b signaling in the liver [19].
Tissue-specific AR signaling has been shown to be involved in the regulation of lipid metabolism (ie, inhibits lipogenesis, prevents hepatic steatosis) and promotes anabolic growth in peripheral tissues [25].
Conclusions
Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. The growth hormone receptor: Mechanism of activation and clinical implications. The prevalence of testosterone deficiency in men over 45 is approximately 38.7% based on total testosterone (T) levels and about 36.3%. An inverse relationship between total testosterone concentration and insulin resistance has also been reported in men [ 77 , 78 ].
Physiological replacement of testosterone has been shown to reduce cholesterol and LDL concentration in men [101, 151]. Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: a review of the current evidence. Inverse relationship between serum levels of interleukin-1β and testosterone in men with stable coronary artery disease.
The role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
Steroid-based supramolecular system for biomolecular recognition Recognition/sensing of biomedically important substances such as specific ions
- Steroid-based macrocyclic molecular receptors
- Steroid-based molecular clefts/tweezers
The steroid-based supramolecular systems can be divided into two groups according to their function: (1) steroid-based supramolecular system for biomolecular recognition and (2) steroid-based supramolecular system for biomolecular transport (Figure 1). Steroid-based supramolecular system for biomolecular recognition Recognition/detection of biomedically important substances such as specific ions. Recently, steroid-based macrocyclic molecular receptors with the combination of multifunctions (eg, chiral recognition-optical properties) have emerged as a new trend of research.
In particular, the steroid-based macrocyclics with higher-order symmetric elements (such as C3, C4, Dxh, etc.), modifiable and derivable sites, various topological diversities [16], as well as chiral/. For practical application, the functionalities (such as optical, radioactive, paramagnetic, etc.) of the steroid-based macrocyclic molecular receptors need to be widely expanded. For the steroid-based molecular slits/tweezers against anion recognition, acidic amide groups (such as NH in ureas or thioureas) were always used to achieve higher affinities [17].
To the best of our knowledge, the molecular recognition of the steroid-based molecular tweezers has so far mainly focused on several simple molecules, including anions, nucleosides and amino acids.
Steroid-based supramolecular system for biomolecular transportation Transportation/delivery technology of biomolecular species (especially thera-
- Steroid-based supramolecular system for gene delivery
- Steroid-based supramolecular system for small molecule/drug delivery Similar to gene delivery, controllable delivering of small molecules, including
In a recent work, our research team successfully prepared a series of steroid-based cationic lipids by integrating various hydrophobic steroid backbones with (l-)-arginine headgroups via a facile and efficient synthetic approach. We found that steroid-based cationic lipid plasmid DNA (pDNA) binding affinity, mean particle sizes, surface potentials, morphologies, as well as stability of steroid-based cationic lipid/pDNA lipoplexes are largely steroid dependent. skeletons. The results of the cellular assay revealed that the cytotoxicity and gene transfection efficiency of steroid-based cationic lipids in H1299 and HeLa cells were strongly dependent on steroids.
Steroid-based cationic lipids/pDNA supramolecular payloads as efficient gene delivery vehicles and the caveolae/lipid-raft mediated cellular uptake pathway. For future research, we envisioned that "smart" features such as enzyme-responsive [67], self-programmable [68], self-replicable, as well as self-evolution technology could be implemented on the steroid-based supramolecular gene carriers by designing/ optimizing the steroid-based molecular structures or supramolecular architectures through molecular or supramolecular engineering approaches. The bile acid-based prodrugs provide efficient building blocks for constructing and developing supramolecular prodrug drug delivery systems (SPDDS), which have also inspired extensive R&D of other steroid-based drugs.
Nowadays, for the requirement of "accurate biomedical treatment", the steroid-based supramolecular prodrug systems with smart ways such as stimulus sensitive (temperature, ultrasound, light, electrical, pH, redox, biomolecules and enzyme) labeling and targeting (cell membrane, subcellular organelles and cell nuclei) properties need to be further developed.
Conclusions
It can be envisioned that by selecting certain functional moieties to construct steroid-based prodrugs and followed by self-assembly, efficient SPDDS towards controllable chemotherapy can be achieved (Figure 10). In this chapter, we reviewed the main biomedical application of steroid-based compounds "beyond the molecule" - the supramolecular level. Renewable, economical natural steroid compounds can be used as building blocks in the design and construction of steroid-based supramolecular systems.
Specific physicochemical and biological properties, good biocompatibility and biological activity give steroid-based supramolecular systems a good feasibility to be used in biomolecular recognition/sensing and biomolecular transport (gene/drug delivery). The examples in this chapter illustrated the transformation of natural steroid-based compounds into functional steroid-based supramolecular systems through molecular and supramolecular engineering technology, which may inspire the systematic study of natural product-based supramolecular (nano)materials towards pharmaceutical and biomedical futures. . industry. Furthermore, we predicted that molecular-level properties of steroid-based molecules/building blocks would be transferred, enhanced, and/or magnified into supramolecular-level properties, providing a "bottom-up" method to create novel nanostructures of renewable resources. and nanomaterials.
Finally, we should note that the steroid-based supramolecular system, as mentioned above in this chapter, is mostly limited to the low-dimensional 0D and 1D level, and therefore, for real practical application in complex systems, the steroid-based supramolecular system is a higher order. systems (such as 2D and 3D) need further development; Especially regarding the emergence of natural tissue engineering materials and the rapid development of 3D bioprinting technology, steroid-based supramolecular system for cell culture and regenerative medicine should be considered and systematically developed in the near future.
