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Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
Figure 6 shows the temporal relationships between the various sulfate conjugates with estradiol as substrate in two separate experiments. One should not critically compare these since, in each case, limiting factors would probably be different. However, one can draw the reasonable conclusion that, in this experimental system, estradiol is rapidly sulfurylated to estradiol-3-sulfate which may act as a substrate for estrone sulfate formation. This latter conjugate appears to maintain a fairly constant level over a 2-hr period and probably plays a precursor role in the formation of 16α-hydroxyestrone-3-sulfate and at least part of the disulfate. Some oxidation of estradiol and subsequent conjugation of the estrone formed cannot, of course, be ruled out.
Steroid sulfatase inhibitors: the current landscape
Published in Expert Opinion on Therapeutic Patents, 2021
Hanan S. Anbar, Zahraa Isa, Jana J. Elounais, Mariam A. Jameel, Joudi H. Zib, Aya M. Samer, Aya F. Jawad, Mohammed I. El-Gamal
Compound 9 (EO-33) is a tetrahydroisoquinoline-based sulfamate derivative that was reported as dual STS inhibitor and selective estrogen receptor modulator (SERM). It was tested against HEK-293 cell line transfected with STS enzyme and exerted strong potency against STS (IC50 = 3.9 nM). Its corresponding phenolic analog (devoid of sulfamate moiety) showed no estrogenic activity in T-47D estrogen-dependent breast cancer cell line. This is a drawback of steroidal sulfamate derivatives that generate estrogenic hormone after attachment of the sulfamoyl moiety to STS enzyme. Thus, compound 9 possesses the merit of no estrogenic side effect. It was further tested against Saos-2 osteoblast-like cells and induced proliferation and alkaline phosphatase activity in a dose-dependent manner. Docking study confirmed the presence of sulfamate group close to N-formylglycine 75 residue hydrated form. Structure-activity relationship (SAR) revealed that the furan and methylthiophene rings are more favorable for activity than 6-membered heterocyclic rings and phenyl [102,103]. Compound 9 was further investigated in vivo. It inhibited STS in liver by 81%, and blocked estrone sulfate-induced uterine weight in ovariectomized mice by 69%. A 30 mg/kg administration of EO-33 produced full recovery of tibia weight and calcium content as a result of its SERM activity. It was also investigated as an in vivo anticancer agent in MCF-7 xenograft model in nude mice. It showed 90% reduction of estradiol sulfate-stimulated growth. It also demonstrated the merit of no significant toxicity on liver or body weights. It is noteworthy that the aqueous solubility of compound 9 is just 5 µg/mL as it is a relatively hydrophobic molecule.[104]
Organic anion transporting polypeptide 2B1 (OATP2B1), an expanded substrate profile, does it align with OATP2B1’s hypothesized function?
Published in Xenobiotica, 2020
Dallas Bednarczyk, Menaka V. Sanghvi
The compound accumulation of a series of compounds previously tested against OATP2B1 were initially repeated here (Figure 1(A,B), Table 1). Repeating previously reported substrates provides context to the transport of newly identified substrates. That is, a comparison of transport of a newly identified substrate to multiple established substrates can be made in the same experimental system to provide a relative rank order of activity, which is challenging to do between multiple labratories. Additionally, the exercise can further validate findings of others which has value to the field as a whole. Compounds classified as “Selective for OATP2B1”, aliskiren, erlotinib, and pemetrexed (McFeely et al., 2019) demonstrated no meaningful OATP2B1-mediated transport (Figure 1(B)). The statins, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin were mixed, where atorvastatin and rosuvastatin demonstrated a significant difference between the HEK-OATP2B1 and HEK-Vector cells, but the more highly permeable statins, fluvastatin and pitavastatin, were more variable and not significant (Figure 1(A), Table 1). The coporpopophyrins both achieved statistical significance, however, the asymmetry previously reported (Bednarczyk & Boiselle, 2016) was strongly maintained here. The steroid sulfates, estradiol-3-sulfate and estrone-3-sulfate, being structurally similar demonstrated similarly strong OATP2B1-mediated uptake (Figure 1(B)). The remaining compounds, fexofenadine, montelukast, and taurocholate did not demonstrate a significant difference between the HEK-OATP2B1 and HEK-Vector cells illustrating those molecules are unlikely to be OATP2B1 substrates (Table 1). Sulfasalzine, had a p value of 0.0502, just missing the cut-off of statistical significance, but did demonstrate at least a 3-fold difference between the HEK-OATP2B1 and HEK-Vector cells in each individual experiment indicating that it was likely a substrate of OATP2B1.