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Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
CYP27A1 was found not only to metabolize vitamin D3 into 25-hydroxyvitamin D3 (25-OH-D3) but also cholesterol into 27-hydroxycholesterol and 7-dehydrocholesterol (7-DHC) into two metabolites, 26/27-hydroxy-7-dehydrocholesterol and 25-hydroxy-7-dehydrocholesterol. Also in this case, a whole cells approach allowed high yield of bioconversion approaching 100% in 48 h for cholesterol turnover (Ehrhardt et al., 2016).
Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Besides the above-mentioned compounds, other compounds, including fatty acids, sterols, pyrethroids, and therapeutic drugs, also displayed strong inhibitory effects against carboxylesterase (Xu et al., 2016; Lei et al., 2017; Wang et al., 2017). Crow et al. found that most naturally occurring fatty acids strongly inhibited the hydrolytic activities of recombinant CES1, with the IC50 values at micromolar range Crow et al. (2010). Unsaturated fatty acids displayed potent inhibitory effects on CES1 than saturated ones, while they also display high specificity towards CES1 over CES2. 27-Hydroxycholesterol (27-HC), an oxidized form of cholesterol, also showed promising inhibitory activity against recombinant CES1 (IC50 46 nM) and high selectivity over CES2. 27-HC functioned as noncompetitive inhibitor against CES1, with the very low Ki value (10 nM) (Crow et al., 2010). Bakuchiol, a natural phenolic compound isolated from Fructus Psoraleae (Bu-gu-zhi in Chinese), strongly inhibited CES2 (Li et al., 2015). Pyrethroids are a class of organic compounds similar to the natural pyrethrins produced by the flowers of pyrethrums (Chrysanthemum cinerariaefolium). Pyrethroids are popular household insecticides for their relatively low toxicity to mammals in contrast to organophosphorus insecticides. Recently, Ge et al. found that six commonly used pyrethroids including deltamethrin showed moderate inhibitory effects against both CES1 and CES2 (Table 9.9) (Lei et al., 2017). Deltamethrin strongly inhibited CES1-mediated DME hydrolysis in HLM, with the IC50 value of 2.39 μM. Deltamethrin was a competitive inhibitor against CES1-mediated BMBT hydrolysis, but it functioned as a noncompetitive inhibitor against CES1-mediated DME or DMCB hydrolysis in HLM. Further investigations on inhibition kinetic analyses and docking simulations suggested that CES1 had at least two ligand-binding sites, and deltamethrin (DMT) could bind with the same ligand binding site as BMBT. Physostigmine, a natural alkaloid, was a highly specific CES2 inhibitor with the Ki value of 0.358 μM (Umehara et al., 2016). Physostigmine potently inhibited the hydrolysis of irinotecan but did not affect the hydrolysis of clopidogrel in human liver S9. By the catalytic asymmetric [3+2] cyclization of novel 4-isothiocyanato pyrazolones and isatin-derived ketimines, Wang and Zou et al. systhsized a wide range of intriguing dispirotriheterocyclic products in high yield with excellent diastereoselectivity and enantioselectivity (Bao et al., 2018). In addition, a chiral sulfoxide derivative (tert-butyl (3R,4′R)-1-benzyl-2′-((S)-methylsulfinyl)-2,5″-dioxo-1″-phenyl-3″-(p-tolyl)-1″,5″-dihydro-1′H-dispiro[indoline-3,5′-imidazole-4′, 4″-pyrazole]-1′-carboxylate) of this dispirocyclic product was identified to be a promising CES1 inhibitor. The IC50 of this chiral sulfoxide derivative was 0.39 μM, which activity was 20-fold stronger than its enantiomer.
Recent advances in multifunctional dendrimer-based nanoprobes for breast cancer theranostics
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Prashant Kesharwani, Rahul Chadar, Rahul Shukla, Gaurav K. Jain, Geeta Aggarwal, Mohammed A.S. Abourehab, Amirhossein Sahebkar
There are several risk factors associated with the development of BC including personal and family history, breast tissue density, diet and specific exposures. Consumption of fatty diet is a highly focused risk factor of BC pathophysiology [60]. In a cohort study, it was demonstrated that dietary consumption of cholesterol resulted in a strong breast cancer risk [61]. Recently in the MMTV-PyMT mouse model, the impact of elevated cholesterol on breast tumor pathogenesis was evaluated [62]. It was found that a diet rich in cholesterol and normal in fat content significantly reduces tumor latency and enhances tumor growth which implied that cholesterol itself can play important role in tumor pathophysiology. Cholesterol affects tumor pathophysiology by enhancing lipid raft formation and membrane signaling in the BC cells. It was found that cholesterol metabolite 27 hydroxycholesterol (27HC), functions as an active signaling molecule of endogenous ER modulator and as liver X receptor (LXR) agonist. While 27HC enhances tumor growth by acting on the estrogen receptor of BC cells and on LXR, it also acts by initiating epithelial to mesenchymal transition and metastasis [63, 64]. It was established through several reports, that 27HC level gets increased in breast tumor biopsies compared to a normal breast cell and this strongly evidenced that 27HC plays a significant role in BC pathophysiology [65]. Additionally, hereditary mechanisms also account for a 10-15% portion of BC cases and is mostly associated with genetic mutation inheritance of BRCA1 or BRCA2 genes [66]. Pathophysiological features of tumors can potentially influence the choice for treatment and even probable results or prognosis. Tumor tissues can be assessed for such features through histology, immunohistochemistry, fluorescent in situ hybridization, molecular and genetic profiling [67].