Endothelial Cell Signaling During Wound Healing
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
The mechanisms of action of the two inhibitors used here bear some discussion. The tyrphostins competitively bind tyrosine kinases and directly interfere with kinase availability for interaction with substrates.80 The phenolic ring structure of tyrphostins imitates that of tyrosine and has been shown to have very low nonspecific toxicity.80 Modifications of this fundamental structure have resulted in enhanced activity against individual growth factors.80,89,93,94 Although tyrphostins have been shown to inhibit FAK activity,42,95 tyrphostins that specifically target and bind to FAK have not been reported. Herbimycin A is benzoquinonoid ansamycin. Its activity may be due to binding protons from reactive sulfhydryl groups of target kinases and the subsequent covering of an active binding site on the kinase.5,96
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In the late 1960s, the Upjohn Company discovered geldanamycin (Figure 6.110), a natural product isolated from Streptomyces hygroscopicus, that has a suitable shape to interact in a “pocket” of the N-terminal domain of HSP90, thus blocking its ability to assist in the folding of proteins. Geldanamycin is a benzoquinone ansamycin, a member of a family of natural products originally attributed with weak antibiotic activity but later discovered to have potent antitumor activity. A natural product with similar activity, radicicol, was isolated from the mycoparasite Humicola fuscoatra (Figure 6.110).Structures of geldanamycin, 17-AAG (Tanespimycin), 17-DMAG, and radicicol.
Rifabutin
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Similar to rifampicin (see Chapter 126, Rifampicin (Rifampin)), rifabutin (also known as ansamycin LM 427) is a derivative of rifamycin S. The most important property of this drug is that it is more active than rifampicin against Mycobacterium avium complex (MAC) in vitro, against this organism growing in alveolar macrophages, and in experimental animals (O’Brien et al., 1987; Perumal et al., 1987; Saito et al., 1988; Young, 1993a; Young, 1993b). The chemical formula of rifabutin is C46H62N4O11 and its molecular weight is 277.23; its molecular structure is shown in Figure 127.1.
Regioselective approach to colchiceine tropolone ring functionalization at C(9) and C(10) yielding new anticancer hybrid derivatives containing heterocyclic structural motifs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Krystian Pyta, Natalia Skrzypczak, Piotr Ruszkowski, Franz Bartl, Piotr Przybylski
In order to demonstrate the utility of C(9)- or C(10)-ether intermediates towards the formation of conjugates, those decorated with alkyne were subjected to Huisgen dipolar cycloaddition of CuAAC type (Figure 3). Alkyne intermediates 3f and 4f were used with benzyl, saccharide, and nucleoside azides as well as with azide congener of the ansamycin antibiotic – geldanamycin to afford triazole-bridged conjugates 5a–f and 6a–f, respectively (Figure 3). Reactions were performed predominantly in THF/methanol, whereas TBA/H2O was a convenient solvent system for the synthesis of hybrids 5f and 6f. In turn, the earlier obtained 3b, 4b, 3j, and 4j ether products were used for assembling conjugates via Heck reactions (Figure 4). Structures of these hybrids were confirmed by NMR, FT-IR, and HR-MS (see Supplemental Material, exemplary 1H-13C HMBC couplings shown in Figure 4S). Irrespectively on the type of group installed at the colchicine scaffold (4-iodobenzyl, 4-vinylbenzyl) the ether-4-vinylbenzyl bridge was formed (products 7 and 8, Figure 4). When ether-allyl reactants were used, the analogous Heck reactions did not yield the expected product and we observed decomposition of 3d and 4d into compound 2.
Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice
Published in Xenobiotica, 2018
Yuki Yamasaki, Kaoru Kobayashi, Asumi Inaba, Daisuke Uehara, Hiroki Tojima, Satoru Kakizaki, Kan Chiba
To examine the effect of RIF on CYP3A11 and CYP2C55 mRNA levels, hepatocytes were treated with either a vehicle control (DMSO) or RIF (1, 10 or 30 μM) at 20 h after changing to Medium O. GA, a benzoquinone ansamycin, binds to an ATP/ADP binding site of heat shock protein 90 (HSP90), resulting in interruption of its chaperoning function (Pratt & Toft, 1997). OA, a protein phosphatase inhibitor, inhibits the protein phosphatase 1/2 A at a low nM concentration (Timsit & Negishi, 2007). GA and OA are known to inhibit the nuclear translocation of CAR and some nuclear receptors (Kawamoto et al., 1999; Mackowiak & Wang, 2016; Yoshinari et al., 2003). To examine the effects of GA and OA on the induction of CYP3A11 and CYP2C55 by RIF, hepatocytes were pretreated with either a vehicle (DMSO), GA (20 μM) or OA (10 nM) for 1 h at 20 h after changing to Medium O, followed by treatment with RIF (10 μM) for 48 h in the presence of either the vehicle (DMSO), GA (20 μM) or OA (10 nM). All compounds were dissolved in DMSO at a final concentration of 0.1% (v/v) and added to medium S (medium O excluding dexamethasone). The medium containing a test compound was replaced every 24 h.
Heat shock proteins as a new, promising target of multiple myeloma therapy
Published in Expert Review of Hematology, 2020
Sebastian Grosicki, Martyna Bednarczyk, Grażyna Janikowska
Several small molecule inhibitors of HSP90 function have been introduced into clinical trials. The best known are derivatives of antibiotics: benzoquinone ansamycin GA or macrolide radicicol [47]. These molecules are not structurally bound (Figure 2), but each one them binds to a nucleotide binding site in the N-terminal domain with much greater affinity than ATP or ADP. It leads to increased degradation of client proteins through the proteasome pathway [48] GA, analogues GA and radicicol were before and now are important tools in discovering unrecognized interactions of HSP90 and client proteins in normal and cancer cells.
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