223718-30-7Relevant academic research and scientific papers
Exploiting polarity and chirality to probe the Hsp90 C-terminus
Forsberg, Leah K.,Davis, Rachel E.,Wimalasena, Virangika K.,Blagg, Brian S.J.
, p. 3096 - 3110 (2018/05/08)
Inhibition of the Hsp90 C-terminus is an attractive therapeutic approach for the treatment of cancer. Novobiocin, the first Hsp90 C-terminal inhibitor identified, contains a synthetically complex noviose sugar that has limited the generation of structure-
NOVOBIOCIN ANALOGUES AND TREATMENT OF POLYCYSTIC KIDNEY DISEASE
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, (2011/04/24)
Novobiocin analogues are useful in methods of treating, inhibiting, and/or preventing cyst formation in autosomal dominant polycystic kidney disease (ADPKD) in a subject. The disclosure provides methods of treating ADPKD comprising administering a therapeutically effective amount of a coumarin-3-carboxamide novobiocin analogue. Accordingly, the method can include administering a novobiocin analogue in a therapeutically effective amount for reducing levels of mTOR pathway phosphoproteins P-mTOR, P-Akt and P-S6K, or combinations thereof. Further, the method can include administering a novobiocin analogue in a therapeutically effective amount for reducing levels of Hsp-90 client proteins CFTR, ErbB2, c-Raf and Cdk4, or combinations thereof.
Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines
Burlison, Joseph A.,Avila, Christopher,Vielhauer, George,Lubbers, Donna J.,Holzbeierlein, Jeffrey,Blagg, Brian S. J.
, p. 2130 - 2137 (2008/09/19)
(Chemical Equation Presented) Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at ～700 μM. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure - activity relationships were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.
Novobiocin: Redesigning a DNA gyrase inhibitor for selective inhibition of Hsp90
Burlison, Joseph A.,Neckers, Len,Smith, Andrew B.,Maxwell, Anthony,Blagg, Brian S. J.
, p. 15529 - 15536 (2007/10/03)
Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitor of DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at ～700 μM. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3′-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3′-descarbamoyl-4- deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90. Both compounds were significantly more potent than the natural product, and DHN2 proved to be more active than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition, these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reduction in gyrase activity. Thus, we have established the first set of compounds that clearly differentiate between the C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selective Hsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family of antibiotics.
Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery
Burlison, Joseph A.,Blagg, Brian S. J.
, p. 4855 - 4858 (2007/10/03)
(Chemical Equation Presented) The coumarin antibiotics are not only potent inhibitors of DNA gyrase but also represent the most effective C-terminal inhibitors of 90 kDa heat shock proteins (Hsp90) reported thus far. In contrast to the N-terminal ATP-binding site, little is known about the Hsp90 C-terminus. In addition, very limited structure-activity relationships exist between this class of natural products and Hsp90. In this letter, the syntheses of dimeric coumarin analogues are presented along with their inhibitory values in breast cancer cell lines.
The synthesis of methyl 2-(benzyloxycarbonyl)amino-3- dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino- 2H-pyran-2-ones, fused 2H-pyran-2-ones and 4H-pyridin-4-ones
Toplak, Renata,Svete, Jurij,Stanovnik, Branko,Golic Grdadolnik, Simona
, p. 225 - 235 (2007/10/03)
Methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate (2) was prepared from methyl N-(benzyloxycarbonyl)glycinate (1) and t- butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6, -2H- pyran-2-ones 17-19, -2H-1-benzopyran-2-ones 28-31, and -naphthopyrans 32-35, -2H-pyrano[3,2-c]pyridine-2,5-dione 46, -pyrano[4,3-b]pyran-2,5-dione 47, - pyrano[3,2-c]benzopyran-2,5-dione 48, -pyrano[2,3-c]pyrazol-6-ones 49 and 50, -pyrano[2,3-d]pyrimidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubstituted pyrroles 14-16 were formed. Selective removal of benzyloxycarbonyl group was achieved by catalytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3- amino compounds 7, 8, 20, 36-38 and 53-57 in yields better than 80%.
