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Coumarins and heat shock proteins

Katherine M Byrd, Chitra Subramanian, Jacqueline Sanchez, Hashim F Motiwala, Weiya Liu, Mark S Cohen, Jeffrey Holzbeierlein, Brian S J Blagg
Development of heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7...
May 10, 2016: Chemistry: a European Journal
Jiacheng Ma, Pan Pan, Mercy Anyika, Brian S J Blagg, Rick T Dobrowsky
We have previously demonstrated that modulating molecular chaperones with KU-32, a novobiocin derivative, ameliorates physiologic and bioenergetic deficits of diabetic peripheral neuropathy (DPN). Replacing the coumarin core of KU-32 with a meta-fluorinated biphenyl ring system created KU-596, a novobiocin analogue (novologue) that showed neuroprotective activity in a cell-based assay. The current study sought to determine whether KU-596 offers similar therapeutic potential for treating DPN. Administration of 2-20 mg/kg of KU-596 improved diabetes induced hypoalgesia and sensory neuron bioenergetic deficits in a dose-dependent manner...
September 16, 2015: ACS Chemical Neuroscience
Weiya Liu, George A Vielhauer, Jeffrey M Holzbeierlein, Huiping Zhao, Suman Ghosh, Douglas Brown, Eugene Lee, Brian S J Blagg
The 90-kDa heat-shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Inhibiting Hsp90 consequently is an attractive strategy for cancer therapy as the concomitant degradation of multiple oncoproteins may lead to effective antineoplastic agents. Here we report a novel C-terminal Hsp90 inhibitor, designated KU675, that exhibits potent antiproliferative and cytotoxic activity along with client protein degradation without induction of the heat-shock response in both androgen-dependent and -independent prostate cancer cell lines...
July 2015: Molecular Pharmacology
İrfan Koca, Mehmet Gümüş, Aykut Özgür, Ali Dişli, Yusuf Tutar
Inhibition of the Hsp90 function is an essential therapeutic approach and several inhibitors were designed as anti-cancer agents. These inhibitors are ATPases and they aim to deregulate Hsp90 folding function. ATPase proteins are common in human metabolism but they form nonspecific targets. Hsp90 functions as dimer with coordinating chaperones. Heat Shock Organizing Protein (Hop) forms a bridge between Hsp90 and Hsp70-Hsp40 complex to form Hsp90-Hsp70 coordination. Perturbing conformational changes of these Hsp proteins, dimer formation, and protein-protein interactions inhibit Hsp90 substrate protein folding function...
2015: Anti-cancer Agents in Medicinal Chemistry
Huiping Zhao, Gaurav Garg, Jinbo Zhao, Elisabetta Moroni, Antwan Girgis, Lucas S Franco, Swapnil Singh, Giorgio Colombo, Brian S J Blagg
Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors...
January 7, 2015: European Journal of Medicinal Chemistry
Samuel E Schriner, Steven Kuramada, Terry E Lopez, Stephanie Truong, Andrew Pham, Mahtab Jafari
Cinnamon is a spice commonly used worldwide to flavor desserts, fruits, cereals, breads, and meats. Numerous health benefits have been attributed to its consumption, including the recent suggestion that it may decrease blood glucose levels in people with diabetes. Insulin signaling is an integral pathway regulating the lifespan of laboratory organisms, such as worms, flies, and mice. We posited that if cinnamon truly improved the clinical signs of diabetes in people that it would also act on insulin signaling in laboratory organisms and increase lifespan...
December 2014: Experimental Gerontology
Jinbo Zhao, Huiping Zhao, Jessica A Hall, Douglas Brown, Eileen Brandes, Joseph Bazzill, Patrick T Grogan, Chitra Subramanian, George Vielhauer, Mark S Cohen, Brian S J Blagg
Hsp90 C-terminal inhibitors are advantageous for the development of new cancer chemotherapeutics due to their ability to segregate client protein degradation from induction of the prosurvival heat shock response, which is a major detriment associated with Hsp90 N-terminal inhibitors under clinical investigation. Based upon prior SAR trends, a 1,2,3-triazole side chain was placed in lieu of the aryl side chain and attached to both the coumarin and biphenyl scaffold. Antiproliferative studies against SKBr3 and MCF-7 breast cancer cell lines demonstrated these triazole-containing compounds to exhibit improved activity...
September 1, 2014: MedChemComm
Anna K Szkaradkiewicz, Tomasz M Karpiński, Andrzej Szkaradkiewicz
BACKGROUND: Novobiocin is a coumarin antibiotic, which affects also eukaryotic cells inhibiting activity of Heat shock protein 90 (Hsp90). The Hsp90 represents a molecular chaperone critical for stabilization and activation of many proteins, particularly oncoproteins that drive cancer progression. Currently, Hsp90 inhibitors focus a significant attention since they form a potentially new class of drugs in therapy of cancer. However, in the process of tumorigenesis a significant role is played also by the microenvironment of the tumour, and, in particular, by cancer-associated fibroblasts (CAFs)...
2014: BMC Pharmacology & Toxicology
Takenori Tomohiro, Akito Yamamoto, Yoko Tatsumi, Yasumaru Hatanaka
A coumarin-fused diazirine photolabeling agent exhibited dramatic enhancement in fluorescence after cross-linking with the target protein. Fluorescence emission from the coumarin moiety was efficiently quenched by the diazirine group, and was then intensively recovered from photolysis treatment by irradiation with light at a wavelength of 365 nm.
December 21, 2013: Chemical Communications: Chem Comm
G M Kamal B Gunaherath, Marilyn T Marron, E M Kithsiri Wijeratne, Luke Whitesell, A A Leslie Gunatilaka
Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure-activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7-noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2)...
September 1, 2013: Bioorganic & Medicinal Chemistry
Bhaskar Reddy Kusuma, Liang Zhang, Teather Sundstrom, Laura B Peterson, Rick T Dobrowsky, Brian S J Blagg
Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor) that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second-generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified that electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket...
June 28, 2012: Journal of Medicinal Chemistry
Gabriella Fabian, Nora Farago, Liliana Z Feher, Lajos I Nagy, Sandor Kulin, Klara Kitajka, Tamas Bito, Vilmos Tubak, Robert L Katona, Laszlo Tiszlavicz, Laszlo G Puskas
Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies...
2011: International Journal of Molecular Sciences
Huiping Zhao, Alison C Donnelly, Bhaskar R Kusuma, Gary E L Brandt, Douglas Brown, Roger A Rajewski, George Vielhauer, Jeffrey Holzbeierlein, Mark S Cohen, Brian S J Blagg
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ∼700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition...
June 9, 2011: Journal of Medicinal Chemistry
L Jin, Y Tabe, S Kimura, Y Zhou, J Kuroda, H Asou, T Inaba, M Konopleva, M Andreeff, T Miida
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies. METHODS: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied. RESULTS: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells...
January 4, 2011: British Journal of Cancer
Alison Donnelly, Brian S J Blagg
The 90 kDa heat shock proteins (Hsp90), which are integrally involved in cell signaling, proliferation, and survival, are ubiquitously expressed in cells. Many proteins in tumor cells are dependent upon the Hsp90 protein folding machinery for their stability, refolding, and maturation. Inhibition of Hsp90 uniquely targets client proteins associated with all six hallmarks of cancer. Thus, Hsp90 has emerged as a promising target for the treatment of cancer. Hsp90 exists as a homodimer, which contains three domains...
2008: Current Medicinal Chemistry
Sumathy Mohan, Ryszard Konopinski, Bo Yan, Victoria E Centonze, Mohan Natarajan
A decline in the bioavailability of nitric oxide (NO) that causes endothelial dysfunction is a hallmark of diabetes. The availability of NO to the vasculature is regulated by endothelial nitric oxide synthase (eNOS) activity and the involvement of heat shock protein-90 (Hsp-90) in the regulation of eNOS activity has been demonstrated. Hsp-90 has been shown to interact with upstream kinases [inhibitor kappaB kinases (IKK)alpha, beta, and gamma] in nonvascular cells. In this study, we have investigated the interaction of Hsp-90-IKKbeta in endothelial cells under conditions of high glucose (HG) as a possible mechanism that diminishes Hsp-90-eNOS interaction, which could contribute to reduced bioavailability of NO...
January 2009: American Journal of Physiology. Cell Physiology
Christine Radanyi, Gaëlle Le Bras, Véronique Marsaud, Jean-François Peyrat, Samir Messaoudi, Maria-Grazia Catelli, Jean-Daniel Brion, Mouâd Alami, Jack-Michel Renoir
We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines...
February 8, 2009: Cancer Letters
Christine Radanyi, Gaëlle Le Bras, Samir Messaoudi, Céline Bouclier, Jean-François Peyrat, Jean-Daniel Brion, Véronique Marsaud, Jack-Michel Renoir, Mouâd Alami
A new series of coumarin inhibitors of hsp90 lacking the noviose moiety as well as substituents on C-7 and C-8 positions of the aromatic ring was synthesised and their hsp90 inhibitory activity has been delineated: for example, their capacity to induce the degradation of client proteins and to inhibit estradiol-induced transcription in human breast cancer cells. In cell proliferation assay, the most active compound 5g was approximately 8 times more potent than the parent novobiocin natural compound.
April 1, 2008: Bioorganic & Medicinal Chemistry Letters
Joseph A Burlison, Christopher Avila, George Vielhauer, Donna J Lubbers, Jeffrey Holzbeierlein, Brian S J Blagg
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 approximately 700 microM. 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...
March 21, 2008: Journal of Organic Chemistry
Gaëlle Le Bras, Christine Radanyi, Jean-François Peyrat, Jean-Daniel Brion, Mouâd Alami, Véronique Marsaud, Barbara Stella, Jack-Michel Renoir
Selective hsp90 inhibitors simultaneously destabilize and deplete key signaling proteins involved in cell proliferation and survival, angiogenesis, and metastasis. Investigation of novobiocin analogues lacking the noviose moiety as novel inhibitors of hsp90 was carried out. A novel series of 3-aminocoumarin analogues has been produced and screened in cell proliferation, and the molecular signature of hsp90 inhibition was assessed by depletion of estrogen receptor, HER2, Raf-1, and cdk4 in human breast cancer cells...
November 29, 2007: Journal of Medicinal Chemistry
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