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Literature DB >> 21553822

Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents.

Huiping Zhao¹, 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.

Abstract

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.

Entities: CellLine Chemical Disease Gene Species

Mesh：

Substances：

Year: 2011 PMID： 21553822 PMCID： PMC3164572 DOI： 10.1021/jm200148p

Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446

41 in total

Review 1. Hsp90: a chaperone for protein folding and gene regulation.

Authors: Rongmin Zhao; Walid A Houry
Journal: Biochem Cell Biol Date: 2005-12 Impact factor: 3.626

2. New novobiocin analogues as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90.

Authors: Gaëlle Le Bras; Christine Radanyi; Jean-François Peyrat; Jean-Daniel Brion; Mouâd Alami; Véronique Marsaud; Barbara Stella; Jack-Michel Renoir
Journal: J Med Chem Date: 2007-11-03 Impact factor: 7.446

Review 3. Heat-shock protein 90, a chaperone for folding and regulation.

Authors: D Picard
Journal: Cell Mol Life Sci Date: 2002-10 Impact factor: 9.261

Review 4. Carbohydrates as the next frontier in pharmaceutical research.

Authors: Daniel B Werz; Peter H Seeberger
Journal: Chemistry Date: 2005-05-20 Impact factor: 5.236

5. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: a thermodynamic and crystallographic study.

Authors: G A Holdgate; A Tunnicliffe; W H Ward; S A Weston; G Rosenbrock; P T Barth; I W Taylor; R A Pauptit; D Timms
Journal: Biochemistry Date: 1997-08-12 Impact factor: 3.162

6. Synthesis of mono- and dihydroxylated furanoses, pyranoses, and an oxepanose for the preparation of natural product analogue libraries.

Authors: Xiao Ming Yu; Huijong Han; Brian S J Blagg
Journal: J Org Chem Date: 2005-07-08 Impact factor: 4.354

Review 7. DNA gyrase: structure and function.

Authors: R J Reece; A Maxwell
Journal: Crit Rev Biochem Mol Biol Date: 1991 Impact factor: 8.250

Review 8. Natural product inhibitors of Hsp90: potential leads for drug discovery.

Authors: M W Amolins; B S J Blagg
Journal: Mini Rev Med Chem Date: 2009-02 Impact factor: 3.862

Review 9. Hsp90: a novel target for the disruption of multiple signaling cascades.

Authors: Stephanie C Bishop; Joseph A Burlison; Brian S J Blagg
Journal: Curr Cancer Drug Targets Date: 2007-06 Impact factor: 3.428

10. KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells.

Authors: Shary N Shelton; Mary E Shawgo; Shawna B Matthews; Yuanming Lu; Alison C Donnelly; Kristen Szabla; Mehmet Tanol; George A Vielhauer; Roger A Rajewski; Robert L Matts; Brian S J Blagg; John D Robertson
Journal: Mol Pharmacol Date: 2009-09-09 Impact factor: 4.436

42 in total

1. Alternative approaches to Hsp90 modulation for the treatment of cancer.

Authors: Jessica A Hall; Leah K Forsberg; Brian S J Blagg
Journal: Future Med Chem Date: 2014-09 Impact factor: 3.808

2. Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities.

Authors: Elisabetta Moroni; Huiping Zhao; Brian S J Blagg; Giorgio Colombo
Journal: J Chem Inf Model Date: 2014-01-15 Impact factor: 4.956

Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents.

Review 1. Hsp90: a chaperone for protein folding and gene regulation.

2. New novobiocin analogues as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90.

Review 3. Heat-shock protein 90, a chaperone for folding and regulation.

Review 4. Carbohydrates as the next frontier in pharmaceutical research.

5. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: a thermodynamic and crystallographic study.

6. Synthesis of mono- and dihydroxylated furanoses, pyranoses, and an oxepanose for the preparation of natural product analogue libraries.

Review 7. DNA gyrase: structure and function.

Review 8. Natural product inhibitors of Hsp90: potential leads for drug discovery.

Review 9. Hsp90: a novel target for the disruption of multiple signaling cascades.

10. KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells.

1. Alternative approaches to Hsp90 modulation for the treatment of cancer.

2. Exploiting conformational dynamics in drug discovery: design of C-terminal inhibitors of Hsp90 with improved activities.

3. Synthesis and structure-activity relationships of EGCG analogues, a recently identified Hsp90 inhibitor.

Review 4. Anticancer Inhibitors of Hsp90 Function: Beyond the Usual Suspects.

5. Synthesis and biological evaluation of arylated novobiocin analogs as Hsp90 inhibitors.

6. Scalable procedure for the fragmentation of hydroperoxides mediated by copper and iron tetrafluoroborate salts.

Review 7. Inhibitors and chemical probes for molecular chaperone networks.

8. Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity.

9. Exploiting polarity and chirality to probe the Hsp90 C-terminus.

10. Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail.