Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: Potent inhibitors of heat shock protein 90 Journal Article
| Authors: | Wrona, I. E.; Gozman, A.; Taldone, T.; Chiosis, G.; Panek, J. S. |
| Article Title: | Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: Potent inhibitors of heat shock protein 90 |
| Abstract: | A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (∼25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (∼100 nM). © 2010 American Chemical Society. |
| Keywords: | unclassified drug; antineoplastic agents; binding affinity; proteins; breast cancer; cell line, tumor; structure-activity relationship; cancer cell; heat shock protein 90 inhibitor; tanespimycin; hsp90 heat-shock proteins; quinones; phenols; molecular structure; aldehydes; chemical reaction; total synthesis; synthesis (chemical); benzoquinones; lactams, macrocyclic; functionalized; geldanamycin; benzoquinone derivative; natural products; breast cancer cells; potent inhibitor; diastereoselective; allylamino; amidation reaction; ansamycins; asymmetric synthesis; binding activities; competitive binding assay; cytotoxicity assays; heat shock protein; hydrometalation; structural analogue; structural compounds; 1 (benzyloxy) 3 bromo 5 4 methoxy 5 (methoxymethoxy) 2,6 dimethylnon 7 ynyl)benzene; 1 (benzyloxy) 3 bromo 5 4 methoxy 5 (methoxymethoxy) 2,6 dimethyloct 7 enyl)benzene; 1 (benzyloxy) 3,5 dibromobenzene; 15 (3 (benzyloxy) 5 bromophenyl) 7 (tert butyldimethylsilyloxy) 6,12 dimethoxy 11 (methoxymethoxy) 2,8,10,14 tetramethylpentadeca 2,8 dienamide; 20 (benzyloxy) 9 tertbutyldimethylsilyloxy) 8,14 dimethoxy 13 (methoxymethoxy) 4,10,12,16 tetramethyl 2 aza bicyclo[16.3.1]docosa 1(21),4,1018(22),19 pentaen 3 one; 3 (benzyloxy) 5 bromobenzaldehyde; 5 ((tert butyldimethylsilyloxy)methyl)dihydrofuran 2(3h) one; 5 (hydroxymethyl)dihydrofuran 2(3h) one; 5 oxotetrahydrofuran 2 carboxylic acid; 6 (3 (benzyloxy) 5 bromophenyl) 3 methoxy 5 methylhexane 1,2 diol; 6 (3 (benzyloxy) 5 bromophenyl) 3 methoxy 5 methyltetrahydro 2h pyran 2 yl)methanol; 8 (3 (benzyloxy) 5 bromophenyl) 5 methoxy 3,7 dimethyloct 1 en 4 ol; ansamycin derivative; autolytimycin; carbamic acid 20 (benzyloxy) 8,14 dimethoxy 13 (methoxymethoxy) 4,10,12,16 tetramethyl 3 oxo 2 aza bicyclo[16.3.1]docosa 1(21),4,10,18(22),19 pentaen 9 yl ester; ethyl 15 (3 (benzyloxy) 5 bromophenyl) 7 (tert butyldimethylsilyloxy) 6,12 dimethoxy 11 (methoxymethoxy) 2,8,10,14 tetramethylpentadeca 2,8 dienoate; ethyl 15 (3 (benzyloxy) 5 bromophenyl) 7 hydroxy 6,12 dimethoxy 11 (methoxymethoxy) 2,8,10 trimethylpentadeca 2,8 dienoate; ethyl 6 methoxy 2 methyl 7 oxohept 2 enoate; ethyl 7 (tert butyldimethylsilyloxy) 6 hydroxy 2 methylhept 2 enoate; ethyl 7 (tert butyldimethylsilyloxy) 6 methoxy 2 methylhept 2 enoate; ethyl 7 hydroxy 6 methoxy 2 methylhept 2 enoate; methyl 6 (3 (benzyloxy) 5 bromophenyl) 3 methoxy 5 methyltetrahydro 2h pyran 2 carboxylate; methyl 6 (3 (benzyloxy) 5 bromophenyl) 5 methylhydroxy 5 methyltetrahydro 2h pyran 2 carboxylate; reblastatin; amidation; binding assay; cytotoxicity test |
| Journal Title: | Journal of Organic Chemistry |
| Volume: | 75 |
| Issue: | 9 |
| ISSN: | 0022-3263 |
| Publisher: | American Chemical Society |
| Date Published: | 2010-05-07 |
| Start Page: | 2820 |
| End Page: | 2835 |
| Language: | English |
| DOI: | 10.1021/jo1000109 |
| PUBMED: | 20392070 |
| PROVIDER: | scopus |
| PMCID: | PMC2906235 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 20 April 2011" - "CODEN: JOCEA" - "Source: Scopus" |
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