Synthesis, characterization, mechanism of decomposition, and antiproliferative activity of a class of PEGylated benzopolysulfanes structurally similar to the natural product varacin
Benzopolysulfanes, 4-CH(3)(OCH(2)CH(2))(3)NHC(O)-C(6)H(4)-1,2-S(x) (x = 3-7 and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C(6)H(4)S(x) (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly, and an S(3) transfer reaction was observed in the presence of norbornene; no S(2) transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG-conjugated polysulfanes had IC(50) values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes at 4 microM for PC3 and DU145 cells and at 12 muM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:75 |
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| Enthalten in: |
The Journal of organic chemistry - 75(2010), 16 vom: 20. Aug., Seite 5549-57 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mahendran, Adaickapillai [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.11.2010 Date Revised 20.10.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1021/jo100870q |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM20026527X |
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| 100 | 1 | |a Mahendran, Adaickapillai |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Synthesis, characterization, mechanism of decomposition, and antiproliferative activity of a class of PEGylated benzopolysulfanes structurally similar to the natural product varacin |
| 264 | 1 | |c 2010 | |
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| 500 | |a Date Completed 24.11.2010 | ||
| 500 | |a Date Revised 20.10.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Benzopolysulfanes, 4-CH(3)(OCH(2)CH(2))(3)NHC(O)-C(6)H(4)-1,2-S(x) (x = 3-7 and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C(6)H(4)S(x) (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly, and an S(3) transfer reaction was observed in the presence of norbornene; no S(2) transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG-conjugated polysulfanes had IC(50) values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes at 4 microM for PC3 and DU145 cells and at 12 muM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Biological Factors |2 NLM | |
| 650 | 7 | |a Ethylamines |2 NLM | |
| 650 | 7 | |a Sulfides |2 NLM | |
| 650 | 7 | |a Sulfur Compounds |2 NLM | |
| 650 | 7 | |a varacin A |2 NLM | |
| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
| 650 | 7 | |a 3WJQ0SDW1A |2 NLM | |
| 700 | 1 | |a Vuong, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Aebisher, David |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Yaqiong |e verfasserin |4 aut | |
| 700 | 1 | |a Bittman, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Arthur, Gilbert |e verfasserin |4 aut | |
| 700 | 1 | |a Kawamura, Akira |e verfasserin |4 aut | |
| 700 | 1 | |a Greer, Alexander |e verfasserin |4 aut | |
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