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.
Mahendran
Adaickapillai
A
Department of Chemistry, Brooklyn College of The City University of New York, Brooklyn, New York 11210, USA.
Vuong
Angela
A
Aebisher
David
D
Gong
Yaqiong
Y
Bittman
Robert
R
Arthur
Gilbert
G
Kawamura
Akira
A
Greer
Alexander
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001685:Biological Factors / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005021:Ethylamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001685:Biological Factors; D005021:Ethylamines; D013440:Sulfides; D013457:Sulfur Compounds; C093885:varacin A; D011092:Polyethylene Glycols