New functionalized mercaptoundecahydrododecaborate derivatives for potential application in boron neutron capture therapy: synthesis, characterization and dynamic visualization in cells.
A series of mercaptoundecahydrododecaborate (B12H11SH(2-), BSH) bearing mono- and dicarboxyalkyl derivatives was prepared, characterized, and their reactivity towards amidation and esterification in DMF was evaluated. Symmetrical alkylation of BSH was achieved by treatment with primary haloalkyl carboxylic acids in aqueous acetonitrile to produce S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate tetramethylammonium salts. Unsymmetrically substituted sulfonium salts were obtained through a similar treatment of cyanoethylthioether-undecahydro-closo-dodecaborate tetramethylammonium salt with haloalkyl carboxylic acid. Selective removal of the remaining cyanoethyl group upon treatment with tetramethylammonium hydroxide yielded S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate ditetramethylammonium salts. N,N'-dicyclohexylcarbodiimide (DCC) activated amidation of S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate or S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate tetramethylammonium salts with propargylamine provided the opportunity to install terminal acetylene groups for further conjugation. These compounds acted as powerful building blocks for the synthesis of a broad range of 1,4-disubstituted 1,2,3-triazole products in high yields, utilizing the Cu(I)-mediated click cycloaddition reaction. The synthesis of BSH-lipid with a two-tailed moiety was also achieved, by esterification of S,S-bis(carboxyethyl)sulfoniumundecahydro-closo-dodecaborate(1-) tetramethylammonium salt with 1,2-O-distearoyl-sn-3-glycerol, which may prove useful in the liposomal boron delivery system. The bio-compatibility of the azide-alkyne click reaction was then utilized by performing this reaction in cell culture. The distribution of BSH in HeLa cells could be visualized by treating the cells first with a BSH-alkyne compound and then with Alexa Fluor 488(®) azide dye. The BSH-dye conjugate, which did not wash out, revealed the distribution of boron in the HeLa cells. Cytotoxicity assays of these BSH derivatives revealed that the synthesized BSH-conjugated triazoles possessed low cytotoxicity in HeLa cancer cells. Of these compounds, BSH conjugated triazole 15 induced a significant increase in the level of boron accumulation in HeLa cells.
Department of Chemistry, Faculty of Science, University of Tanta, 31527 Tanta, Egypt; Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street W., Hamilton, Ontario L8S 4M1, Canada. Electronic address: genadyafaf@yahoo.com.
Afaf R
AR
Genady
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street W., Hamilton, Ontario L8S 4M1, Canada; Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide SA 5000, Australia.
Joseph A
JA
Ioppolo
Department of Chemistry, Faculty of Science, University of Tanta, 31527 Tanta, Egypt.
Mohamed M
MM
Azaam
Department of Chemistry, Faculty of Science, University of Tanta, 31527 Tanta, Egypt.
Mohamed E
ME
El-Zaria
D000478:Alkylation; D000577:Amides / Q000737:chemistry; D001692:Biological Transport / Q000187:drug effects; D001894:Borohydrides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001895:Boron / Q000378:metabolism; D016754:Boron Neutron Capture Therapy; D060326:Chemistry Techniques, Synthetic; D057930:Click Chemistry; D004951:Esterification; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D057054:Molecular Imaging; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry
D000577:Amides; D001894:Borohydrides; D013438:Sulfhydryl Compounds; D014230:Triazoles; C014651:mercaptoundecahydrododecaborate; D001895:Boron
Amidation; BNCT; Click chemistry; Esterification; Imaging; NMR spectroscopy