Tailoring the AIE Chromogen 2-(2-Hydroxyphenyl)benzothiazole for Use in Enzyme-Triggered Molecular Brachytherapy

Abstract

A targeted strategy for treating cancer is antibody-directed enzyme prodrug therapy, where the enzyme attached to the antibody causes conversion of an inactive small-molecule prodrug into an active drug. A limitation may be the diffusion of the active drug away from the antibody target site. A related strategy with radiotherapeutics entails enzymatically promoted conversion of a soluble to insoluble radiotherapeutic agent, thereby immobilizing the latter at the target site. Such a molecular brachytherapy has been scarcely investigated. In distinct research, the advent of molecular designs for aggregation-induced emission (AIE) suggests translational use in molecular brachytherapy. Here, several 2-(2-hydroxyphenyl)benzothiazole substrates that readily aggregate in aqueous solution (and afford AIE) were elaborated in this regard. In particular, (1) the 2-(2-hydroxyphenyl) unit was derivatized to bear a pegylated phosphodiester that imparts water solubility yet undergoes enzymatic cleavage, and (2) a p-phenol unit was attached to the benzo moiety to provide a reactive site for final-step iodination (here examined with natural abundance iodide). The pegylated phosphodiester-iodinated benzothiazole undergoes conversion from aqueous-soluble to aqueous-insoluble upon treatment with a phosphatase or phosphodiesterase. The aggregation is essential to molecular brachytherapy, whereas the induced emission of AIE is not essential but provides a convenient basis for research development. Altogether, 21 compounds were synthesized (18 new, 3 known via new routes). Taken together, blending biomedical strategies of enzyme prodrug therapy with materials chemistry concerning substances that undergo AIE may comprise a step forward on the long road toward molecular brachytherapy.

Indoxyl-glucosides bearing tethers for enzymatically triggered cross-linking

“…O-acetyl-b-D-glucopyranosyloxy)-1H-indol-5-yloxy]-3,6-dioxaoctyl 4-nitrophenyl carbonate (11). A suspension of 9 (83 mg, 0.10 mmol), 4-nitrophenyl chloroformate (V, 30 mg, 0.15 mmol), and activated molecular sieves 4 Å (250 mg) in anhydrous CH 2 Cl 2 (4.0 mL) was treated with pyridine (17 mL, 0.21 mmol) and stirred at room temperature for 90 min.…”

“…20–23 Alternative approaches are under development for targeted localization of radionuclides in cancerous tissue. 11,24,25…”

“…One possible application of the latter is molecular brachytherapy, where a radionuclide-containing compound undergoes assembly into an immobile precipitate upon enzymatic action. Such a method, while far from realization, [6][7][8][9][10][11][12][13][14][15][16][17] would complement present-day brachytherapy, 18,19 wherein a radionuclide-containing object of macroscopic scale (e.g., pin or bead or wire) is surgically implanted in tissue. Numerous cancerous tissues are known to contain elevated levels of enzymes.…”

“…[20][21][22][23] Alternative approaches are under development for targeted localization of radionuclides in cancerous tissue. 11,24,25 We recently reported the synthesis of tethered indoxylglucosides, including 15 monomers 7 and 5 dimers (built around a triazine core). 8 The indoxyl bears 4,6-dibromo groups for efficient indigo formation and a tether (for derivatization) at the 5-position.…”

Molecular design for sub-micromolar enzyme-instructed self-assembly (EISA)

“…Still, there were perceived limitations to the molecular design and/or studies of I: (1) the concentration examined of I was 68 mM, which is likely B10 000 fold higher than relevant for radiotherapy; and (2) the enzyme treatment was carried out in Tris-HCl buffer at pH 9.0, which is not physiologically relevant. Several other substrates for EISA strategies were examined, [20][21][22][23][24] yet each proved to have idiosyncratic limitations.…”