Cucurbit[7]uril Nanocarrier for Benzimidazole Drugs

Na'il Saleh,^1* and Werner M. Nau²

¹Chemistry Department, College of Science, Yarmouk University, Irbid 21163, Jordan.

²School of Engineering and Nanomolecular Science, Jacobs University Bremen, Bremen D-28759, Germany.

Abstract.

Important examples of potential drug carriers at the nanoscale are safe and water-soluble compounds with a rigid pocket-like supramolecular structure, which carry out the drugs through non-covalent interactions of a host-guest type. Such macrocyclic hosts offer advantages that allow a more targeted drug delivery and controllable release of the therapeutic guests. We present the use of cucurbit[7]uril for the activation of proton pump inhibitors, such as omeprazole, which are used worldwide to cure gastric acid-related diseases. We demonstrate how the complexation of these drugs catalyzes with a 15-fold rate enhancement an intramolecular nucleophilic substitution reaction, which leads to the formation of a cyclic sulfenamide as the active form of the drug. This effect combines with a 500-fold increase in stability of the active form in its complex. The complex also retains its medicinally relevant reactivity with cysteine. By comparison with other benzimidazole drugs, we can rationalize the observed catalytic effect mechanistically through a supramolecular pK_a shift affected by the macrocycle. The combined results are expected to stimulate follow-up work on the use of pK_a shifts by cucurbit[7]uril to deliver efficiently and stably benzimidazole carbamate anticancer drugs, such as albendazole. Also the results underscore the pharmaceutical potential of cucurbiturils as promising alternatives to cyclodextrins in drug delivery.

*Corresponding author: Tel: +962 797054780; fax: 962 2 7211117. E-mail address: nsaleh@yu.edu.jo or nailsaleh@yahoo.com