Enhanced cytotoxicity of benzimidazole carbamate derivatives and solubilisation by encapsulation in cucurbit[n]uril.
The albendazole derivatives (2-methoxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (MEABZ), N1-(2-methoxyethoxycarbonyl)-2-amino-5-propylthiobenzimidazole and N1-(2-methoxyethoxycarbonyl)-2-amino-6-propylthiobenzimidazole (MEABZ isomers A and B) and (2-hydroxyethyl) 5-propylthio-1H-benzimidazole-2-yl carbamate (HEABZ) have been synthesised. The cytotoxicity of these compounds was evaluated against a human colorectal cancer cell line (HT-29) and a human prostate cancer cell line (PC-3). The results demonstrate MEABZ, a new benzimidazole, is up to ten times more cytotoxic than the parent drug albendazole, whereas the MEABZ isomers A and B and HEABZ show no activity. A comparison of the cytotoxicity of these compounds, relative to ABZ, provides structure-activity data for this important class of anticancer agents. The aqueous solubilities of MEABZ encapsulated in Q[n] have been determined by (1)H NMR spectroscopy. The aqueous solubility of MEABZ at a physiologically relevant pH increased by 1200-fold by encapsulation in Q[8], from 8 microM to 9.4 mM, while Q[6,7] encapsulation substantially increased the solubility to more than 2 mM. Encapsulation in Q[7] and Q[8] induced significant upfield shifts for the MEABZ propyl and benzimidazole resonances. The upfield shifts indicate that the propyl and benzimidazole protons are located within the Q[7] and Q[8] cavity upon encapsulation. By contrast, encapsulation in Q[6] induced large upfield shifts for the (1)H resonances from the carbamate functional group, indicating that MEABZ associates with Q[6] at its portals, with only the carbamate group binding within the cavity.
School of Physical, Environmental and Mathematical Sciences, University College, University of New South Wales, Australian Defence Force Academy, Northcott Drive, Campbell, ACT 2600, Australia.
Yunjie
Y
Zhao
Mohammad H
MH
Pourgholami
David L
DL
Morris
J Grant
JG
Collins
Anthony I
AI
Day
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001952:Bridged-Ring Compounds; D002219:Carbamates; D014867:Water; C031000:benzimidazole