Improvement of the Anticancer Activity of Chlorambucil and Ibuprofen via Calix[4]arene Conjugates.

BACKGROUND: One of the possible ways of improving the activity and selectivity profile of anticancer agents is to design drug carrier systems employing nanomolecules. Calix[4]arene derivatives and chlorambucil and ibuprofen are important compounds that exhibit interesting anticancer properties. OBJECTIVE: The objective of this article is the synthesis of new calix[4]arene-derivative conjugates of chlorambucil or ibuprofen with potential anticancer activity. METHODS: Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth as described [19, 20]. Conjugates of chlorambucil and resorcinarene-dendrimers were prepared in 2% DMSO and added into the culture medium immediately before use. Control cells were treated with 2% DMSO. RESULTS: Thus, calix[4]arene-derivative conjugates of chlorambucil or ibuprofen showed good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the calix[4]arene chlorambucil or ibuprofen conjugates employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) and U-251 (human glioblastoma cells) demonstrated that the conjugate was more potent as an antiproliferative agent than free chlorambucil and ibuprofen. The conjugates did not show any activity against the COS-7 African green monkey kidney fibroblast cell line. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new calix[4]arene derivative conjugates of chlorambucil or ibuprofen. Cytotoxicity assays revealed that at 10 µM, the conjugates were very active against K-562 (human chronic myelogenous leukemia cells) and U- 251 (human glioblastoma cells) cancer cells' proliferation. In order to explain the molecular mechanisms involved in the anticancer activity of calix[4]arene chlorambucil or ibuprofen conjugates, our research will be continued.

In vitro activity of resorcinarene-chlorambucil conjugates for therapy in human chronic myelogenous leukemia cells.

A possible way of improving the activity and selectivity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules. Thus, four resorcinarene-PAMAM-dendrimer conjugates of chlorambucil with different groups in the lower part of the macrocycle and different length dendritic arms showed a good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the resorcinarene-PAMAM-dendrimer-chlorambucil conjugate employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) demonstrated that the conjugate was more potent as an antiproliferative agent than chlorambucil.

Anticancer Activity of Resorcinarene-PAMAM-Dendrimer Conjugates of Flutamide.

METHODS: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. RESULTS: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. CONCLUSION: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.

Synthesis, Characterization, and Nanomedical Applications of Conjugates between Resorcinarene-Dendrimers and Ibuprofen.

Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene-dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB-231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses.