Design, synthesis, and biological evaluation of novel bioactive thalidomide analogs as anticancer immunomodulatory agents

Abstract

Cancer is still a dangerous disease with a high mortality rate all over the world. In our attempt to develop potential anticancer candidates, new quinazoline and phthalazine based compounds were designed and synthesized. The new derivatives were built in line with the pharmacophoric features of thalidomide. The new derivatives as well as thalidomide were examined against three cancer cell lines, namely: hepatocellular carcinoma (HepG-2), breast cancer (MCF-7) and prostate cancer (PC3). Then the effects on the expression levels of caspase-8, VEGF, NF-κB P65, and TNF-α in HepG-2 cells were evaluated. The biological data revealed the high importance of phthalazine based compounds (24a-c), which were far better than thalidomide with regard to the antiproliferative activity. 24b showed IC₅₀ of 2.51, 5.80 and 4.11 μg mL^-1 compared to 11.26, 14.58, and 16.87 μg mL^-1 for thalidomide against the three cell lines respectively. 24b raised caspase-8 level by about 7 folds, compared to 8 folds reported for thalidomide. Also, VEGF level in HepG-2 cells treated with 24b was 185.3 pg mL^-1, compared to 432.5 pg mL^-1 in control cells. Furthermore, the immunomodulatory properties were proven to 24b, which reduced TNF-α level by approximately half. At the same time, NF-κB P65 level in HepG-2 cells treated with 24b was 76.5 pg mL^-1 compared to 278.1 and 110.5 pg mL^-1 measured for control cells and thalidomide treated HepG-2 cells respectively. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. This work suggests 24b as a promising lead compound for development of new immunomodulatory anticancer agents.

Fig. 1. Illustration for the rationale of the design.

Scheme 1. General procedure for preparation of target compounds 6 and 7a,b.

Scheme 2. General procedure for preparation of target compounds 11a,b, 13a,b, 15a,b, and 19a,b.

Scheme 3. General methods for preparation of the new derivatives 24a–c.

Fig. 2. Structure–activity relationship based on in vitro anti-proliferative activity.

Fig. 3. Computational prediction of ADMET parameters.