Abstract
Cancer is the second leading cause of death worldwide. This work is an effort to find new effective and safe anticancer agents. In accordance with thalidomide features as immunomodulator anticancer drug, we designed and synthesized ten new thalidomide analogs. The synthesized compounds were biologically evaluated for their anti-tumor activity against three human cancer cell lines namely; hepatocellular carcinoma (HepG2), prostate cancer (PC3) and breast cancer (MCF-7). Thalidomide was used as a reference drug. The obtained data showed that compound 10a is far better than thalidomide against the three cancer cell lines. It exhibited IC50 = 3.89, 4.01 and 2.91 µg/mL against the cell lines, respectively. While thalidomide exhibited IC50 values of 11.26, 14.58, and 16.87 µg/mL against the three cell lines, respectively. Moreover, compounds 7a, 6a and 8 were found to be better than thalidomide against MCF-7 cell line. As they showed IC50 values of 10.32, 12.15 and 15.32 µg/mL, respectively. Furthermore, compounds 6a, 7a, and 8 showed strong activity against the three cell lines. Results of docking studies showed that our compounds can accommodate the pocket of CRBN with binding energies too close to that of thalidomide.
Highlights
Cancer is a life threatening disease and is reported as the second leading cause of death worldwide(Siegel, Miller, and Jemal 2020)(Jemal et al 2008)
Several years later the serendipitous finding that thalidomide could allay the symptoms of erythema nodosum leprosum (ENL) led to its re-emergence as a treatment for various pro-inflammatory and autoimmune conditions (Okafor 2003)
In 1994, speculation that thalidomide teratogenicity is linked to the repression of angiogenesis (Ito, Ando, and Handa 2011) resulted in a new wave of clinical investigations that expanded the use of thalidomide for the treatment of various malignancies, including multiple myeloma (MM) (Singhal et al 1999), melanoma, renal-cell carcinoma and prostate cancer (Eleutherakis-Papaiakovou, Bamias, and Dimopoulos 2004)
Summary
Cancer is a life threatening disease and is reported as the second leading cause of death worldwide(Siegel, Miller, and Jemal 2020)(Jemal et al 2008). Thalidomide was given FDA approval for the treatment of acute ENL in 1998, after further investigations found an immunological basis for this effect. Modification of thalidomide afforded anticancer drugs of significant activity e.g. lenalidomide (II) (Lopez-Girona et al 2012), pomalidomide (III) (Lopez-Girona et al 2012) and CC-122 (IV) (Fig.1) (Hagner et al 2015). Pomalidomide (III) was 10-fold more potent than lenalidomide (2) as a TNF-α inhibitor and interleukin-2 (IL-2) stimulator (Galustian and Dalgleish 2011) It showed better anti-angiogenic results than thalidomide (1) and lenalidomide (2). The first position is phthalimido moiety which was replaced by benzodiazine (quinoxaline) which is a bioisostere to quinazoline of CC-122 This is because thalidomide is not a flexible compound. The second site of modification was the glutarimido moiety It was replaced with sulfonylpiperazine, piperazinocarboxamide and piperazinocarboxylate. Several compounds with similar extensions were reported to have promising activities (see Fig.3)
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