# Simple Thalidomide Analogs in Melanoma: Synthesis and Biological Activity
## 1 Introduction  
Cancer is still a great health concern, as it is one of the main causes of death worldwide. A total of 19.3 million new cases of cancer were diagnosed last year, of which 10 million were fatal [1]. Among the different types of cancer, malignant melanoma is one of the most aggressive and deadly skin cancers, with an enormously increasing occurrence over the past few decades [2; 3; 4]. Melanoma is notoriously chemoresistant; nevertheless, chemotherapy represents the primary treatment for metastatic melanoma. Considering the major impact of chemotherapy in cancer management, and the problems related to chemotherapy that have not yet been solved, such as drug toxicity and resistance, particularly in the case of melanoma, research for newer and potent anticancer agents is of great significance. Over the past few years, numerous biologically active heterocyclic compounds have been synthesized and evaluated as anticancer drugs. Among these, many phthalimidic compounds have turned out to be antitumor drug candidates. The phthalimidic core represents the main pharmacophoric feature of thalidomide (Figure 1), a drug infamous for its teratogenic action, which, nevertheless, represents one of the most successful examples of drug repositioning in the treatment of cancer. Indeed, over the last few decades, the interest in this old drug has been renewed because of its efficacy in severalimportant disorders (such as multiple myeloma, breast cancer, and HIV-related diseases [5]) and its antiangiogenic and immunomodulatory properties. Several studies regarding the effects of thalidomide on metastatic melanoma have been reported. Since angiogenesis, and specifically the increased expression of vascular endothelial growth factor (VEGF), has been reported as an important step in disease progression, the use of thalidomide to enhance the antitumor activity of chemotherapy has been investigated in metastatic melanoma [6]. Furthermore, a number of literature data report the effect of thalidomide and its derivatives on tubulin polymerization, causing a perturbation of microtubule dynamics. Microtubules represent important biological targets in cancer treatment due to their involvement in crucial cellular functions [7; 8]. It became clear that thalidomide exerts multifaceted properties; however, many aftereffects, such as deep vein thrombosis, peripheral neuropathy, constipation, somnolence, pyrexia, pain, and teratogenicity, have been reported, showing the need for careful and monitored use [9]. Thus, research efforts are directed toward the synthesis and optimization of new thalidomide analogs, mostly as new anticancer agents, lacking toxic effects and that are able to remove these limits and improve the pharmacological profile. [10; 11]. As a part of an ongoing research program, directed toward the synthesis of several antitumor heterocyclic compounds [12; 13; 14; 15; 16], and our previous paper [17] concerning the antitumor activity of a thalidomide-correlated compound, we report herein the synthesis of a small series of phthalimide derivatives, obtained by directly connecting the N-terminus of the phthalimide moiety with a differently substituted aromatic ring (**2a-l**, Figure 1). These compounds have been investigated for their cytotoxic effects in a large panel of cancer cells, including two melanoma cell lines, namely A2058 derived from a metastatic site, and malignant melanoma cells Sk-Mel28, two breast cancer cell lines (triple negative MDA-MB-231 and ER(+) MCF-7) and a human cervix carcinoma HeLa cell line. The best cytotoxic activity was recovered for compound **2k** on A2058 melanoma cell line. The ability of compound **2k** to inhibit tubulin polymerization has also been reported and a molecular docking study supported the obtained results.