# Synthesis and Preliminary Screening of the Biological Activity of Sulindac Sulfoximine Derivatives
## 1 Introduction  
Anti-inflammatory agents have been studied as adjuvants in cancer therapy during the past four decades [1, 2]. This therapeutic strategy is well recognized, and its side effects are controlled. Sulindac was one of the anti-inflammatory agents employed for this purpose [3, 4]. Sulindac is an aryl methyl sulfoxide prodrug. It is inactive in vitro but is activated upon metabolic reduction to sulindac sulfide in vivo. Thus, the sulfide is the corresponding drug and it is active both in vitro and in vivo [3, 4]. Sulindac is a bioprecursor prodrug and therefore differs from its active metabolite from a physicochemical and biological point of view [5]. Sulindac sulfide blocks prostaglandin synthesis [6]. Moreover, sulindac and its metabolites (i.e., sulindac sulfide 3a and suindlac sulfone 3b, Figure 1) have been reported to shown interesting effects in the prevention of colon carcinogenesis, as shown in human trials, including their potential properties as antiapoptotic agents [7, 8]. As a further example, the amide of Sulindac sulfide, which actually has reduced COX inhibitory activity compared to sulindac, showed interesting antitumor activity against human colon cancer. Therefore, many other amide derivatives of sulindac were synthesized and their activity was tested against cancer cell lines (prostate, colon, and breast) and against lymphoblastic leukemia cell lines with satisfactory antitumor and a clear reduction in side effects [9, 10]. Combining two chemotherapeutic agents into a single drug is a common strategy to enhance their activity. A representative example is shown with the combination of platinum complexes, known anticancer agents, with anti-inflammatory drugs [11, 12, 13]. It was reported that these complexes enter tumor cells more efficiently. Later, the two species are released and act. It was reported that this strategy resulted in fewer side effects, with increased therapeutic efficiency. Nowadays, considerable interest is attached to the molecular class of sulfoximines [14; 15], compounds that are isosteres with sulphones. Sulfoximines are small hydrophilic molecules with a sulfur atom in a stable configuration also connected to a nitrogen atom that is nucleophilic and basic. The basicity of nitrogen allows metal ion coordination and the formation of salts with strong acids. Moreover, sulfoximine moiety is metabolized by an oxidative process to its corresponding sulfoxide and sulfone by the cytochrome P450 family [16]. The proposed mechanism of reaction consists of an initial oxidation of the imine nitrogen with the release of nitrous derivatives to yield the sulfoxide. When the secondary or tertiary amines are replaced with sulfoximines in various bioactive compounds, interesting pharmacological, physicochemical and drug metabolism properties emerge, because sulfoximine derivatives, although similar in pharmacological potency and lipophilicity, exhibit more possibilities of hydrogen bonding [17]. Sulfoximines were synthesized for the first time more than seventy years ago, but they were seldom employed on a large scale until new and effective synthetic methods were discovered [15; 16; 17; 18; 19]. For example, a simple protocol of wide applicability for the synthesis of sulfoximines is based upon the reaction of the corresponding sulfoxides with PhI(OAc)\({}_{2}\) as the oxidant and solutions of ammonium carbamate as the N source. The resulting availability of sulfoximes has encouraged new investigations into the applications of these compounds as bioactive compounds. A recent review highlighted the opportunity connected to sulfoximines in the period 2013-2020, analyzing the enzymes that could be inhibited [14; 15]. Compounds containing the sulfoximine group showed interesting activities as anti-asthmatics, spasmolity, benzodiazepine receptor partial agonists, and COX-2 enzyme inhibitors. A very promising field of application is the investigation of their antitumor activity, targeting the inhibition of cyclin-dependent kinases (CDKs).