In organic chemistry, sulfonates are the organic esters of sulfonic acids with the general formula R1-SO2O-R2. Here, both R1 and R2 groups are organic groups. Notably, when the R1 group is a methyl group and R2 is an alkyl group, the sulfonate belongs to the family of alkyl methane sulfonates. The general formula is shown in Fig. 1. Alkyl methane sulfonate, also known as alkyl mesylate ester, is a class of lipids and has received a lot of attention.
Fig. 1 General formula of alkyl methane sulfonate.
Alkyl methane sulfonates can be synthesized by the esterification of sulfonic acids and alkyl alcohols or the transesterification reaction of methane sulfonates and alkyl alcohols. For example, isopropyl methane sulfonate can be formed by adding methane sulfonic acids (MSA) to isopropanol or by transesterification reaction of isopropanol with preformed methyl methane sulfonate (MMS). The specific synthetic routes are shown in Fig. 2.
Fig. 2 Esterification and transesterification for formation of isopropyl methane sulfonate .
Alkyl methane sulfonates show potential genotoxicity and seriously threaten human health. Methane sulfonic acids are often used to create conjugates with active pharmaceutical ingredients (APIs) to improve pharmacological properties. Therefore, it may result in the presence of trace amounts of alkyl methane sulfonates in the final products.
Notably, methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and isopropyl methanesulfonate (IMS) have been proven to be carcinogens and genotoxins with potential health hazards. Among them, MMS and EMS present in the anticancer drug imatinib mesylate (INM) and synthesized by MSA, as shown in Fig. 3.
Fig. 3 Formation of MMS and EMS from INM .
Therefore, it is necessary to develop analytical methods to regulate and control sulfonate impurities in pharmaceutical products. The presence of toxic alkyl methane sulfonates can also be avoided by methods such as pH control, use of high-purity MSA or non-hydroxyl reaction solvents.
Alkyl methane sulfonates can be divided into short-chain and long-chain alkyl menthane sulfonates. Long-chain alkyl sulfonates are commonly used to separate water-soluble basic analytes in the analysis of water-soluble vitamins . And short-chain alkyl methane sulfonates are DNA-reactive genotoxins and possibly carcinogenic alkylating agents. Here we mainly introduce the application of alkyl methane sulfonates as DNA alkyl reagents.
Methane sulfonate is an extremely good leaving group, so alkyl methane sulfonates can act as DNA alkylating reagents. The mechanism of most anticancer drug to kill cancer cell involves interfering with DNA replication, which can be achieved via DNA alkylation. Some alkyl methane sulfonates act as alkylating reagents, which can cause alkylation in a certain site within the DNA molecule, inducing DNA intrastrand and interstrand cross-links, thereby blocking DNA replication.
Some bis(methanesulfonate) compounds have been used as alkylating reagents for antitumor, where two methanesulfonate groups are separated by a polymethyl chain. For instance, busulfan has good activity as a DNA alkylating reagent and can induce intrastrand DNA cross-links, mainly at 5'-GA-3' sequence, as shown in Fig. 4. Besides, it also reacts with guanine N-7 through the SN2 mechanism .
Fig. 4 DNA alkylation by busulfan .
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