Cancer comprises a spectrum of disorders marked by the unregulated proliferation of irregular cells, defying the typical rules governing cellular growth [1]. These cancerous cells have the ability to infiltrate neighboring tissues and extend to different areas of the body, resulting in the formation of malignant tumors or neoplasms [2].

In contrast, benign tumors do not exhibit uncontrolled cell division, nor do they invade surrounding tissues or metastasize throughout the body. About 90 % of cancer-related deaths are attributed to metastasis, which is the mechanism by which tumors spread [3].

The sulfonamide structure, commonly represented as RSO2NHR plays a crucial role in combating various diseases including, but not limited to, urinary tract infections, respiratory tract infections, toxoplasmosis, glaucoma, epilepsy, gout, and fluid retention [4], [5], [6]. It serves as a key scaffold in the development of drugs with inhibitory effects on anticancer activities, as exemplified by Pazopanib, Belinostat, Dabrafenib, Vemurafenib, Indisulam [7], [8], [9], which have a notable influence on a wide range of pharmacological aspects, encompassing pharmacokinetics, pharmacodynamics, bioavailability, half-life, and more (Fig. 1) [10], [11].

Furthermore, dabrafenib and vemurafenib, both BRAF inhibitors, target melanoma with BRAF V600E mutation, disrupting the mutated BRAF protein's role in cancer cell proliferation [12], [13]. Belinostat, an HDAC inhibitor, is utilized in peripheral T-cell lymphoma treatment, modifying histone acetylation to impede cancer cell growth [14]. Pazopanib is a multi-kinase inhibitor approved for advanced renal cell carcinoma and soft tissue sarcoma [15], [16].

Indisulam, a sulfonamide-based compound, exhibits diverse mechanisms of action and has been under investigation in clinical trials for various cancers, affecting cell cycle regulation and the ubiquitin–proteasome system [17], [18].

Within the realm of medicinal chemistry, the sulfonamide moiety is frequently employed as a bioisostere for the carboxylic group due to its related physicochemical properties [19]. More precisely, the sulfonamide structure can create a hydrogen bonding network akin to that formed by the carboxylic group. Furthermore, the separation between the two oxygen atoms within these functional clusters is relatively similar [20]. By serving as a bioisostere for the carboxylic group, the sulfonamide moiety can overcome certain limitations associated with carboxylic groups, including instability in metabolism, potential for toxicity, and constrained passive movement through cellular membranes [21].

So far, sulfonamides can be organized into distinct categories based on their cancer-fighting mechanisms (Fig. 2). The first category, “tyrosine kinase inhibitors,” can be further subdivided into three classes. The initial class focuses on LMTK3 inhibitors, harnessing sulfonamides' potential for targeted cancer therapy. The second class encompasses sulfonamides adept at inhibiting EGFR, offering a promising avenue against EGFR-driven malignancies. The third-class harnesses sulfonamides' inhibitory prowess against Bruton's Tyrosine Kinase (BTK), broadening their applicability to hematologic cancers.

In the second category, sulfonamides take on the role of aromatase inhibitors, holding promise in disrupting estrogen synthesis via aromatase inhibition, especially in hormone-sensitive cancers like breast cancer. The third category explores sulfonamides as “carbonic anhydrase inhibitors”. While initially used in conditions like glaucoma, they have garnered attention for their potential to impact tumor pH regulation and angiogenesis, opening new avenues for cancer research. In the fourth category, there is ongoing exploration of sulfonamides for their potential to inhibit matrix metalloproteinases (MMPs), enzymes associated with extracellular matrix degradation. The fifth category includes sulfonamides as inhibitors of histone deacetylases (HDACs), which play a role in epigenetic regulation. These diverse classes of sulfonamides underscore their adaptability in targeting a spectrum of cancer-related molecular pathways, underscoring their potential as valuable tools in the fight against cancer. Ongoing research will uncover their full therapeutic potential.