Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375

Abstract

Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of tasisulam and lead to further clinical trials in metastatic melanoma.

Novel Broccoli Sulforaphane-Based Analogues Inhibit the Progression of Pancreatic Cancer without Side Effects

“…However, the establishment of sulforaphane analogues by molecular single atom changes in form of oxygen-to-nitrogen substitutions at the central sulfur, are unprecedented in the context of sulforaphane chemistry. This is surprising, considering that a significant number of other structural variations of sulforaphane are known [10][11][12][13], and that such one-atom modifications have recently led to significant improvements in other medically relevant areas [14][15][16][17][18][19][20].…”

Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy‐amino‐λ6‐sulfanenitrile Intermediate

“…[2,3] High metabolic and chemical stability,along with hydrogen bond donor/acceptor capabilities,can impart improved physicochemical properties to these aza derivatives. [5] Thes ulfonimidamide group on the other hand has been less developed, but presents similar opportunities.B iologically active examples of sulfonimidamides include the aza analogues of the sulfonamides celecoxib [6] and tasisulam, [7] as well as asodium channel inhibitor published by Genentech in ap atent application (Scheme 1b). [5] Thes ulfonimidamide group on the other hand has been less developed, but presents similar opportunities.B iologically active examples of sulfonimidamides include the aza analogues of the sulfonamides celecoxib [6] and tasisulam, [7] as well as asodium channel inhibitor published by Genentech in ap atent application (Scheme 1b).…”

Exploration of Novel Chemical Space: Synthesis and in vitro Evaluation of N‐Functionalized Tertiary Sulfonimidamides

“…However,a sr ecently pointed out by Arvidssona nd co-workers, the sulfonimidamide group is currently gaining popularity as a novelp harmacophore in thel ifes ciences. [3] Examplesi nclude thes ulfonimidamide analogues 5 and 6 of thec linicals ulfonamide-containing anticancer agenttasisulam [5] andn on-steroidal anti-inflammatory drug celecoxib, [6] respectively,aswellasanincreasing number of sulfonimidamides claimedi npatentapplications, fori nstancet he sodium channeli nhibitor 7 (Figure2). [7] However, to the best of our knowledge,as ulfonimidamide candidate for clinicaltesting has yet to be disclosed.…”

“…The described N-functionalization reactions provide as hort and efficient approach to structurally diverses ulfonimidamidesw hich have been the subject of recent, growingi nterest in the life sciences.[a] F. Figure 2. Structures of the sulfonimidamide analogues 5 and 6 of the clinical sulfonamide-containing anticancer agent tasisulam [5] and non-steroidal anti-inflammatory drugc elecoxib, [6] as well as of the sodium channel inhibitor 7 [7] disclosed in ar ecent patent application.Scheme1.Synthesis of N-functionalized tertiarysulfonimidamides by various methods using =NH sulfonimidamide 2aa as amodel compound.…”