Sulfoximines as ATR inhibitors: Analogs of VE-821.

The ATM- and Rad3-related (ATR) kinases play a key role in DNA repair processes and thus ATR is an attractive target for cancer therapy. Here we designed and synthesized sulfilimidoyl- and sulfoximidoyl-substituted analogs of the sulfone VE-821, a reported ATR inhibitor. The properties of these analogs have been investigated by calculating physicochemical parameters and studying their potential to specifically inhibit ATR in cells. Prolonged inhibition of ATR by the analogs in a Burkitt lymphoma cell line resulted in enhanced DNA damage and a substantial amount of apoptosis. Together our findings suggest that the sulfilimidoyl- and sulfoximidoyl-substituted analogs are efficient ATR inhibitors.

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

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.

Asymmetric Copper-Catalyzed Vinylogous Mukaiyama Michael Addition of Cyclic Dienol Silanes to Unsaturated α-Keto Phosphonates.

A highly stereoselective vinylogous Mukaiyama Michael reaction (VMMR) leading to α-keto phosphonate-containing γ-butenolides with two stereogenic centers is described. The presented transformation is catalyzed by a combination of a commercially available C2 -symmetric bisoxazoline (BOX) ligand and a copper salt and tolerates a variety of nucleophiles and electrophiles. The stereoselectivities of the reactions are good to excellent and the products are obtained in moderate to high yields.

Building Block Approach for the Synthesis of Sulfoximines.

A cross-coupling strategy for the preparation of novel sulfoximines via preformed sulfoximidoyl-containing building blocks has been developed. It allows obtaining a wide range of products in good yields under mild reaction conditions, and it can be applied in late-stage functionalizations, as demonstrated by the synthesis of a sulfoximine-based analogue of a recently reported potent valosine-containing protein inhibitor.