NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F1 Fo -ATPase, which suppresses viability of cancerous cells.

BACKGROUND AND PURPOSE: The mitochondrial F1 Fo -ATPsynthase is pivotal for cellular homeostasis. When respiration is perturbed, its mode of action everts becoming an F1 Fo -ATPase and therefore consuming rather producing ATP. Such a reversion is an obvious target for pharmacological intervention to counteract pathologies. Despite this, tools to selectively inhibit the phases of ATP hydrolysis without affecting the production of ATP remain scarce. Here, we report on a newly synthesised chemical, the NH-sulfoximine (NHS), which achieves such a selectivity. EXPERIMENTAL APPROACH: The chemical structure of the F1 Fo -ATPase inhibitor BTB-06584 was used as a template to synthesise NHS. We assessed its pharmacology in human neuroblastoma SH-SY5Y cells in which we profiled ATP levels, redox signalling, autophagy pathways and cellular viability. NHS was given alone or in combination with either the glucose analogue 2-deoxyglucose (2-DG) or the chemotherapeutic agent etoposide. KEY RESULTS: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement of autophagy which impairs cell viability. NHS achieves such a function independently of the F1 Fo -ATPase inhibitory factor 1 (IF1). CONCLUSION AND IMPLICATIONS: The novel sulfoximine analogue of BTB-06584, NHS, acts as a selective pharmacological inhibitor of the mitochondrial F1 Fo -ATPase. NHS, by blocking the hydrolysis of ATP perturbs the bioenergetic homoeostasis of cancer cells, leading to a non-apoptotic type of cell death.

Conversion and degradation pathways of sulfoximines.

In recent years, sulfoximines have received significant attention in both academia and industry. This development has been reinforced by the introduction of new methods for preparing and efficiently accessing key sulfur-based reagents allowing further functionalisations. For all fields and in particular those related to pharmaceutical and agrochemical applications, the knowledge of potential degradation pathways of sulfoximines is vital. Being aware of possible metabolites minimises the risks of late stage failures. In this review, we describe chemical transformations in the laboratory leading to sulfoximine degradations. Those include reductive and oxidative pathways as well as C-S bond cleavage reactions. In a wide frame the intention of this summary is to provide a better understanding of decomposition-like reactions of sulfoximines thereby enabling a more focussed search and analysis of byproducts and potential metabolites in biorelevant systems.

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.

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.