Synthesis of N-cyano-substituted sulfilimine and sulfoximine derivatives of S0859 and their biological evaluation as sodium bicarbonate co-transport inhibitors

Abstract

We synthesized two analogs of S0859 with modified sulfur substituents and evaluated their effects on Na⁺,HCO₃⁻ co-transport activity in cancer cells and tissue. Substitution of the N-cyano sulfonylamido moiety in S0859 by an N-cyano sulfimidoyl or an N-cyano sulfoximidoyl group eliminated the inhibitory action against Na⁺,HCO₃⁻ co-transport in human MCF-7 breast cancer cells. The analogs of S0859 also did not inhibit Na⁺,HCO₃⁻ co-transport in epithelial organoids freshly isolated from breast cancer tissue of ErbB2-overexpressing mice. Consistent with previous suggestions of poor tissue penetration, S0859 inhibited Na⁺,HCO₃⁻ co-transport in MCF-7 cells but had no effect in breast cancer organoids. The inactivity of the tested analogs and the ability of S0859 to inhibit Na⁺,HCO₃⁻ co-transport only in isolated cells underscore the need for new approaches to selectively inhibit Na⁺,HCO₃⁻ co-transport in tissue preparations and in vivo.