Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Singlet energy transfer as the main pathway in the sensitization of near-infrared Nd3+ luminescence by dansyl and lissamine dyes.

In general, sensitization of lanthanide(III) ions by organic sensitizers is regarded to take place via the triplet state of the sensitizers. Herein, we show that in dansyl- and lissamine-functionalized Nd3+ complexes energy transfer occurs from the singlet state of the sensitizers to the Nd3+ center. No sensitized emission was observed in the corresponding complexes with Er3+, Yb3+, and Gd3+ ions. Furthermore, the fluorescence of the sensitizers was quenched only in the Nd3+ complex and not in the complexes with the other ions. Only Nd3+ centers can accept energy from the singlet state of the dyes, because the excited states of Nd3+ have a high spectral overlap with the fluorescence of the dansyl and lissamine sensitizers, and because the selection rules allow a fast energy transfer, which apparently is competitive with the fluorescence.