Boron in Medicinal Chemistry: Powerful, but Neglected

Boron is a fascinating element due to its chemical versatility. In nature, boron can be found as boric acid (1, Fig. 1A), which is essential for plants due to its pivotal function in cell wall synthesis (cross linking of pectin in the primary cell wall), protein synthesis, germination and pollination, and increase of sugar translocation.[1] Synthetic boron-containing compounds are well investigated due to their unique properties and widespread applications. In organic chemistry, boronic acids (R-B[OH] 2 ), or their derivatives are commonly used. Boron has a deficiency of two valence electrons and possesses a vacant p-orbital. As a consequence, the neutral form of boronic acids (pK a between 6 and 9 for substituted phenylboronic acids, 2, Fig. 1) show a trigonal planar geometry, but allow conversion to sp-hybridized boron (by coordination of a hydroxyl group), resulting in tetrahedral adducts with a carbon-like configuration (see Fig. 1A). Boronic acids are also mild Lewis acids, chemically stable and easy to handle.[2] Therefore, organoboron compounds represent an attractive class of synthetic intermediates (examples are depicted in Fig. 1B), e.g. in hydroborations (C–H/C–OH bond formation), in the Noble-prize awarded Suzuki–Miyaura coupling (C–C bond formation), or in Chan–Lam coupling (C–N/C–O bond formation).[3] Even though boron, in the form of boric acid (1), is known as a mild antiseptic since the early 19th century, the use of boron in medicinal chemistry and drug discovery has been neglected.[4] Themain reason for this may be due to the unfounded assumption that boron is unstable and toxic. Although boric acid (1), the major metabolite of organoboron compounds, is as toxic as sodium chloride (LD 50 (B(OH) 3 ) = 2660 mg/kg (rat, oral); LD 50 (NaCl) = 3000 mg/kg (rat, oral)), the mindset of medicinal chemists was always like this: “Only a moron would put boron in a drug!”[5] With the FDA-approval of bortezomib (3, Fig. 2) in 2003, the first boron-containing drug for treatment of non-Hodgkin’s lymphoma and multiple myeloma, the mindset of the medicinal chemistry community concerning boron seemed to change. Additionally, it was the first-in-class 26S proteasome inhibitor. The proteasome is the key regulator of (intracellular) protein degradation and pivotal for the disassembly of transcription factors or tumor suppressors. As a consequence, dysregulation of this process leads to uncontrolled cell cycle, which could result in tumor growth. The boronic acid moiety is the key player in the mode of action of bortezomib (3) due to the formation of a tetrahedral, pseudo-covalent complex by accepting a lone pair of electrons from the threonine residue in the active site, resulting