Medicinal Chemistry Profiling of Monocyclic 1,2‐Azaborines

Abstract

The first examples of biologically active monocyclic 1,2-azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison to the corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research.

Control of Excited‐State Conformations in B,N‐Acenes

“…Similar considerations can be made for one of the smallest possible nitrogen‐containing compounds with such a property, aminoborane (H 2 N−BH 2 ; Figure ). The B−N scaffold has been discussed as C=C surrogate because of its isoelectronic character . However, it has been shown early on that the B−N rotational barrier (29.3 kcal mol −1 ) of aminoborane is much smaller than that of the C=C bond in ethylene (62.5 kcal mol −1 ) .…”

“…In the excited state, the conformation resulting from a 90° rotation around the B−N bond is not the lowest in energy, though. Further relaxation by pyramidalization is more favored owing to negative hyperconjugation resulting in a twisted out‐of‐plane arrangement of the amine . Based on this, we designed a system that would allow favoring an electronic transition to one specific conformer in the excited state (Figure ).…”

Recent Developments in Azaborinine Chemistry

“…Several of the new functionalization methods described above allowed the synthesis of BN isosteres of biologically active molecules (Scheme ). Recently, Liu et al reported on the medicinal chemistry profiling of three BN isosteres of biologically active carbonaceous biphenyl carboxamides ( 28a – c ) (Scheme ) . The compounds were prepared from the BN isostere of non‐steroidal anti‐inflammatory drug felbinac by amide‐coupling in the presence of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine/ N ‐methylmorpholine.…”

Control of Excited‐State Conformations in B,N‐Acenes

“…TheB ÀNs caffold has been discussed as C=Cs urrogate because of its isoelectronic character. [9][10][11][12][13][14] However,i th as been shown early on that the B À Nr otational barrier (29.3 kcal mol À1 ) [2,15] of aminoborane is much smaller than that of the C = Cb ond in ethylene (62.5 kcal mol À1 ). [3,15] Interestingly,a nalogous behavior has been observed for aminoborane theoretically [4,16] as well as experimentally.…”