Recent developments in the medicinal chemistry of single boron atom-containing compounds

Abstract

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

Keywords: ACTs, artemisinin combination therapies; ADCs, Acinetobacter-derived cephalosporinases; AML, acute myeloid leukemia; AMT, aminopterin; BLs, β-lactamases; BNCT, boron neutron capture therapy; BNNPs, boron nitride nanoparticles; BNNTs, boron nitride nanotubes; Boron-containing compounds; CEs, carboxylesterases; CIA, collagen-induced arthritis; COVID-19, coronavirus disease 2019; ClpP, casein protease P; Covalent inhibitors; GSH, glutathione; HADC1, class I histone deacetylase; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; LeuRS, leucyl-tRNA synthetase; Linker components; MBLs, metal β-lactamases; MDR-TB, multidrug-resistant tuberculosis; MERS, Middle East respiratory syndrome; MIDA, N-methyliminodiacetic acid; MM, multiple myeloma; MTX, methotrexate; Mcl-1, myeloid cell leukemia 1; Mtb, Mycobacterium tuberculosis; NA, neuraminidase; NS5B, non-nucleoside polymerase; OBORT, oxaborole tRNA capture; OPs, organophosphate; PBA, phenylboronic acid; PDB, Protein Data Bank; PPI, protein–protein interaction; Prodrug; QM, quinone methide; RA, rheumatoid arthritis; ROS, reactive oxygen species; SARS-CoV-2, syndrome coronavirus 2; SBLs, serine β-lactamases; SERD, selective estrogen receptor downregulator; SHA, salicyl hydroxamic acid; SaClpP, Staphylococcus aureus caseinolytic protease P; TB, tuberculosis; TTR, transthyretin; U4CR, Ugi 4-component reaction; cUTI, complex urinary tract infection; dCTPase, dCTPase pyrophosphatase.

Graphical abstract

Figure 1

Timeline and structures of FDA-approved boron-containing drugs.

Figure 2

Diverse structures of boron compounds and their interaction modes with biological targets.

Figure 3

Design of HDAC/proteasome dual inhibitor 14.

Figure 4

Design of dCTPase inhibitor 18.

Figure 5

The structure of inhibitor 19.

Figure 6

Structure-based design identified covalent Mcl-1 inhibitors targeting Lys234: Docked structure of inhibitor 21 (PDB ID:3WIX) and structures of compounds 20–22.

Figure 7

Oxidation of boronic prodrugs to release the active drug.

Figure 8

Targeting ROS-producing cancer cells; the structures of prodrugs 23 and 24.

Figure 9

A dual-stimulus-responsive hybrid anticancer drug 27.

Figure 10

Metabolic conversion of ZB483 to endoxifen.

Figure 11

Design of ZB716.

Figure 12

The structures of inhibitors 33–35.

Figure 13

Structures of BPA and BSH.

Figure 14

Mechanisms of β-lactam cleavage by (A) SBLs and (B) MBLs, exemplified by the hydrolysis of a carbapenem. (C) Mode of action of boronate inhibitors for inhibition of SBLs and MBLs.

Figure 15

Design strategy for compound 38.

Figure 16

Planar structure of 39 and X-ray crystal structure of ADC-7/inhibitor complex (PDB code: 6TZJ).

Figure 17

(A)–(D) Design strategies of vaborbactam, 41, taniborbactam and QPX7728, respectively. (B) Co-crystallization of 41 with VIM-2 (B1). The overlay compares the binding modes of 41 and hydrolysed cefuroxime complexed with NDM-1 (B2) (PDB ID: 4RL2). (C) Crystal structures of VNRX-5133 complexed with NDM-1 (PDB ID: 6RMF); chain A shows the major observed bicyclic form (C1), while chain B shows the tricyclic form (C2). (E) Activities of vaborbactam, 41, taniborbactam and QPX7728.

Figure 18

X-ray structure analyses of the VIM-2/45 (A) and KPC-2/45 (B) complexes, leading to the development of 46.

Figure 19

Mechanism of inhibition of LeuRS by tavaborole and X-ray cocrystal structure of LeuRS complexed with 47 (PDB ID: 5AGR).

Figure 20

Design of multimeric boronic acids specifically targeting the extracellular Mtb cell-envelope glycans. The complex Mtb cell envelope and peptidoglycan layer are indicated by lines and hexagons, respectively.

Figure 21

Integrated strategies to optimize hit compound 49.

Figure 22

Structures of compounds 51–56 and interactions between 56 and the S2ʹ subsite of HIV-1 protease.

Figure 23

The design of GSK8175 and the cocrystal structure of GSK8175 bound to GT 1a 316Y protein (PDB ID: 6MVO).

Figure 24

Structures of compounds 59 and 60.

Figure 25

(A) Structures of compounds 61–63. (B) Crystal structure of the ZIKV NS2B-NS3 in complex with compound 63 (PDB ID: 5LC0). (C) Schematic illustration of 63 in the substrate-binding site of WNV NS2B-NS3 protease.

Figure 26

Structures of antiparasitic agents 64–67.

Figure 27

Structures of antiparasitic agents 68–70.

Figure 28

Planar structure of diboronic acid 71, and structure of the wild-type transthyretin complexed with 71 (PDB ID: 5u4f).

Figure 29

Structures of tetrahedral and trigonal planar boronic acid adducts (A) and compound 72 (B).

Figure 30

Chemical structures of prodrugs of AMT and MTX.

Figure 31

Schematic representation of the self-assembling dimer approach.

Figure 32

Schematic representation of the equilibria of boronic acid and diol/salicylhydroxamic acid that are utilized for dimer formation.

Figure 33

(A) Structures of boronic acid and partner molecules, and the self-assembled dimers. (B) X-ray crystallographic structure of the dimer of 77 and 78 bound to tryptase (PDB ID: 6P0P).

Figure 34

Intracellular co-assembly of peptides.

Figure 35

“Tag and modify” protein conjugation with dynamic covalent chemistry.