Diazaborines Are a Versatile Platform to Develop ROS-Responsive Antibody Drug Conjugates**

被引：23

作者：

Antonio, Joao P. M. ^{[1
]}

Carvalho, Joana Ines ^{[1
]}

Andre, Ana S. ^{[2
]}

Dias, Joana N. R. ^{[2
]}

Aguiar, Sandra, I ^{[2
]}

Faustino, Helio ^{[1
]}

Lopes, Ricardo M. R. M. ^{[1
]}

Veiros, Luis F. ^{[3
,4
]}

Bernardes, Goncalo J. L. ^{[5
,6
]}

Silva, Frederico A. ^{[2
]}

Gois, Pedro M. P. ^{[1
]}

机构：

[1] Univ Lisbon, Fac Farm, Res Inst Med iMed ULisboa, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal

[2] Univ Lisbon, Fac Med Vet, Ctr Invest Interdisciplinar Sanidade Anim, Av Univ Tecn, P-1300477 Lisbon, Portugal

[3] Univ Lisbon, Ctr Quim Estrutural, Inst Super Tecn, Av Rovisco Pais 1, P-1049001 Lisbon, Portugal

[4] Univ Lisbon, Dept Engn Quim, Inst Super Tecn, Av Rovisco Pais 1, P-1049001 Lisbon, Portugal

[5] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal

[6] Univ Cambridge, Yusuf Hamied Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2021年 / 60卷 / 49期

关键词：

antibody-drug conjugates; boronic acids; cleavable linkers; diazaborines; reactive oxygen species; ELECTROPHILIC DISPLACEMENT-REACTIONS; MECHANISM;

D O I：

10.1002/anie.202109835

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Antibody-drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. In this study we show for the first time the synthesis of a reactive-oxygen-species (ROS)-responsive ADC (VL-DAB31-SN-38) that is highly selective and cytotoxic to B-cell lymphoma (CLBL-1 cell line, IC50 value of 54.1 nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS-responsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed a favorable energetic profile (Delta GR=-74.3 kcal mol(-1)) similar to the oxidation mechanism of aromatic boronic acids. DABs' very fast formation rate and modularity enabled the construction of different ROS-responsive linkers featuring self-immolative modules, bioorthogonal functions, and bioconjugation handles. These structures were used in the site-selective functionalization of a VL antibody domain and in the construction of the homogeneous ADC.

引用

页码：25914 / 25921

页数：8

共 37 条

[1] Boronic acids as building blocks for the construction of therapeutically useful bioconjugates [J].