107326-30-7Relevant academic research and scientific papers
Dual intra- and extracellular release of monomethyl auristatin E from a neutrophil elastase-sensitive antibody-drug conjugate
Mohamed Amar, Imene Ait,Huvelle, Steve,Douez, Emmanuel,Letast, Stéphanie,Henrion, Sylvain,Viaud-Massuard, Marie-Claude,Aubrey, Nicolas,Allard-Vannier, Emilie,Joubert, Nicolas,Denevault-Sabourin, Caroline
, (2022/01/06)
Antibody-drug conjugates (ADCs) are targeted therapies, mainly used in oncology, consisting in a three-component molecular architecture combining a highly potent drug conjugated via a linker onto a monoclonal antibody (mAb), designed for the selective delivery of the drug to the tumor site. The linker is a key component, defining the ADC stability and mechanism of action, and particularly the drug release strategy. In this study, we have developed and synthesized a cleavable linker, which possesses an Asn-Pro-Val (NPV) sequence sensitive to the human neutrophil elastase (HNE), overexpressed in the tumor microenvironment. This linker permitted the site-specific conjugation of the cell-permeable drug, monomethyl auristatin E (MMAE), onto trastuzumab, using a disulfide re-bridging technology. The resulting ADC was then evaluated in vitro. This conjugate demonstrated retained antigen (Ag) binding affinity and exhibited high subnanomolar potency against Ag-positive tumor cells after internalization, suggesting an intracellular mechanism of linker cleavage. While no internalization and cytotoxic activity of this ADC was observed on Ag-negative cells in classical conditions, the supplementation of exogenous HNE permitted to restore a nanomolar activity on these cells, suggesting an extracellular mechanism of drug release in these conditions. This in vitro proof of concept tends to prove that the NPV sequence could allow a dual intra- and extracellular mechanism of drug release. This work represents a first step in the design of original ADCs with a new dual intra- and extracellular drug delivery system and opens the way to further experimentations to evaluate their full potential in vivo.
Microwave-assisted convenient synthesis of α,β-unsaturated esters and ketones via aldol-adduct elimination
Suman, Pathi,Nageswara Rao, Rayala,China Raju, Bhimapaka
, p. 1548 - 1559 (2013/09/02)
Various fluorinated 3-oxo ester/1,3-diketones were reacted with carbonyl compounds, in presence of piperidine and under microwave irradiation, to afford (E)-α,β-unsaturated esters and ketones in good yields. The systematic study reveals that the reaction proceeded through the formation of aldol adduct. The method provides a new and simple way for C,C bond formations. Copyright
