A click-ready pH-triggered phosphoramidate-based linker for controlled release of monomethyl auristatin E

Olatunji, Feyisola P.; Herman, Jacob W.; Kesic, Brittany N.; Olabode, Damilola; Berkman, Clifford E.

doi:10.1016/j.tetlet.2020.152398

Cited by 21 publications

(14 citation statements)

References 18 publications

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“…We prepared the individual spacer-dye modules ( 4 – 6 ) to study specifically the pH-dependence of the self-immolative release, and concomitant turn-on, of the latent fluorophores that would be independent of P–N hydrolysis. While P–N bond hydrolysis is known to be promoted by acidic conditions, ,− the opposite was observed to be true for the self-immolation of the N,N′- dimethylethylenediamine spacer. To prepare the modules ( 4 – 6 ) (Scheme ), Boc-protected amine ( 13 ) and alcohols (14, 15 ) were reacted with activated fluorogenic payloads ( Coum-OCOCl and Coum-NCO ), as depicted in Scheme .…”

Section: Results and Discussionmentioning

confidence: 99%

“…As anticipated, the rate of P−N bond hydrolysis of the payload-phosphoramidate system 1−3 followed pseudo-firstorder kinetics at all pH values (Figure 2B), consistent with our initial studies. 44,47,48 The rate constants (k 1 ) are summarized in Table 1. Importantly, there was no detectable hydrolysis observed for the modules at physiological pH (Figure 2C−E).…”

Section: Resultsmentioning

confidence: 99%

“…We have recently reported on the development of an acidcleavable phosphoramidate-based linker capable of releasing MMAE (Figure 1A). 44 This linker contains two key structural components: (1) a biologically stable and cleavable pHtriggered phosphoramidate scaffold and (2) a self-immolative spacer. MMAE is released when the self-immolative spacer is hydrolyzed from the phosphoramidate scaffold through exposure to acidic conditions.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently reported on the development of an acid-cleavable phosphoramidate-based linker capable of releasing MMAE (Figure A) . This linker contains two key structural components: (1) a biologically stable and cleavable pH-triggered phosphoramidate scaffold and (2) a self-immolative spacer.…”

Section: Introductionmentioning

confidence: 99%

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Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

et al. 2021

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The tunable nature of phosphoramidate linkers enables broad applicability as pH-triggered controlled-release platforms, particularly in the context of antibody- and small-molecule-drug conjugates (ADCs and SMDCs), where there remains a need for new linker technology. Herein, we explored in-depth the release of turn-on fluorogenic payloads from a homoserinyl-based phosphoramidate acid-cleavable linker. Kinetics of payload release from the scaffold was observed in buffers representing the pH conditions of systemic circulation, early and late endosomes, and lysosomes. It was found that payload release takes place in two key consecutive steps: (1) P–N bond hydrolysis and (2) spacer immolation. These two steps were found to follow pseudo-first-order kinetics and had opposite dependencies on pH. P–N bond hydrolysis increased with decreasing pH, while spacer immolation was most rapid at physiological pH. Despite the contrasting release kinetics of these two steps, maximal payload release was observed at the mildly acidic pH (5.0–5.5), while minimal payload release occurred at physiological pH. We integrated this phosphoramidate-payload linker system into a PSMA-targeted fluorescent turn-on probe to study the intracellular trafficking and release of a fluorescent payload in PSMA-expressing prostate cancer cells. Results showed excellent turn-on and accumulation of the coumarin payload in the late endosomal and lysosomal compartments of these cells. The release properties of this linker mark it as an attractive alternative in the modular design of ADCs and SMDCs, which demand selective intracellular payload release triggered by the pH changes that accompany intracellular trafficking.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

et al. 2021

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“…The P−N linkages are acid labile and degrade into their respective phosphates and amines at low pH. This tunable acid triggered hydrolytic degradation of phosphoramidates has noteworthy potential in drug delivery due to the postulated biocompatible and biodegradable nature of the compounds [15–18] …”

Section: Introductionmentioning

confidence: 99%

The Step‐Wise Synthesis of Oligomeric Phosphoramidates

et al. 2021

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In this study, the step‐wise synthesis to a series of higher phosphoramidates was explored, affording compounds containing N−P−N, symmetric and asymmetric P−N−P and P−N−P−N−P linkages. Salt elimination and lithiation strategies were employed to create the new P−N bonds. It was found that the steric bulk and electronic contribution of the substituents on the P(V) centers were important factors to the success of the reactions. The oligomeric phosphoramidates were characterized by multinuclear NMR and IR spectroscopies as well as ESI mass spectrometry. A selection of the synthesized P−N oligomers were evaluated for their antimicrobial activity against E.coli, S.aureus, C.albicans, and A.fumigatus at varying concentrations. The results suggest their potential use as environmentally friendly fire retardants as the minimal inhibitory concentration (MIC) value for all the compounds was found to be >128 μM, indicating that the compounds do not have any detectable antimicrobial activity.

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Insertion of Chemical Handles into the Backbone of DNA during Solid‐Phase Synthesis by Oxidative Coupling of Amines to Phosphites

et al. 2023

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Conjugation of molecules or proteins to oligonucleotides can improve their functional and therapeutic capacity. However, such modifications are often limited to the 5′ and 3′ end of oligonucleotides. Herein, we report the development of an inexpensive and simple method that allows for the insertion of chemical handles into the backbone of oligonucleotides. This method is compatible with standardized automated solid‐phase oligonucleotide synthesis, and relies on formation of phosphoramidates. A unique phosphoramidite is incorporated into a growing oligonucleotide, and oxidized to the desired phosphoramidate using iodine and an amine of choice. Azides, alkynes, amines, and alkanes have been linked to oligonucleotides via internally positioned phosphoramidates with oxidative coupling yields above 80 %. We show the design of phosphoramidates from secondary amines that specifically hydrolyze to the phosphate only at decreased pH. Finally, we show the synthesis of an antibody‐DNA conjugate, where the oligonucleotide can be selectively released in a pH 5.5 buffer.

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A click-ready pH-triggered phosphoramidate-based linker for controlled release of monomethyl auristatin E

Cited by 21 publications

References 18 publications

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

The Step‐Wise Synthesis of Oligomeric Phosphoramidates

Insertion of Chemical Handles into the Backbone of DNA during Solid‐Phase Synthesis by Oxidative Coupling of Amines to Phosphites

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