Synthesis and Biological Evaluation of an <i>iso</i>DGR‐Paclitaxel Conjugate Containing a Cell‐Penetrating Peptide to Promote Cellular Uptake

Bodero, Lizeth; Parente, Sara; Arrigoni, Federico; Klimpel, Annika; Neundorf, Ines; Gazzola, Silvia; Piarulli, Umberto

doi:10.1002/ejoc.202100241

Cited by 2 publications

(1 citation statement)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Integrins are transmembrane receptors that are over-expressed on the cell surface of several tumors like glioblastoma ( Gladson and Cheresh, 1991 ), melanoma ( Brooks et al, 1994 ), prostate ( Heß et al, 2014 ), pancreatic cancer ( Hosotani et al, 2002 ) and others, and are involved in several biological processes linked to the tumor growth. To this aim, we designed a cyclic peptidomimetic containing a diketopiperazine (DKP) and the α v β 3 integrin recognizing sequence Arg-Gly-Asp (RGD) ( Marchini et al, 2012 ; da Ressurreição et al, 2009 ) or iso Asp-Gly-Arg ( iso DGR) ( Mingozzi et al, 2013 ; Panzeri et al, 2015 ) with low-nanomolar affinity, which were conjugated to different cytotoxic payloads such as α-amanitin ( Bodero et al, 2018 ), paclitaxel (PTX) ( Dal Corso et al, 2015 ; Dias et al, 2017 ; Rivas et al, 2018 ; Bodero et al, 2021 ), and auristatin derivatives ( Dias et al, 2019 ) through the cathepsin-sensitive VA linker. In addition, the self-immolative spacer p -aminobenzyloxycarbamate (PABC) was inserted to facilitate the release of the drug upon enzymatic cleavage.…”

Section: Introductionmentioning

confidence: 99%

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

et al. 2023

Self Cite

View full text Add to dashboard Cite

Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug Conjugates (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects of conventional chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through a linker that releases the drug inside or in proximity of the tumor cell, and that represents a key component for the final therapeutic effect of the conjugate. Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] αVβ3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the “kiss-and-run” protocol, and the relative potency were clearly consistent with the expression of the αVβ3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15 min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems.

show abstract

Section: Introductionmentioning

confidence: 99%

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

Design, Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl β‐Carboline Derivatives for the Development of Drug Conjugates Targeting MDM2

Arrigoni,

Prpić,

Ferrari

et al. 2024

Eur J Org Chem

View full text Add to dashboard Cite

The mouse‐double‐minute‐2 (MDM2) protein, the main downregulator of the tumor suppressor p53 protein, represents a promising target for the development of novel anticancer therapies. However, the lack of selectivity and poor effectiveness in tumors bearing mutated‐p53 impaired the approval of several MDM2 inhibitors for the market. In this context, the possibility of generating drug‐conjugates within a MDM2 inhibitor is a growing research area aimed to overcome these drawbacks. Considering the promising MDM2 inhibition by the β‐carboline‐based 1, in this work we explored the introduction of a new functionalization on it for a future conjugation while preserving its anticancer properties. Based on preliminary docking studies, we synthesized derivatives 2a‐d having linear hydroxyalkyl chains with different lengths at the 6‐position of the β‐carboline core, which effectively preserved the submicromolar IC50 on wild‐type‐p53‐U87MG glioblastoma cell line observed with 1. Candidates 2a,d showed the functionalization was tolerated with respect of bioactivity also on mutated‐p53‐U138MG glioblastoma cell line, and their hydroxyl groups proved to be easily accessible when coupled to 4‐pentynoic‐N,N’‐dimethylethylenediamine affording derivatives 10a,d with high yields. In summary, our results led to generating novel 6‐hydroxyalkyl‐β‐carboline compounds displaying a suitable hydroxyl‐site useful to improve the efficacy and/or the tumor specificity of 1 through conjugation strategies.

show abstract

Synthesis and Biological Evaluation of an isoDGR‐Paclitaxel Conjugate Containing a Cell‐Penetrating Peptide to Promote Cellular Uptake

Cited by 2 publications

References 47 publications

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

Design, Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl β‐Carboline Derivatives for the Development of Drug Conjugates Targeting MDM2

Contact Info

Product

Resources

About