A Peptide–Duocarmycin Conjugate Targeting the Thomsen-Friedenreich Antigen Has Potent and Selective Antitumor Activity

Abstract

Solid phase synthesis allowed the rapid generation of a peptide-drug conjugate. A peptide targeting the Thomsen-Friedenreich antigen (TFα) was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The compound, containing a cathepsin B cleavable linker, was shown to be active and selective against TFα expressing tumour cell lines.

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

“…Another strategy targeting TF-antigen showing potent and selective antitumor activity is a peptide specific for TF-α conjugated to the alkylating subunit of the cytotoxin duocarmycin [238]. Duocarmycin is a cytotoxin exhibiting effective antitumor activity in breast and ovarian cancer treatment when conjugated to trastuzumab.…”

Borylation via iridium catalysed C–H activation: a new concise route to duocarmycin derivatives

“…The densely substituted pyrroloindoline core of the natural products continues to interest synthetic chemists and there have been numerous reports of the total synthesis of the natural compounds and synthetic analogues. Efforts to translate this activity to clinical advantage have tended to focus on targeted systems through prodrugs with bioreductive, [6][7][8] bio-oxidative, 9 esterase 10,11 or glycosylase enzymes [12][13][14][15][16] or through antibody, 17 peptide 18 or small molecule conjugates. 19 Many of these efforts have focussed on the use of the synthetic duocarmycin alkylation subunit known as CBI (2, CBI = 1,2,9,9a-tetrahydroCyclopropa[c]Benzo[e]Indol-4-one), as it is considered to be synthetically accessible, available in six steps from commercially available 1,3-dihydroxynaphthalene 3, 20 whereas the routes to the natural products tend to be significantly longer.…”

Novel N-Methylated Cyclodepsipeptide Prodrugs for Targeted Cancer Therapy

“…The utilization of peptides allows the tuning of the physicochemical and biological properties of drugs, in addition to providing targeting ability and improving hydrophilicity . The conditionally labile linkers responsive to pH, redox, , enzymes, , and reactive oxygen species (ROS), , among others, have been developed to temporarily mask the toxicity of drugs and release active molecules under specific tumor microenvironments. In recent years, self-immolating spacers, such as p -aminobenzyl derivatives, that can be spontaneously eliminated to yield active molecules using enzyme or glutathione (GSH) have been utilized in drug delivery and fluorescence-based probe design. − To connect with p -aminobenzyl derivatives, functional groups such as amino or hydroxy groups in drugs are commonly required for carbamate or carbonate formation.…”