Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy

Abstract

A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7a. The photochemical labile protecting groups in (S,S)-7a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J cm(-2). The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC(50) value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (-)-(S,S)-5 with an IC(50) value of about 110 fM. The big therapeutic window makes (S,S)-7a very suitable for its use in selective cancer therapy.

Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy

“…Figure 22), which is a natural antibiotic. [85] Through the introduction of an ONP-based moiety in the seco drug ( Figure 22 A surprising result found in this study is that the prodrugs that contain a free carboxylic acid in the benzyl position of the ortho-nitrophenyl derived group (51c, 52b) showed even higher toxicity before irradiation than after. As an explanation for this enhanced toxicity, an active transport mechanism of this compound to the active site was proposed [85] , but this presumption was not investigated further.…”

Photoactivated Colibactin Probes Induce Cellular DNA Damage

“…Given the suspected instability of colibactins towards isolation, probes in which the N ‐terminal amine is masked by a photolabile group (nitroveratryloxycarbonyl, NVOC) were used (Figure ) . Analogous to the work of Tietze et al, probes could be activated via photolysis and then added to the relevant biological system for evaluation. This approach would avoid the enzymatic maturation strategy used by the colibactin‐producing bacteria and, importantly, provide proof of concept that genotoxicity can be affected conditionally by alternate means of activation.…”

Observation by NMR of cationic Wheland-like intermediates in the deiodination of protected 1-iodonaphthalene-2,4-diamines in acidic media

“…3,4) for selective delivery of CPIs and CBIs to tumours. 2,4 Efficient routes to the required hydroxy-seco-CBIs are available but access to the corresponding amino-seco-CBIs is more challenging. 5,6 As part of our research towards a general route to amino-seco-CBIs, di-Boc-1-iodonaphthalene-2,4-diamine 11 was prepared from 2,4-dinitronaphthalen-1-ol 6 in five steps, as shown in Scheme 1.…”