Nitrobenzyl-Based Photosensitive Phosphoramide Mustards:  Synthesis and Photochemical Properties of Potential Prodrugs for Cancer Therapy

Abstract

Several nitrobenzyl-based photosensitive phosphoramide mustards were synthesized. The nitrobenzyl moiety was structurally varied to find the most promising prodrug candidates in respect to photorelease and activity of the alkylating species. The synthesis of these compounds proved to be applicable even in regard to compounds with additional functionalization. The target molecules 13a,b to 14 exhibited the expected red shift in their absorption spectra maximum compared to the parent nitrobenzyl moiety. As seen by UV and (31)P NMR spectroscopy, the phosphoramide mustard was quickly liberated upon irradiation with mercury arc lamps. Assaying the structurally different prodrugs on their alkylating activity showed that compounds 13b and 14, derived from secondary benzyl alcohols, are promising prodrug candidates. Their water solubility and the possibility of attaching macromolecules are encouraging vis-à-vis future investigations on their in vitro cytotoxicity.

Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy

“…Twenty years ago, the first examples of photocaged chemotherapeutics were published. [63], [64] The general design involves an organic or metalorganic cytotoxic agent that carries a photoremovable protecting group (PPG) that cages its activity. To date, development of a wide range of such drugs have been published with studies showing very promising results.…”

“…One of the first photocaged chemotherapeutics was reported by Reinhard and Schmidt [63] , who presented derivatives of phosphoramide mustard (49a,b and 50, Figure 21). Phosphoramide mustard is the active metabolite of cyclophosphamide and is cytotoxic due to its ability to alkylate DNA.…”

Optical Gating of Photosensitive Synthetic Ion Channels

“…Numerous photolabile protecting groups (PPGs) have been reported, which are based on different mechanisms involving the excitation of chromophores 27–29. PPGs have been widely used in organic synthesis,30 for protecting carbohydrates,31 in biochemistry (e.g., as “caged compounds”),32 and in solid phase and combinatorial synthesis 33, 34. The most interesting feature of PPGs is that they can be cleaved upon exposure to long UV wavelength (UV 365 ) without causing any damage to the rest of the molecule directly attached to the substrate.…”

A Model for Light‐Triggered Porphyrin Anticancer Prodrugs Based on an o‐Nitrobenzyl Photolabile Group

“…[19,17] To the best of our knowledge, no examples of porphyrin anticancer prodrugs that are able to release anticancer drugs have ever been disclosed in the literature. In addition, although a light-triggered strategy has been applied in the design of the prodrug, [16][17][18][19] there is no report of light-triggered anticancer prodrugs with a porphyrin. To continue our efforts in the development of porphyrin anticancer prodrugs, [10,11] in this communication, we present the first paradigm of an anticancer prodrug: it contains a porphyrin, but it is also able to release anticancer drugs upon photolysis by long-wavelength UV light.…”