Nitro-Containing Self-Immolative Systems for Biological Applications

Abstract

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to the release of smaller molecules. The particular reactivity of the nitro group, due to its powerful electron-withdrawing nature, has been exploited in the field of self-immolative chemistry. In this context, the present review describes the major role of the nitro group in self-immolative processes depending on its position.

Keywords: nitro; probe; prodrug; self-immolation.

Scheme 1

Schematic representation of a self-immolative compound.

Scheme 2

Structure of double-release compound 1 and proposed mechanism of liberation of two leaving groups L after chemical activation of 1.

Scheme 3

Elimination of two paclitaxel molecules in a single triggering nitro reduction of compound 2.

Scheme 4

Release of tryptamine from 3 after reduction with Zn/AcOH.

Scheme 5

Reduction mechanisms of nitroaromatic compound by type 1 and 2 nitroreductases.

Scheme 6

The formation of actinomycin D from its 4-nitrobenzyloxycarbonyl derivative 4 by reduction of the nitro group by the nitroreductase enzyme, followed by self-immolation of the resulting 4-(hydroxyamino)benzyloxycarbonyl derivative.

Figure 1

Two nitroarylcarbamate prodrugs 5 and 6 of doxorubicin.

Scheme 7

Liberation of two pharmacophores, acetazolamide and indomethacin, from prodrug 7 after nitroreductase activation.

Scheme 8

Complete degradation of photocleavable polymer 8 into small molecules after UV irradiation.

Scheme 9

Reduction mechanism of o-nitrobenzyl derivatives using light.

Scheme 10

Depolymerization of polyglyoxylate 9 into non-toxic products upon UV irradiation.

Scheme 11

Deprotection of the ONB photocleavable group of 10 to release melatonin.

Scheme 12

Mechanism of PC4AP-based drug delivery system.

Scheme 13

Camptothecin release from polymer 11 after near-infrared and nitroreductase activation.

Scheme 14

Switchable phototherapeutic strategy.

Scheme 15

Release of dopamine after UV activation of the prodrug 20.

Scheme 16

Replacement of the labile nitroazo group of compound 12 by the addition of GSH induced strong fluorescence.

Scheme 17

Plausible mechanism for the selective reaction of probe 13 to GSH.

Scheme 18

Mechanism of camptothecin and NIR dye release from the dual self-immolative system 14 after GSH activation followed by linker self-immolation.

Scheme 19

The activation mechanism of photosensitizer 15.

Scheme 20

Release of paclitaxel from prodrug 16 after β-D-glucuronidase activation and self-immolation of the nitro-containing linker.

Figure 2

Paclitaxel prodrugs containing a carbonate moiety on the linker.

Scheme 21

Release of 10-hydroxycamptothecin from prodrug 18 by β-glucuronidase activation.

Scheme 22

Structure of the PET tracer and its activation mechanism.

Scheme 23

Mechanism of caged hapten protein proximity immunohistochemistry assay. (A) First protein target of interest; (B) second protein target of interest; (C) primary antibody against A; (D) primary antibody against B; (E) secondary antibody labeled with AP; (F) secondary antibody labeled with nitropyrazole-caged hapten; (G) anti-hapten tertiary antibody labeled with HRP.

Scheme 24

Schematic illustration of the mechanism of HDAC-mediated decaging reactions.

Figure 3

Dendrimer 21 resulting in dendritic amplification.

Scheme 25

Retrosynthetic analysis of dendrimer 22 to reduce the incubation time.

Scheme 26

β-Galactosidase-catalyzed release mechanism of the two drug units of doxorubicin from the chemical system 23.

Scheme 27

Proposed self-immolative mechanism using electrophiles.

Figure 4

Best self-immolative system 24 for disclosure of reactive electrophilic alkylating agents.

Scheme 28

Mechanism of FRET probe 25 activation for the detection of alkylating agents.

Figure 5

Chemical structure of the prodrug neuraminidase substrate 26.

Scheme 29

A plausible mechanism of neuraminidase-triggered activation of 26.