Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition

Abstract

Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD⁺ reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca²⁺ levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.

Figure 1

Representative dual PARP-1/2 inhibitors on the market or under late-stage clinical development.

Figure 2

Mitochondria-targeting veliparib analogs and related prodrug derivatives. Color scheme: blue = veliparib or veliparib analog; red = linker or prodrug moiety; black = mitochondria-targeting moiety.

Figure 3

Mechanism of veliparib release from prodrugs 3 and 4 by enzymatic cleavage followed by a vinylogous elimination cascade.

Scheme 1. Synthesis of Covalently Modified Veliparib Analog 2

Scheme 2. Synthesis of Veliparib Prodrugs 4 and 5 and Reference Compound 7

Scheme 3. Synthesis of Veliparib Prodrug 3

Scheme 4. Synthesis of Reference Prodrug 6

Figure 4

Graphical display of PARP-1 inhibitory activities of covalently linked derivative 2 and prodrugs 3–7 as well as veliparib before and after treatment with HLLLs after 30 min, 2 h, and 24 h. All analogs were tested at 0.5 μM concentration in the assay buffer. Veliparib was used as a positive control and displayed complete inhibition at 0.5 μM concentration. Statistically significant differences based on P value are indicated as follows: ns, P > 0.05; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.