Synthesis and evaluation of a new series of spiro aryl dioxolane compounds: A new scaffold as potential poly(ADP‐ribose)polymerase‐1 (PARP‐1) inhibitors

Abstract

AbstractA new series of spiro aryl dioxolane derivatives were synthesized and evaluated to find a new scaffold as potential poly(ADP‐ribose)polymerases‐1 (PARP‐1) inhibitors. This key starting compound, 2,6‐bis(methoxybenzylidene)cyclohexanone, was functionalized with different nucleophilic reagents via cyclocondensation reactions to obtain new benzylidene scaffolds containing diverse aryl groups such as spiroindazoleorquinazoline [1,3]dioxolane compounds. Furthermore, the Michael addition reaction of bis‐benzylidene with some active methylene compounds afforded spirochromene‐ or naphthalene‐[1,3]dioxolane compounds. All the synthesized compounds revealed promising inhibition with IC50 values in the nanomolar range (0.997–2.698 nM), not significantly different from that of Olaparib (IC50 = 0.861 nM). Compounds 5b and 15 (IC50 = 1.009 and 0.997 nM) showed the highest potency among all the prepared compounds and accordingly their ability to inhibit the growth of BRCA1 mutated breast cancer cell line MDA‐MB‐436 was tested, where compound 5b (IC50 = 0.67 μM) showed a potency ten folds higher than that of Olaparib but compound 15 (IC50 = 7.47 μM) exerted lower activity but still comparable to that of Olaparib (IC50 = 6.84 μM). Both resulted in the arrest of cell cycle at S phase and caused cell apoptosis. In silico studies including absorption, distribution, metabolism, excretion (ADME) properties, drug‐likeness, and molecular docking were carried out to support the above‐mentioned findings. This work presents compounds 5b and 15 as promising scaffolds as PARP‐1 inhibitors.