摘要：

A 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 mu M) showed a potency ten folds higher than that of Olaparib but compound 15 (IC50 = 7.47 mu M) exerted lower activity but still comparable to that of Olaparib (IC50 = 6.84 mu M). 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.

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