Abstract
A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins
3a–f
(isatin,
3a
, 6-chloroisatin,
3b
, 5-fluoroisatin,
3c
, 5-nitroisatin,
3d
, 5-methoxyisatin,
3e
, and 5-methylisatin,
3f
, and (2
S
)-octahydro-1
H
-indole-2-carboxylic acid
2
, in situ azomethine ylides reacted with the cyclohexanone based-chalcone
1a–f
to afford the target di-spirooxindole compounds
4a–n
. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound
4b
was identified as the most active member of this series against prostate cancer cell line PC3 (IC
50
= 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs
4a
and
4l
(IC
50
= 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO
2
substituted isatin ring and
meta
-fluoro-substituted (2
E
,6
E
)-2,6-dibenzylidenecyclohexanone containing
4i
(IC
50
= 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.