The Therapeutic Potential of Spirooxindoles in Cancer: A Focus on p53-MDM2 Modulation

Abstract

The p53, often referred to as the "guardian of the genome", is a well-established tumor-suppressor protein that plays a critical role in regulating the cell cycle, DNA repair, differentiation, and apoptosis, with its activity primarily modulated by the MDM2 protein (murine double minute 2, also known as HDM2 in humans). Disrupting the protein-protein interaction between p53 and MDM2 represents a promising therapeutic strategy for developing anticancer agents. Recent studies have shown that several spirooxindole-containing compounds exhibit significant antitumor properties, primarily by inhibiting the p53-MDM2 interaction. This review provides an overview of structure-based spirooxindoles that could have therapeutic potential. It highlights findings from the past decade concerning their antiproliferative properties and implications for interfering with the p53-MDM2 interaction. The discussion includes various analogs of spirooxindoles as promising candidates for optimizing leads in drug discovery programs aimed at developing novel and clinically effective agents.

Keywords: MDM2; cancer; p53; spirooxindole.

Figure 1

Compounds entered in clinical trials as p53–MDM2 inhibitors.

Figure 2

Natural spirooxindole-containing compounds with antiproliferation properties.

Figure 3

Some synthetic methodologies for spirooxindoles.

Figure 4

Nutlin-3 (15, p53–MDM2 inhibitor).

Scheme 1

Synthesis of spiro[oxindole-3,2′-pyrrolidines] 18.

Scheme 2

Synthesis of stereoidal spirooxindoles 23.

Scheme 3

Synthesis of spirooxindoles bearing isoxazol-5-yl heterocyclic scaffold 26.

Scheme 4

Synthesis of spirooxindoles linked to pyrrole heterocycle through a carbonyl function/spacer 30 and 31.

Figure 5

Chemical structure of marinopyrrole A 32.

Scheme 5

Synthesis of spirooxindoles 36.

Scheme 6

Synthesis of spirooxindole linked to benzimidazolyl heterocycle through carbonyl group 38.

Figure 6

Spirooxindole linked to benzimidazolyl heterocycle 39.

Scheme 7

Synthesis of spiroindolinone–pyrrolidinecarboxamide 44.

Scheme 8

Synthesis of spirooxindoles 47.

Scheme 9

Synthesis of spirooxindoles 49.

Scheme 10

Synthesis of spirooxindoles linked to 3-acylindole 51.

Figure 7

Chemical structure of BI-0252 52.

Scheme 11

Synthesis of spirooxindoles 62/63.

Scheme 12

Synthesis of dispirooxindole–pyrrolidines 65–68.

Scheme 13

Synthes of dispirooxindole–pyrrolidines 70.

Scheme 14

Synthesis of dispirooxindole–pyrrolidines collaborated benzofuranyl heterocycle 74–79.

Scheme 15

Synthesis of dispirooxindole–pyrrolidines linked to thiohydantoin 81.

Scheme 16

Synthesis of dispirooxindole–pyrrolidines 84.

Scheme 17

Synthesis of dispirooxindole–pyrrolidines 89.

Scheme 18

Synthesis of dispirooxindole–pyrrolidines 92.

Scheme 19

Synthesis of dispirooxindole–pyrrolidine 94.

Scheme 20

Synthesis of spirooxindole–pyrazolines 97.

Scheme 21

Synthesis of spirooxindole–pyrazolines linked to triazolyl heterocycle 101.

Scheme 22

Synthesis of spirooxindole–pyrazolines conjugated with flavone 104 and 105.

Scheme 23

Synthesis of spirooxindole–isoxazolines 107.

Scheme 24

Synthesis of spirooxindole–triazoles 108.

Scheme 25

Synthesis of spirooxindole–oxadiazoles 110.

Scheme 26

Synthesis of spirooxindole–piperidines 116–119.

Scheme 27

Synthesis of spirooxindole–pyrans 123–125.

Scheme 28

Synthesis of spirooxindole–benzopyran 128.

Scheme 29

Synthesis of spirooxindole–benzopyran 133.

Scheme 30

Synthesis of spirooxindole–thiopyrans 136, and 135.

Scheme 31

Synthesis of spirooxindole–thiopyrans 136, 142–144.

Scheme 32

Synthesis of spirooxindole–thiopyrans 146–149.

Scheme 33

Synthesis of spirooxindole–thiopyrans 144 and 150.