Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents

Abstract

An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC₅₀ values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC₅₀ of 1.287, 0.117 and 1.185 μM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.

Keywords: Carbonic anhydrase; Design; Docking; Indolin-2-one; Protein kinases; Synthesis.

Fig. 1

Structures of some reported anticancer CAIs, zinc binding groups are represented by pink color

Fig. 2

Structures of representative 2-oxindol and diphenyl urea multi-kinase inhibitors acting as anticancer drugs

Fig. 3

Design strategy for proposed CAIs compounds (4a–d, 5, 7, 9a–c, 11a–c, 13a–c and 15a–c)

Fig. 4

Synthesis of compounds 2 and 4a–d

Fig. 5

Synthesis of compounds 5–7

Fig. 6

Synthesis of compounds 9a–c, 11a–c, 13a–c, and 15a–c

Fig. 7

Structural insights of compound 15c, showing the main pharmacophoric features reported for the multi-kinase inhibition activity of sorafenib and oxindole-based inhibitors

Fig. 8

2D interaction diagrams and 3D representations showing compound 4d docking pose interactions with the key amino acids in the CA II (A), CA IX (B), and CA XII (C) active sites. (Distances in Å)

Fig. 9

2D interaction diagrams and 3D representations showing compound 15c docking pose interactions with the key amino acids in the VEGFR-2 (A), FGFR1 (B), and RET (C) active sites. (Distances in Å)