Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity

Abstract

Development of targeted anticancer modalities has prompted a new era in cancer treatment that is notably different from the age of radical surgery and highly toxic chemotherapy. Behind each effective compound is a rich and complex history from first identification of chemical matter, detailed optimization, and mechanistic investigations, ultimately leading to exciting molecules for drug development. Herein we review the history and on-going journey of one such anticancer scaffold, the 3-(4-hydroxyphenyl)indoline-2-ones. With humble beginnings in 19th century Bavaria, we review this scaffold's synthetic history and anticancer optimization, including its recent demonstration of tumor eradication of drug-resistant, estrogen receptor-positive breast cancer. Compounds containing the 3-(4-hydroxyphenyl)indoline-2-one pharmacophore are emerging as intriguing candidates for the treatment of cancer.

Scheme 1. Generalized chemical structure for 3,3-disubstituted oxindoles and 3-(4-hydroxyphenyl)indoline-2-ones.

Scheme 2. Chemical structure of oxyphenisatin and its pro-drug, oxyphenisatin acetate.

Scheme 3. Synthesis of oxyphenisatin as reported by von Baeyer (structure on the right is reproduced from original report in 1885).

Scheme 4. Chemical structure of phenolphthalein.

Scheme 5. Generalized chemical structure of 3,3-diaryl-indoline-2-ones.

Scheme 6. Retrosynthetic disconnection to isatin is an ideal starting point for the synthesis of 3,3-diaryl-indoline-2-ones.

Scheme 7. Summary of reaction scope reported by Olah and coworkers. Ph: phenyl, TfOH: triflic acid (CF₃SO₃H), r.t.: room temperature.

Fig. 1. Summary of a-UPR signalling pathway. For a review of a-UPR see: Shapiro, D. J.; et al. 2016. Red circles are calcium (Ca²⁺) ions. E2: estrogen/estradiol.

Scheme 8. Chemical structure of BHPI.

Scheme 9. Generalized chemical structure of a chiral 3-(4-hydroxyphenyl)indoline-2-one.

Scheme 10. Synthesis of racemic 3-(4-hydroxyphenyl)indoline-2-ones as reported by Christensen et al. R = H; 7-CF₃; 5,7-di-CH₃; 5-F,7-CH₃; 6,7-di-CH₃; 6-F,7-CH₃; 6-Cl,7-CH₃; 6-CH₃,7-Cl; 6-OCH₃,7-CH₃. n = 1 (cyclopentyl), 2 (cyclohexyl), 3 (cycloheptyl), 4 (cyclooctyl). X = Cl or Br.

Fig. 2. ErSO is a potent killer of ERα-positive cancer in both cell culture and in vivo models. A, Chemical Structure of ErSO. B, Crystal violet staining of T47D cells (ERα-positive breast cancer) 24 hours post-treatment with indicated compounds. (±)-1 is the racemic mixture of ErSO (active enantiomer) and (S)-1 (inactive enantiomer). OHT: 4-hydroxytamoxifen, Fulv.: fulvestrant. C, ErSO IC₅₀ values in indicated ERα+/− (ESR1 status) cancer cell lines after 24 hours compound incubation. D, ErSO treatment of ST941/HI patient derived xenograft (PDX). po: per os (oral administration). E and F, ErSO's antitumor effect is ERα-dependent. More comprehensive details of these models (D–F) are reported elsewhere. Panels B–F were reproduced from Boudreau, et al. Reprinted with permission from American Association for the Advancement of Science (AAAS), copyright 2021.

Scheme 11. Summary of chemical derivatization that arrived at ErSO-DFP. Further details of exact derivatives synthesized and displayed clog D_7.4 values are reported by Boudreau et al.

Fig. 3. ErSO-DFP and ErSO-TFPy have enhanced selectivity for ERα-positive cancer cells in cell culture. Chemical structures, lipophilicity, and biological activity values (IC₅₀ and LipE) plotted as reported by Boudreau et al. ERα+: ERα-positive; ERα−: ERα-negative; LipE (lipophilic efficiency) was calculated clog D_7.4 − pIC₅₀.

Matthew W. Boudreau

Paul J. Hergenrother