Elucidation of Structure–Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action

Abstract

Indolo[3,2- d ][1]benzazepines (paullones), indolo[3,2- d ][2]benzazepines, and indolo[2,3- d ][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2- d ][2]benzazepine-derived ligands HL 1 – HL 4 and copper(II) complexes 1 – 4 . All compounds were characterized by spectroscopic methods ( 1 H and 13 C NMR, UV–vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3 , in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1 H NMR and UV–vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure–activity relationships were deduced from the comparison of anticancer activities of HL 1 – HL 4 and 1 – 4 with those of structurally similar paullone-derived ( HL 5 – HL 7 and 5 – 7 ) and latonduine-derived scaffolds ( HL 8 – HL 11 and 8 – 11 ). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs

“…This reaction was realized only when absolute hydrazine was used. Upon use of hydrazine hydrate, sulfur atom was replaced by oxygen and starting lactams were recovered . Finally, Schiff base condensation reactions of h 2 and h 3 with 2-formylpyridine and 2-acetylpyridine afforded four potentially tridentate ligands HL 2 –HL 5 in very good yields (72–86%).…”

“…Treatment of g 2 and g 3 with hydrazine hydrate in chloroform afforded hydrazine derivatives h 2 and h 3 in almost quantitative yields. It is worth noting that under analogous conditions, the reactions of seven-membered-ring-containing indolobenzazepines produced only 20–30% of the required thionated products . Even more disappointingly, the further reaction of the thionated indolobenzazepine with hydrazine hydrate failed.…”

“…The effect of this structural change on antiproliferative activity and underlying mechanism of cytotoxicity has been elucidated recently. 15−17 Moreover, it was shown that the position of the sp 3 -hybridized carbon atom in a seven-membered N-containing ring has a marked effect on scaffold folding, 18 which distinctly impacts the molecular shape of the drug molecule. The most widely used chemotherapeutics continue to be cisplatin-and platinum-based complexes, such as carboplatin and oxaliplatin.…”

“…Escape from flatland has been realized by us via substitution of the six-membered N-containing ring in indoloquinolines by the seven-membered azepine ring in indolobenzazepines. The effect of this structural change on antiproliferative activity and underlying mechanism of cytotoxicity has been elucidated recently. − Moreover, it was shown that the position of the sp 3 -hybridized carbon atom in a seven-membered N-containing ring has a marked effect on scaffold folding, which distinctly impacts the molecular shape of the drug molecule.…”

“…C NMR (176 MHz, DMSO): δ 168.59 (Cq, C 8 ), 165.14 (CH, C15 ), 155.92 (CH, C18 ), 154.97 (Cq, C16 ), 145.12 (Cq,10 ), 139.87 (CH, C20 ), 139 16. (Cq, C 4a ), 137.91 (Cq, C 13b ), 136.79 (Cq, C 12a ), 131.24 (Cq, C 13a ), 130.56 (CH, C 3 ), 130.25 (CH, C 1 ), 129.55 (CH, C 21 ), 129.24 (CH, C 4 ), 128.43 (CH, C 19 ), 127.43 (Cq, C 8b ), 126.46 (CH, C 2 ), 117.13 (CH, C 11 ), 115.58 (CH, C 9 ), 112.10 (CH, C 12 ), 110.99 (Cq, C 8a ), 104.88 (Cq, C 27 ), 104.06 (Cq, C 24 ), 87.68 (CH, C 23 ), 86.37 (CH, C 23 ), 84.74 (CH, C 22 ), 84.18 (CH, C 22 ), 43.97 (CH 2 , C 6 ), 34.08 (CH 2 , C 5 ), 30.49 (CH, C 25 ), 22.13 (CH 3 , C 26 ), 21.30 (CH 3 , C 26 ), 18.53 (CH 3 , C 28 ).…”