Design, synthesis and biological evaluation of 2-quinolyl-1,3-tropolone derivatives as new anti-cancer agents

Abstract

Tropolones are promising organic compounds that can have important biologic effects. We developed a series of new 2-quinolyl-1,3-tropolones derivatives that were prepared by the acid-catalyzed reaction of 4,7-dichloro-2-methylquinolines with 1,2-benzoquinones. 2-Quinolyl-1,3-tropolones have been synthesized and tested for their anti-proliferative activity against several human cancer cell lines. Two compounds (3d and mixture B of 3i-k) showed excellent activity against six cancer cell lines of different tissue of origin. The promising compounds 3d and mixture B of 3i-k also demonstrated induction of apoptotic cell death of ovarian cancer (OVCAR-3, OVCAR-8) and colon cancer (HCT 116) cell lines and affected ERK signaling. In summary, 2-quinolyl-1,3-tropolones are promising compounds for development of effective anticancer agents.

Scheme 1. Synthesis of 2-quinolyl-1,3-tropolone derivatives 3 by an alternative pathway of the reaction.

Scheme 2. Formation of the mixture of three polychloro-substituted 1,3-tropolones 3i–k.

Fig. 1. Molecular structure of 5,7-di(tert-butyl)-2-(4,7-dichloro-8-methyl-2-quinolyl)-4-nitro-1,3-tropolone 3c with representation of the atoms by thermal vibration ellipsoids of 50% probability (а); a tropolone cycle in a crystal in the “bath” conformation (b).

Scheme 3. Intramolecular proton transfer in compounds 3a–k.

Fig. 2. Effect of 3d and mixture B of 3i–k tropolones at IC₂₅ and IC₅₀ concentrations on colony formation ability of ovarian and colon cancer cells. (A) OVCAR-8 under 3d treatment for 7 days; (B) OVCAR-8 under mixture B (3i–k treatment for 7 days); (C) OVCAR-3 under 3d treatment for 7 days; (D) OVCAR-3 under mixture B of treatment of 3i–k for 7 days; (E) HCT 116 under 3d treatment for 7 days; (F) HCT 116 under mixture B of treatment of 3i–k for 7 days.

Fig. 3. Effect of 3d on apoptosis induction in ovarian and colon cancer cell lines. Cells were treated 3d at indicated concentration, or with DMSO. Flow cytometry results after at 0 h, 24 h, 48 h using Annexin V and propidium iodide are shown for OVCAR-8 (A), OVCAR-3 (B) and HCT 116 (C) cell line.

Fig. 4. Effect of mixture B of 3i–k on apoptosis induction in ovarian and colon cancer cell lines. Flow cytometry results after at 0 h, 24 h, 48 h treatment using Annexin V and propidium iodide are shown for OVCAR-8 (A), OVCAR-3 (B) and HCT 116 (C) cell line.

Fig. 5. Effect of the 3d compound on apoptosis, as measured by PARP cleavage, and ERK-signaling pathway in OVCAR-8, OVCAR-3 and HCT 116 cell lines. Cells were treated with 3d compound for 0, 12, 24 and 48 hours, and western blot analysis was done. (A) OVCAR-8 cell line; (B) OVCAR-3 cell line; (C) HCT 116 cell line.

Fig. 6. Effect of the mixture B of 3i–k compound on apoptosis, as measured by PARP cleavage and ERK-signaling pathway in OVCAR-8, OVCAR-3 and HCT 116 cell lines. Cells were treated with mixture B of 3i–k compound for 0, 12, 24 and 48 hours. Western blot analysis: (A) OVCAR-8 cell line; (B) OVCAR-3 cell line; (C) HCT 116 cell line.