Synthesis and Anticancer Activity of Phosphinoylated and Phosphonoylated N‐Heterocycles Obtained by the Microwave‐Assisted Palladium Acetate‐Catalyzed Hirao Reaction

• Published in: Chemistry : a European journal 2023-12, Vol.29 (68), p.e202302465-n/a
• Main Authors: Huszár, Bianka, Szolga, Renáta, Bősze, Szilvia, Oláhné Szabó, Rita, Simon, András, Karaghiosoff, Konstantin, Czugler, Mátyás, Drahos, László, Keglevich, György
• Format: Article
• Language: English
• Subjects: Acetic acid; Acute monocytic leukemia; Anticancer properties; Antitumor activity; Biological activity; Carbazole; Carbazoles; Carcinoma, Non-Small-Cell Lung; Catalysis; Catalysts; Chemistry; cross-coupling; Cytotoxicity; Ethanol; Humans; Inorganic salts; Irradiation; Leukemia; Ligands; Literature reviews; Lung carcinoma; Lung Neoplasms; microwave chemistry; Microwave radiation; Microwaves; Monocytes; Monocytic leukemia; Oxides; Palladium; Palladium - chemistry; Phenyl phosphonate; Phosphine; Phosphine oxide; Phosphonates; phosphorylation; Reagents; Single crystals; synthetic methods; Triethylamine
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202302465

A literature survey showed that different derivatives with the 9‐phenyl‐9H‐carbazole or the dihydroindoline scaffold may be of biological activity including cytotoxic effect. Driven by this experience, P‐functionalized derivatives of these N‐heterocycles were synthesized. Three N‐heterocycles, 9‐(4‐bromophenyl)‐9H‐carbazole, 3‐bromo‐9‐phenyl‐9H‐carbazole and 1‐(5‐bromoindolin‐1‐yl)ethan‐1‐one, were coupled with dialkyl phosphites and diarylphosphine oxides using Pd(OAc)2 (10 %) as the catalyst precursor and triethylamine as the base in ethanol under microwave irradiation. The excess of the Y2P(O)H reagent (Y=alkoxy, aryl) (30 %) served as the P‐ligand in its trivalent tautomeric form (Y2POH), hence there was no need for the usual P‐ligands meaning cost and environmental burden. Hence, the presented method is a “green” approach that proved to be more efficient than the preparation by the traditional method. The products, dialkyl phosphonates and tertiary phosphine oxides obtained in 58–84 % yields were characterized, one of them also by single crystal X‐ray analysis, and were subjected to in vitro biological activity evaluation. A (carbazol)yl‐phenylphosphonate, an N‐phenyl‐(carbazol)yl‐phosphonate, a (carbazol)yl‐phenylphosphine oxide and an N‐phenyl‐(carbazol)ylphosphine oxide revealed a significant cytotoxic activity on A549 human non‐small‐cell lung carcinoma and MonoMac‐6 acute monocytic leukemia cancer cells. The cytotoxic effect was significant as compared to that of the reference compounds. The bromo derivatives of 9‐phenyl‐9H‐carbazoles and an indoline were converted to the corresponding phosphonoyl and phosphinoyl derivatives by the microwave‐assisted “P‐ligand‐free” Hirao P−C coupling. A part of the fifteen phosphorylated N‐heterocycles showed significant cytotoxic effect on A549 human non‐small‐cell lung carcinoma and MonoMac‐6 acute monocytic leukemia cell cultures.