Regioselective synthesis and stereochemical structure of anti-tumor active dispiro[3 H-indole-3,2′-pyrrolidine-3′,3″-piperidine]-2(1 H),4″-diones

• Published in: European journal of medicinal chemistry 2009-03, Vol.44 (3), p.1257-1264
• Main Author: Girgis, Adel S.
• Format: Article
• Language: English
• Subjects: 3,5-Bis(arylmethylene)-1-methyl-4-piperidinones; Animals; Anti-inflammatory; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-tumor; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Azomethine ylides; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line, Tumor; Crystallography, X-Ray; Dispiro[3 H-indole-3,2′-pyrrolidine-3′,3″-piperidine]-2(1 H),4″-diones; Female; General aspects; Humans; Magnetic Resonance Spectroscopy; Male; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Pyrrolidines - chemistry; Rats; Rats, Wistar
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.09.007

Reaction of 3,5-bis(arylmethylene)-1-methyl-4-piperidinones 1a– 1g with azomethine ylides (generated in situ via decarboxylative condensation of isatins 2a, 2b with sarcosine 3) in refluxing ethanol afforded 4′-aryl-5″-(arylmethylene)-dispiro[3 H-indole-3,2′-pyrrolidine-3′,3″-piperidine]-2(1 H),4″-diones 4a– 4m as the sole product in a high regioselective manner. Anti-tumor activity screening of 4e, 4f, 4k, 4m, as representative examples of the synthesized compounds, at a dose of 10 μM utilizing 59 different human tumor cell lines representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney exhibited that, the tested compounds reflect mild activity against most of the used human tumor cells. Meanwhile, all the tested compounds reveal considerable anti-tumor properties against colon (HCT-116), breast (T-47D), leukemia [HL-60 (TB), MOLT-4, RPMI-8226] and prostate (PC-3) cancers. Anti-inflammatory properties of the prepared compounds (at a dose of 50 mg/kg body weight) using in vivo acute carrageenan-induced paw oedema in rats exhibited that all the tested compounds possess considerable anti-inflammatory activity especially 4a, 4k, 4l which reveal remarkable activities with potency 125.5, 139.3 and 126.4, respectively, relative to indomethacin which was used as a reference standard (at a dose of 10 mg/kg body weight). Regioselective synthesis and stereochemical structure of anti-tumor active dispiro[3 H-indole-3,2′-pyrrolidine-3′,3″-piperidine]-2(1 H),4″-diones. [Display omitted]