Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds

• Published in: European journal of medicinal chemistry 2002-12, Vol.37 (12), p.961-972
• Main Authors: Dimmock, Jonathan R, Jha, Amitabh, Zello, Gordon A, Quail, J.Wilson, Oloo, Eliud O, Nienaber, Kurt H, Kowalczyk, Earl S, Allen, Theresa M, Santos, Cheryl L, De Clercq, Erik, Balzarini, Jan, Manavathu, Elias K, Stables, James P
• Format: Article
• Language: English
• Subjects: 4-Piperidones; Animals; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Aspergillus fumigatus - drug effects; Candida albicans - drug effects; Cell Death - drug effects; Cell Line, Tumor; Crystallography, X-Ray; Cytotoxicity; Cytotoxins - chemical synthesis; Cytotoxins - chemistry; Cytotoxins - pharmacology; Cytotoxins - toxicity; Drug Design; Humans; Inhibitory Concentration 50; Mice; Murine toxicity; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Piperidones - toxicity; Species Specificity; Structure–activity relationships; Substrate Specificity; T-Lymphocytes - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(02)01414-9

A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone ( 2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones ( 3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones ( 4). A cytotoxic evaluation of the compounds in series 1– 4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC 50 values of 54% of the enones were less than 10 μM when all four screens were considered and less than 1 μM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett σ, Hansch π and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2– 4 as novel candidate antineoplastic agents should be pursued.