Novel cytotoxins 3-5 containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are disclosed. The compounds in series 3 and 5 have the potential to liberate niacin which may reduce some of the side effects of antineoplastic compounds. 3a-c emerged as the most potent cytotoxic compounds with IC50 values in the low micromolar range against human Molt4/C8 and CEM CD4+ T-lymphocytes as well as murine L1210 leukemia cells. QSAR studies revealed that cytotoxic potencies were negatively correlated with the magnitude of the Hammett sigma values of the aryl substituents. The compounds 3a-e displayed tumour-selective toxicity against human HL-60, HSC-2, HSC-3 and HSC-4 neoplasms as compared to human HGF, HPC and HPLF nonmalignant cells. A representative potent compound 3a caused PARP1 cleavage and G0/G1 cell cycle arrest in HSC-2 cells. These compounds are well tolerated in mice at doses up to and including 300mg/kg of the compounds and no mortalities were noted after 4h. The stability studies undertaken did not reveal that a representative compound 3a underwent hydrolysis to the related phenol 2a. Some guidelines for further analog development of the novel esters 3 were made.
Keywords: Conjugated unsaturated ketones; Cytotoxins; Niacin; QSAR; Structure-activity relationships; Tumour-selective toxicity.
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