Background: Cancer continues to be the major health burden worldwide. There is an
urgent need for the development of novel antineoplastic compounds to treat this devastating condition.
Various alkylating anticancer drugs have been employed in the clinic for treating cancers.
Unsaturated conjugated ketones are a group of alkylators which are of significant interest as potent
Objective: The goal of this study is to discover unsaturated conjugated ketones which are novel
potent cytotoxins displaying growth-inhibitory properties towards neoplasms and also to serve as
cytotoxic warheads in drug development.
Methods: A variety of 3,5-bis (benzylidene)-4-piperidones 2a-n were synthesized and evaluated
against a number of neoplastic cell lines. The short-term neurotoxicity of 2a-k, n was evaluated in
mice by i.p. administration using doses level of 30, 100 and 300 mg/kg. Statistical correlations for
determining structure-activity relationships were performed using an SPSS software.
Results: A number of compounds display cytotoxic potencies in the region of 10 -7 to 10 -8 M and
some of the structural features contributing to the cytotoxicity were identified. Compounds 2a-d,
2h demonstrated substantially higher cytotoxic potencies compared to melphalan and 5-
fluorouracil against a panel of leukemic and colon cancer cell lines. These lead cytotoxins comply
with drug-likeness properties. In general, the antineoplastics 2 are well tolerated in mice using a
short-term neurotoxicity screening.
Conclusion: In general, this group of compounds comprises excellent cytotoxic agents, which
warrant their further development as cytotoxic warheads.