Synthesis of 9-(heteroarylmethylidene)amino derivatives of homocamptothecin with biological activities.
ABSTRACT Six 9-(heteroarylmethylidene)amino derivatives, 2a-2f, of homocamptothecin were synthesized for the first time by total synthesis in 22 steps and biologically evaluated as inhibitors of topoisomerase I. Moreover, the antitumor activities of 2a-2f against three human tumor cell lines, i.e., A-549, MDA-MB-435, and HCT-116, were determined and the results showed that compound 2c was the most active homocamptothecin derivative against the A-549 (IC(50) =0.046 μM) and HTC-116 tumor cells (IC(50) =3.67 μM), with a ca. 50 times higher activity than the reference drug topotecan (TPT) against the lung cancer cell line A-549.
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ABSTRACT: Camptothecin (CPT), a natural topoisomerase (Topo) I inhibitor, exhibits powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. However, the poor solubility and the inherent instability of the lactone E-ring in physiological pH resulted in low therapeutic efficacy and severe toxicity. In the past several decades' substantial progress toward understanding its pharmacology, lots of analogs have been prepared to overcome its drawbacks. The review provides a detailed discussion of the evolution in medicinal chemistry of CPT analogs with modification of the E-ring lactone.European Journal of Medicinal Chemistry 03/2013; 63C:746-757. · 3.43 Impact Factor