title: New strategies in the discovery of novel non-camptothecin topoisomerase I inhibitors.
abstract: Topoisomerase I (Top1) represents an important target of active interest in developing novel anticancer agents. Camptothecin derivatives are the only class of clinically approved Top1 inhibitors and show potent efficacy in anticancer therapy. However, there are also several major limitations for them, such as poor chemical stability, drug resistance, long infusions and side effects. To overcome the drawbacks of the camptothecins, the discovery of non-camptothecin Top1 inhibitors has recently emerged as a promising field to find better antitumor agents. Non-camptothecin Top1 inhibitors are expected to possess better chemical stability, different therapeutic activities and antitumor spectrum, improved pharmacokinetics and lower toxicity. This review focuses on various strategies that were used in the discovery of non-camptothecin Top1 inhibitors. In particular, the chemical scaffolds, structure-activity relationships and binding modes of the newly identified non-camptothecin Top1 inhibitors are discussed in detail.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China. shengcq@hotmail.com
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D007546:Isoquinolines; D010617:Phenanthridines; D011725:Pyridines; D011799:Quinazolines; D059004:Topoisomerase I Inhibitors; C049639:evodiamine; D004264:DNA Topoisomerases, Type I