Antitumor agents 294. Novel E-ring-modified camptothecin–4β-anilino-4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents

Abstract

Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.

Application of Amino Acids in the Structural Modification of Natural Products: A Review

“…CPT mainly forms a ternary complex by interacting with DNA and topoisomerase I, blocking DNA replication, leading to cell death, and thus showing significant antitumor activity (Fan et al, 1998 ; Cincinelli et al, 2013 ). The shortcomings of CPT, such as poor solubility and large side effects, have seriously affected its clinical application (Ye et al, 2012 ). Many researchers have synthesized a large number of CPT derivatives, hoping to find targets with fewer side effects.…”

Natural Products, Synthetic and Non-Nucleoside Compounds as Inhibitors of Enzymes Related to DNA: Update 2013

“…Also, there are two new synthetic conjugates (63-64) (Fig. 5) with activity against topo I and II [47]. Benzimidazoles.…”

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

“…Exploring the properties of the inversion of the configuration at position C-7 of podophyllotoxin structure, a huge structure–activity relationship has been carried out, taking hybridization as a tool and combining the cyclolignan skeleton with other compounds with different pharmacological activities, and obtaining interesting results on the bioactivity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”