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Topoisomerase inhibitors as anticancer agents: a patent update
Khadka, Daulat B,Cho, Won-Jea Informa UK, Ltd. 2013 Expert opinion on therapeutic patents Vol.23 No.8
<P><B><I>Introduction:</I></B> Topoisomerases (topos) are nuclear enzymes that resolve topological problems associated with DNA during various genetic processes. The essential role of topos in vital processes of the cell, their elevated level in solid tumors and cell death due to their inhibition make topos inhibitors as a potent class of antineoplastic agents.</P><P><B><I>Areas covered:</I></B> This review specifically summarizes patents embracing topo I, topo I and II inhibitors. The review covers topos inhibitors which are structurally close to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. It largely focuses on chemical entities developed by systematic structure-activity relationship (SAR) studies of natural benzo[<I>c</I>]phenanthridine (nitidine) and synthetic protoberberine (coralyne) established as antineoplastic agents targeting topo(s). In addition, indenoisoquinolines and evodiamines initially discovered through COMPARE analysis and receptor-based virtual screening (VS) respectively have been discussed.</P><P><B><I>Expert opinion:</I></B> Along with conventional techniques, computer-aided VS, molecular modeling and docking studies have been applied for drug design, discovery and development. Computer-aided tools provide a rational way to explain pharmacological activities of topos inhibitors under study. Comparative study of crystal structures of topo I/II-DNA-drug ternary complex and use of appropriate pharmacological screening methods will lead to potential anticancer drugs in the coming days.</P>
( Suhui Yang ),( Jyothi K. R. ),( Sangbin Lim ),( Tae Gyu Choi ),( Jin-Hwan Kim ),( Salima Akter ),( Miran Jang ),( Hyun-Jong Ahn ),( Hee-Young Kim ),( Marc P. Windisch ),( Daulat B. Khadka ),( Chao Z 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have Significant potential to extend the arsenal of HCV therapeutics.