Title:Natural Products as Anti-Cancerous Therapeutic Molecules Targeted towards Topoisomerases
Volume: 21
Issue: 11
Author(s): Swati Singh, Veda P. Pandey, Kusum Yadav, Anurag Yadav and U. N. Dwivedi*
Affiliation:
- Department of Biochemistry & Institute for Development of Advanced Computing, ONGC Centre for Advanced Studies, University of Lucknow, Lucknow, U.P.,India
Keywords:
Topoisomerase, topos inhibitors, cancer, alkaloids, flavonoids, terpenoids, molecular docking, molecular dynamics
simulation, pharmacophore, QSAR, virtual screening.
Abstract: Topoisomerases are reported to resolve the topological problems of DNA during several
cellular processes, such as DNA replication, transcription, recombination, and chromatin remodeling.
Two types of topoisomerases (Topo I and II) accomplish their designated tasks by introducing
single- or double-strand breaks within the duplex DNA molecules, and thus maintain the proper
structural conditions of DNA to release the topological torsions, which is generated by unwinding
of DNA to access coded information, in the course of replication, transcription, and other processes.
Both the topoisomerases have been looked at as crucial targets against various types of cancers
such as lung, melanoma, breast, and prostate cancers. Conceptually, targeting topoisomerases will
disrupt both DNA replication and transcription, thereby leading to inhibition of cell division and
consequently stopping the growth of actively dividing cancerous cells. Since the discovery of camptothecin
(an alkaloid) as an inhibitor of Topo I in 1958, a number of derivatives of camptothecin
were developed as potent inhibitors of Topo I. Two such derivatives of camptothecin, namely,
topotecan and irinotecan, have been commonly used as US Food and Drug Administration (FDA)
approved drugs against Topo I. Similarly, the first Topo II inhibitor, namely, etoposide, an analogue
of podophyllotoxin, was developed in 1966 and got FDA approval as an anti-cancer drug in
1983. Subsequently, several other inhibitors of Topo II, such as doxorubicin, mitoxantrone, and
teniposide, were developed. These drugs have been reported to cause accumulation of cytotoxic
non-reversible DNA double-strand breaks (cleavable complex). Thus, the present review describes
the anticancer potential of plant-derived secondary metabolites belonging to alkaloids, flavonoids
and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made
in the field of computer-aided drug design, the present review also discusses the use of computational
approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to
assess and predict the safety, efficacy, potency and identification of these potent anti-cancerous
therapeutic molecules.
