GL-331

Podophyllotoxin (PPT) is a naturally occurring antimitotic agent and an interesting lead in the development of anticancer agents. Its optimization led to the development of etoposide and teniposide used in combination chemotherapy with other anticancer drugs; unlike PPT these drugs act by inhibiting topoisomerases. Clinical success and toxicity issues at later stages of etoposide usage inclined researchers to develop structurally modified PPT derivatives. Some of the compounds obtained are under clinical investigations and are anticipated to reach the market.

The present review summarizes the attempts made by researchers across the globe to find out newer anticancer agents based on the PPT structure. It brings out the outline of the inventions filed in the form of patents during the years 2012 - 2014.

After the successful development of etoposide and teniposide there has been considerable interest in the PPT skeleton to develop newer chemotherapeutic agents. In this regard, several PPT derivatives such as TOP53, GL331, NK611, F11782, and so on, have been developed and are undergoing clinical trials. However, its low natural abundance is a major problem in carrying out research on PPT skeleton. This issue is expected to be addressed with the development of newer synthetic strategies to access structurally modified PPTs.

GL331, a topoisomerase II inhibitor, has been found to trigger DNA damage response (DDR) to induce cell cycle arrest. However, the underlying mechanism has not yet been fully understood. This study investigated the molecular mechanism involved in the GL331-induced cell cycle arrest via DDR in human hepatocellular carcinoma HepG2 cells. As a result, GL331 could induce S arrest and up-regulate the phosphorylation of the histone H2AX variant (γ-H2AX). Ataxia telangiectasia mutated protein kinase (ATM) was activated by GL331 through its autophosphorylation at Ser1981, which led to the activation of DNA damage signaling pathways including p53/p21 and Chk2/Cdc25A cascades. The DNA damage cascades triggered by GL331 finally induced the inactivation of cyclin A/Cdk2 complexes to some extent. These phenomena could be reversed by ATM siRNA, followed by a partial disruption of S arrest. The present results suggested that the S arrest induced by GL331 via DDR was in an ATM-dependent manner to some degree.