ON 01910.Na is a novel non-ATP competitive anticancer agent that inhibits mitotic progression, promotes G2/M arrest and induces apoptosis in a number of cancer cells while leaving nonmalignant cells virtually unaffected. ON 01910.Na has exhibited both antitumor activity and antiangiogenic activity with a low toxicity profile in various preclinical tumor xenograft models. Unlike other hypomethylating agents, ON 01910.Na exerts potent antitumor activity against Mantle Cell Lymphoma (MCL) cells by inhibition of PI-3K/Akt/mTOR pathway and down regulation of Cyclin D1 translation. The fact that MDS patient's bone marrow over expresses cyclin D1 (particularly trisomy 8) and targeted deletion of this gene was selectively toxic to trisomy 8 cells. A pivotal phase III trial of ON 01910.Na in MDS patients is now underway. Additional blood cancer and solid tumor indications are being developed, both as a single agent and in combination therapy.The structure activity studies of ON 01910.Na confirmed that the nature, number, and position of substituents on both aromatic rings of the molecule are critical for it's activity. As geometry of a molecule is known to play a critical role in SAR, we have undertaken the synthesis of (Z)- isomer (ON 02180.Na) of ON 01910.Na, which is an active (E)-isomer. In this presentation, we describe the total synthesis, configurational assignment and compare the biological profile of ON 02180.Na with that of ON 01910.Na. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/239nm/uploads/14997_nnano.jpg' alt='' />

Synthesis and biological evaluation of Z-isomer of Rigosertib™ (ON 01910.Na) −  a clinical stage (Phase III) multi kinase anticancer agent

243rd National Meeting (2012)

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