Study On The Synthetic Methods Of Antitumor Drug ON01910.Na

Cancer is one of the major diseases serious threaten to our health,inventors regard the development of anti-cancer drug as a primary task.Cancer is now believed to result from unlimited growth of a given cell, whichis often due to a block in the ability of cells to undergo differentiation and/orapoptosis. The aberrant growth of cancer cells can often been attributed todysregulation of cell cycle control and cell division. Most of ourunderstanding of how cells grow and divide comes from the study of cellsgrown in vitro. The cell cycle is typically divided into four phases: G1, S, G2,and M. Current oncology drug development is focused largely on theidentification and development of agents that target specific pathwaysimportant in cancer development, growth and progression. Cellularproliferation is a tightly controlled set of events that is regulated by numerousnuclear protein kinases. In cancer, these nuclear kinases are often dysregulatedand cause uncontrolled cell proliferation and growth. The kinases involvedinclude checkpoint kinases (CHK), cyclin-dependent kinases (CDK), whichregulate the cell cycle and aurora kinases (AURK) and polo-like kinases(PLK), which regulate mitosis. Much work has gone into developing noveltherapeutics that target each of these protein kinases in cancer.The polo-like kinases (PLK) are a family of serine/threonine kinasescomprised of5members (PLK1–5). The Plks are similar in structure and arecharacterized by conserved regulatory domains known as polo boxes. PLK1isthe best studied of this family of kinases and is known to play a vital role inmultiple mitotic activities including mitotic entry, centrosome maturation,spindle pole formation and stabilization, and cytokinesis. Like the Aurorakinases, PLK1localizes to various regions in the nucleus to carry out theseroles during mitosis, first at the centrosome during prophase, then to the kinetochores and central spindle poles through metaphase, and finally to themidbody during telophase and cytokinesis. Inhibition of PLK1is associatedwith monopolar spindle formation during prolonged mitotic arrest, andultimately death of arrested cells. Overexpression of PLK1has beenassociated with tumor formation in vitro and in vivo and has been documentedin many human tumors including breast, non-small cell lung, and head andneck cancers in addition to various gastrointestinal and gynecologicmalignancies. In addition to increases in the normal proliferative functions ofPLK1as a mechanism of tumorigenesis, overexpression of this kinase isthought to override cell cycle checkpoints, ultimately resulting in genomicinstability.Sodium (E)-{N-[2-methyloxy-5-(2,4,6-trimethoxystyryl sulfonyl)met-hylnephenyl]amino}acetate (ON01910.Na, Onconova Therapeutics Inc.) is anovel anticancer agent currently in clinical trials in patients. ON01910.Na is acell-cycle inhibitor and selectively causes mitotic arrest by creating spindleabnormalities and abnormal centrosome localization and fragmentationleading to apoptosis in cancer cells. It has been shown to inhibit PLK1pathway activity at a nanomolar range in a substrate-dependent andATP-independent manner, although targeting other kinases has alsobeen reported. This compound inhibits a broad spectrum of human tumour cellgrowth with GI50values in the nanomolar range and is active in a number ofhuman xenograftsin mice. Currently, the drug is in several clinical trials inadult patients with a variety of solid tumours as well as hematologicalmalignancies. Anti-tumour activity was observed in all phase I trials. Recentphase I studies in human B-cell chronic lymphocytic leukaemia(CLL)demonstrated that ON01910.Na selectively induced apoptosis in all CLLsamples tested and reduced PLK1activity in the leukemic cells. ON01910.Nais currently also being tested in phase I combination therapy in patients withsolid tumors. ON01910.Na has a bright development prospect. This drug iscurrently in phase III clinical trials.Objective: To synthesize ON01910.Na and to optimize the synthetic conditions.Methods: P-cresol used as the starting material, after nitration,methylation, bromation,4-(bromomethyl)-1-m ethoxy-2-nitro-benzene(8) wasobtained. With4-(bromomethyl)-1-methoxy-2-nitrobenzene (8) as rawmaterial, by reaction with2-mercaptoacetic acid,2-((4-methoxy-3-nitrobenzyl)thio)acetic acid(9) was obtained. Compound9was treated with hydrogen peroxide to produce2-((4-methoxy-3-nitrobenzyl)sulfonyl)acetic acid(10). The intermediate2,4,6-trimethoxybenzaldehyde (4) was prepared through methylation ofbenzene-1,3,5-triol (2) with dimethyl sulfate, followed by Vilsmeier acylationreaction with phosphorus oxychloride and N,N-Dimethylformamide. The keyintermediate (E)-1,3,5-trimethoxy-2-(2-((4-methoxy-3-nitrobenzyl)sulfonyl)v-inyl)benzene(11) was generated from the reaction of condensation anddecarboxylation between compound4and compound10. The reaction of(E)-2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)aniline (12),prepared from intermediate11and sodium dithionite in a mixture of acetoneand water, with methyl2-bromoacetate gave the desired product (E)-methyl2-((2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)phenyl)amino)acetate(13). Under the heating and alkaline condition of NaOH, the targetcompound sodium (E)-2-((2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)phenyl)amino)acetate(1) be synthesized by hydrolyzation andsalification. The structure of intermediates and target products were confirmedby melting point, mass spectrum, nuclear magnetic.Results: ON01910.Na has been synthesized according to the processwe designed, and was confirmed by1H-NMR and MS-ESI(m/z). Some of thesynthetic conditions were optimized.ON01910.Na: white solid, mp.173-177℃.Conclusion: ON01910.Na was synthesized. Some of the reactionconditions were optimized. The starting materials was inexpensive and easyto obtain. The reaction conditions were mild, and the work-up processing wassimple.