To understand the molecular basis for the antitumoureffects of aspirin and identify more effective alternatives, wepreviously synthesised a series of derivatives of the aspirinmolecule. These studies revealed that diaspirin (DiA) and fumaryldiaspirin (F-DiA) inhibit proliferation of CRC cell lines atsignificantly lower concentrations than aspirin (). To extend these studies and identifyfurther lead molecules, we synthesised an additional series ofaspirin derivatives ().Cytotoxicity (MTT) assays demonstrated that at 0.5 mM(pharmacologically relevant dose for aspirin), DiA (PN508) andF-DiA (PN517) and to an even greater extent, isopropylm-bromobenzoylsalicylate (PN529) reduced the viability of SW480 CRCcells (). To investigate thespecificity of compound toxicity in more detail, we tested thecapacity of DiA, F-DiA and PN529 to affect proliferation of anumber of established cell lines ( and ), controlling for any variabilitythat could arise from cell culture conditions through culturing allcells with DMEM as the basal medium. While we noted that culturingSW480 cells in their non-native medium (DMEM rather than L-15medium) reduced the sensitivity of the cells to the compoundstested, DiA and F-DiA in this assay system arguably showed amodicum of specificity towards the other CRC cell lines tested(HCT116 and LoVo), and given our finding that PN529 can inducenecrosis (), we focused ourattention on the anti-proliferative activity of DiA and F-DiA inmore detail and .
Abundant evidence indicates that non-steroidalanti-inflammatory drugs (NSAIDs), including aspirin, areanti-tumorigenic and can prevent CRC (– andrefs. therein). For instance, in chemical and genetic animalmodels, NSAIDs reduce the initiation and progression of CRC (oraberrant crypt foci) (–). Recent meta-analysis of a largenumber of patient studies indicates that treatment with dailyaspirin for 5 years or longer reduces the risk of developingmultiple cancer types, including CRC (). Furthermore, in a randomisedcontrolled trial of carriers with Lynch syndrome (CAPP2 study),ingestion of a 600 mg daily dose of aspirin for ~2 years wascapable of substantially reducing CRC incidence (). Aspirin has also been proposed tosuppress metastasis (), andregular aspirin use after diagnosis of non-metastatic CRC isassociated with a reduced CRC-specific mortality, an associationthat was strongest when the primary tumour overexpressedcyclooxygenase-2 (COX-2) ().Despite these promising data, the use of aspirin forchemopreventative purposes universally is restricted by thepotential gastropathy associated with long-term use (). Thus, there is an overwhelmingrationale to identify aspirin-related compounds that retain thespecific toxicity to CRC but are safer and more effective thanaspirin itself.
Hantzsch Dihydropyridine (Pyridine) Synthesis
The first part of the study involved looking comprehensively at the metabolic profiles from the blood of 40 individuals who had taken aspirin for 60 days. The design was rigorous, with participants each having a phase with and without aspirin. More than 360 metabolites, or small molecule chemicals such as sugars, amino acids, and vitamins, were analyzed, says Ulrich. This study covered most of the known biochemical pathways in the body.
Preparation of Acetylsalicylic Acid?
Walder JA, Zaugg RH, Walder RY, Steele JMand Klotz IM: Diaspirins that cross-link beta chains of hemoglobin:bis(3,5-dibromosalicyl) succinate and bis(3,5-dibromosalicyl)fumarate. Biochemistry. 18:4265–4270. 1979. : :