Synthesis And Characterization Of 1 1-diaryl Vinyl Sulfones As Potential Anticancer Agents

Cancer has become a major health concern globally. Interestingly, anticancer agents are being synthesized from small molecules derived from either plants or aquatic organisms. For example, Combretastatin A-4 (CA-4) isolated from the bark of the South African tree Combretum caffrum. CA-4 is one of such important anticancer agents which have gained the attention of a vast majority of investigators. However, it has problems of bioavailability and isomerisation of the biologically active Z-configured double bond into the inactive E-configuration. There is therefore the need to synthesize a new library of CA-4 analogues. The objectives were to: (i) synthesize 1,1-diarylethene derivatives having a sulfonyl (SO2R) group at the 2 - carbon position; (ii) characterize all synthesized compounds; and (iii)determine the cytotoxicity of the synthesized compounds using various human cancer cell lines.rnThe desired target molecules were obtained from 3,4,5-trimethoxy benzaldehyde prepared by Corey-Fuchs olefination to yield 5-(2,2-dibromovinyl)-1,2,3-trimethoxybenzene. This was reacted with 1, 8- diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile to give 5-ethynyl-1,2,3- trimethoxybenzene. Further treatment of the product with diacetoiodobenzene (DIB), sodium-p-toluenesulfonate and potassium iodide in acetonitrile yielded (E)-5-(1-iodo-2-tosylvinyl)-1,2,3-trimethoxybenzene). This was made to undergo Suzuki-Miyaura coupling with different substituted arylboronic acids in tetrahydrofuran (THF) to give different combretastatin sulfonyl compounds. The compounds were characterized using proton (1H) and carbon-13 (13C) Nuclear Magnetic Resonance (NMR) Spectroscopy, Fourier Transform Infra Red Spectroscopy (FTIR), Electro Spray Ionization Mass Spectrometry (ESI-MS) and High Resolution Mass Spectrometry (HRMS). The in vitro cytotoxicity assay was carried out against four human cancer cell lines MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with normal cell line HEK-293 (human embryonic kidney cell)by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay.rnThe following results were obtained:rn(i) twenty novel 1,1, diaryl sulfones analogues of combretastatin CA-4 were successfully synthesized;rn(ii) the sulfonyl group was fully characterized with the following signals: 1H and 13C NMR at ẟ2.36 ppm and ẟ21.50 ppm respectively, which confirmed the presence of the methyl group attached to the aryl sulfonyl group. Proton resonating around ẟ7.14 ppm - 7.46 ppm also established the presence of the aromatic protons attached to the aryl sulfonyl group. Infra red (IR) band around 1361cm-1 and 1150cm-1 signified the presence of SO2 in the compound. HRMS molecular formula C26H28O7NaS also supported the presence of SO2 in the compound;rn(iii) the compounds showed significant cytotoxicity with IC50 values ranging from 4.10 - 23.94 µM when compared to the standard, doxorubicin (IC50 values ranging from 0.23 – 2.06 µM);rn(iv) conjugate (Z)-1,2,3-trimethoxy-5-(1-(4-methoxyphenyl)-2-tosylvinyl)benzene displayed potent antiproliferative activity against A549 and IMR-32 cancer cell lines; and rn(v) all the synthesized compounds were non toxic to normal cell line HEK-293.with the exception of 4-methylphenyl(3,4,5-trimethoxyphenyl)ethynyl sulfone.rnIn conclusion, the synthesized CA-4 analogues were found to be effective against A549 cancer cell lines especially compound (Z)-1,2,3-trimethoxy-5-(1-(4-methoxyphenyl)-2-tosylvinyl)benzene. It is therefore recommended for consideration as a possible drug for lung cancer treatment.

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